Diabetes Research: 2002-2006
     
Pharmacotherapy. 2006 Nov;26(11):1626-40.
Adjunctive therapy with pramlintide in patients with type 1 or type 2 diabetes mellitus.
Nogid A, Pham DQ.
1 Department of Pharmacy Practice, Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, New York; Department of Pharmacy, Bellevue Hospital Center, New York.

Uncontrolled diabetes mellitus is associated with both microvascular and macrovascular complications. Despite an array of treatment options available, achievement of euglycemia in most patients with diabetes is still lacking. Pramlintide acetate, a synthetic analog of the human hormone amylin and belonging to a new class of agents, was approved in March 2005 as adjunctive treatment in patients with type 1 or 2 diabetes mellitus. To evaluate the data available on the efficacy and safety of pramlintide, we conducted a search of MEDLINE (January 1966-May 2006) and International Pharmaceutical Abstracts (January 1970-May 2006). Bibliographies of clinical trials were reviewed for additional references. The literature reviewed demonstrated that pramlintide is effective in reducing levels of glycosylated hemoglobin and potentially preventing weight gain. The most commonly reported adverse effects associated with pramlintide were nausea, anorexia, and hypoglycemia. These adverse effects occurred more often during the initiation of therapy and were usually mild to moderate in nature. Whether this therapy is a cost-effective option for patients with type 1 or type 2 diabetes mellitus is yet to be determined.

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Drugs Aging. 2006;23(10):781-93.
Post-transplant diabetes mellitus : risk reduction strategies in the elderly.
Duclos A, Flechner LM, Faiman C, Flechner SM.
Transplant Center/Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA.

New-onset diabetes mellitus in a previously non-diabetic transplant recipient is a serious adverse event that confers significant morbidity and mortality. The most significant consequences of post-transplant diabetes mellitus (PTDM) in solid organ transplant recipients include decreased patient and graft survival, an increased risk of infectious complications, and morbid cardiovascular events. The development of PTDM in the elderly is of particular concern because this group is already at increased risk of progression of cardiovascular disease. Because the elderly, especially those aged >65 years, are the fastest-growing segment of the renal transplant population, attention needs to be given to PTDM risk reduction and post-transplant management. PTDM develops as a consequence of both impaired insulin production and enhanced peripheral insulin resistance. A number of non-modifiable factors such as age, race, family history, hepatitis C, polycystic kidney disease and emerging genetic causes have been identified as risk factors for PTDM. However, a number of modifiable factors can be targets for intervention in high-risk patients, including bodyweight (through dietary restriction and exercise), hypertension, hyperlipidaemia and the effects of certain immunosuppressive agents. The two agents most responsible for PTDM are tacrolimus and corticosteroids, especially when used in combination. Attempts to modify doses and regimens designed to eliminate or avoid these drugs should be considered. Use of HMG-CoA reductase inhibitors ('statins') and ACE inhibitors is particularly helpful in controlling hypertension and hyperlipidaemia in the elderly because these agents confer protection against future adverse cardiovascular events. Bisphosphonates are also advantageous in controlling the progression of osteoporosis and possible increased risk of bone fractures. Future trials in the elderly should focus on such endpoints as PTDM, post-transplant neoplasia, cardiovascular events and bone fracture events in order to identify the safest regimens that provide the optimal control of rejection while limiting the morbidity from these secondary events.

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J Clin Endocrinol Metab. 2006 Oct 24; [Epub ahead of print]
Chronic Treatment With Pioglitazone Does Not Protect Obese Patients With Diabetes Mellitus Type II from Free Fatty Acid-Induced Insulin Resistance.
Serlie MJ, Allick G, Groener JE, Ackermans MT, Heijligenberg R, Voermans BC, Aerts JM, Meijer AJ, Sauerwein HP.
Department of Endocrinology and Metabolism, Department of Medical Biochemistryand Department of Clinical Chemistry, Laboratory of Endocrinology, Academic Medical Center, Amsterdam, the Netherlands; Department of Internal Medicine, Hospital Gelderse Vallei (R.H.), Ede, The Netherlands.

Context: Thiazolidinediones (TZDs) increase peripheral insulin sensitivity and decrease plasma free fatty acids (FFA). Their exact mechanism of action however has not been fully elucidated. Objective: We studied the protective effect of pioglitazone on FFA-induced insulin resistance and the effects on intramyocellular glycosphingolipids. Design: We studied glucose metabolism in the basal state and during a hyperinsulinemic euglycemic clamp by using stable isotopes. Studies were performed at baseline and after 4 months of treatment with pioglitazone. Patients were then studied on a third occasion during infusion of a lipid emulsion to increase plasma FFA to pretreatment levels. All studies were combined with muscle biopsies to measure intramyocellular ceramide and glycosphingolipids. Patients: Obese patients with poorly controlled T2DM Intervention: Patients were treated with 30 mg pioglitazone once daily. Main Outcome Measure: Change in peripheral insulin sensitivity after treatment with pioglitazone and during the infusion of the lipid emulsion. Results: Peripheral glucose uptake (Rd) increased significantly, but returned to baseline levels after increasing plasma FFA to pretreatment levels. Insulin-mediated suppression of FFA was increased significantly. Intramyocellular ceramide concentrations were higher during the hyperinsulinemic clamp after treatment with pioglitazone, but not in the basal state. The intramyocellular content of glycosphingolipids and plasma concentrations of ceramide and glycosphingolipids did not change. Conclusions: Pioglitazone increases Rd and insulin-mediated suppression of plasma FFA, but does not protect patients with T2DM from FFA-induced insulin resistance. This effect of pioglitazone is not attained via a decrease in intramyocellular concentrations of ceramide or glycosphingolipids.

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Ned Tijdschr Geneeskd. 2006 Oct 7;150(40):2183-7.
[Therapeutic possibilities for diabetic macular oedema]
[Article in Dutch]
Wiemer NG, Polak BC, Veckeneer MA.
VU Medisch Centrum, afd Oogheelkunde, Amsterdam. ngm.wiemer@vumc.nl

The number of patients with diabetes mellitus will increase over the coming years, so that there will also be more patients with diabetic macular oedema. Diabetic macular oedema and diabetic retinopathy are the most important causes of legal blindness in adults. The current therapy of diabetic macular oedema consists of the prevention, detection and treatment of risk factors (e.g., hypertension, hyperglycaemia, dyslipidaemia, proteinuria and obesity), complemented if necessary by photocoagulation therapy. Photocoagulation therapy may prevent or reduce vision loss in many patients, but usually does not improve visual acuity. New treatment strategies include intravitreal corticosteroids or vascular endothelial growth factor (VEGF) inhibitors, and oral protein kinase C inhibitors, angiotensin converting enzyme (ACE) inhibitors, acetylsalicylic acid or statins. The long-term positive effect of these strategies is controversial and the side effects can be serious.

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Obes Surg. 2006 Oct;16(10):1337-41.
Long-term effect of ileogastrostomy surgery for morbid obesity on diabetes mellitus and sleep apnea.
Cleator IG, Birmingham CL, Kovacevic S, Cleator MM, Gritzner S.
Department of Surgery, University of British Columbia, Vancouver, BC, Canada. cleator@interchange.ubc.ca

BACKGROUND: The long-term effects of ileogastrostomy surgery for morbid obesity on diabetes mellitus and sleep apnea were investigated. METHODS: All patients who had the ileogastrostomy for morbid obesity at the Bariatric Surgery Clinic of St. Paul's Hospital between 1997 and 2002 were registered in the International Bariatric Surgery Registry (IBSR). In 2005, IBSR follow-up was supplemented with a survey. RESULTS: Of the 592 consecutive patients registered in the IBSR, 311 were available for follow-up. Of the 15 patients who had diabetes mellitus preoperatively, 12 (80%) had cure of their diabetes mellitus and 3 (20%) were improved. Remission or improvement of diabetes occurred early postoperatively. Of the 20 who had sleep apnea preoperatively, 11 (55%) were cured and 6 (30%) were improved. CONCLUSIONS: This is the first report of the long-term effect of the ileogastrostomy on diabetes mellitus and sleep apnea. The ileogastrostomy was associated with rapid improvement or normalization of diabetes mellitus, similar to the biliopancreatic diversion and the Roux-en-Y gastric bypass, but faster than other bariatric operations. Improvement in sleep apnea was slower and was related to weight loss, similar to other bariatric operations.

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Neth J Med. 2006 Oct;64(9):319-25.
Efficacy and safety of inhaled insulin in the treatment of diabetes mellitus.
de Galan BE, Simsek S, Tack CJ, Heine RJ.
B.E. de Galan Department of General Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.

Many patients with diabetes mellitus view subcutaneous injections of insulin as a daily burden. Pulmonary delivery of insulin offers an alternative route of administration and may as such improve diabetes treatment. Inhaled insulin provides a rapid absorption of insulin, but with low bioavailability. Phase III clinical trials in type 1 and type 2 diabetes have disclosed clinical equivalence between three inhaled insulin products (Exubera, AErx idMs, and hIIp) and regular human insulin, both in terms of glycaemic control and hypoglycaemic risk. Inhaled insulin cannot be used to replace basal insulin requirements. The most commonly reported adverse effects of inhaled insulin are cough and insulin antibody formation, the clinical significance of which is uncertain. No or minimal deterioration in pulmonary function parameters have been recorded, although studies were typically of short duration. Patients participating in inhaled insulin trials generally expressed satisfaction with the product and chose to remain on it. The availability of inhaled insulin may increase willingness in type 2 diabetic patients to consider insulin therapy. More studies of longer duration are required to determine (pulmonary) safety and cost-effectiveness of inhaled insulin, and to disclose which patients may benefit the most.

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Cochrane Database Syst Rev. 2006 Oct 18;(4):CD006060.
Pioglitazone for type 2 diabetes mellitus.
Richter B, Bandeira-Echtler E, Bergerhoff K, Clar C, Ebrahim SH.
Universitaetsklinikum Duesseldorf, Department of Endocrinology, Diabetes and Rheumatology, Moorenstr. 5, Duesseldorf, Germany. richterb@uni-duesseldorf.de

BACKGROUND: Diabetes has long been recognised as a strong, independent risk factor for cardiovascular disease, a problem which accounts for approximately 70% of all mortality in people with diabetes. Prospective studies show that compared to their non-diabetic counterparts, the relative risk of cardiovascular mortality for men with diabetes is two to three and for women with diabetes is three to four. The two biggest trials in type 2 diabetes, the United Kingdom Prospective Diabetes Study (UKPDS) and the University Group Diabetes Program (UGDP) study did not reveal a reduction of cardiovascular endpoints through improved metabolic control. Theoretical benefits of the newer peroxisome proliferator activated receptor gamma (PPAR-gamma) activators like pioglitazone on endothelial function and cardiovascular risk factors might result in fewer macrovascular disease events in people with type 2 diabetes mellitus. OBJECTIVES: To assess the effects of pioglitazone in the treatment of type 2 diabetes. SEARCH STRATEGY: Studies were obtained from computerised searches of MEDLINE, EMBASE and The Cochrane Library. The last search was conducted in August 2006. SELECTION CRITERIA: Studies were included if they were randomised controlled trials in adult people with type 2 diabetes mellitus and had a trial duration of at least 24 weeks. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. Pooling of studies by means of random-effects meta-analysis could be performed for adverse events only. MAIN RESULTS: Twenty-two trials which randomised approximately 6200 people to pioglitazone treatment were identified. Longest duration of therapy was 34.5 months. Published studies of at least 24 weeks pioglitazone treatment in people with type 2 diabetes mellitus did not provide convincing evidence that patient-oriented outcomes like mortality, morbidity, adverse effects, costs and health-related quality of life are positively influenced by this compound. Metabolic control measured by glycosylated haemoglobin A1c (HbA1c) as a surrogate endpoint did not demonstrate clinically relevant differences to other oral antidiabetic drugs. Occurrence of oedema was significantly raised. The results of the single trial with relevant clinical endpoints (Prospective Pioglitazone Clinical Trial In Macrovascular Events--PROactive study) have to be regarded as hypothesis-generating and need confirmation. AUTHORS' CONCLUSIONS: Until new evidence becomes available, the benefit-risk ratio of pioglitazone remains unclear. Different therapeutic indications for pioglitazone of the two big U.S. and European drug agencies should be clarified to reduce uncertainties amongst patients and physicians.

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Diab Vasc Dis Res. 2006 Sep;3(2):108-19.
New perspectives on the management of diabetic peripheral neuropathic pain.
Jensen TS, Backonja MM, Hernandez Jimenez S, Tesfaye S, Valensi P, Ziegler D.
Department of Endocrinology, Diabetology and Nutrition, Hopital Jean-Verdier APHP Paris-Nord University, Bondy, France. tsjensen@ki.au.dk

Peripheral neuropathy affects about 30% of people with diabetes mellitus. Between 16% and 26% of diabetes patients experience chronic pain. This may be referred to as diabetic neuropathic pain (DNP) or diabetic peripheral neuropathic pain (DPNP). Minimum requirements for diagnosis of DPNP should include assessment of pain and symptoms and neurological examination, with the accent on sensory examination. Given that depression and other co-morbidities are commonly associated with this condition, a broad approach to management is essential. Lifestyle intervention and optimisation of glycaemic control are recommended as initial steps in management. An evidence-based treatment algorithm for DPNP has been proposed, recommending initial use of either a tricyclic antidepressant, selective serotonin noradrenaline re-uptake inhibitor or alpha-2-delta agonist, depending on patient co-morbidities and contra-indications. Addition of an opioid agonist may be required in the event of inadequate pain control. Irrespective of which treatment is offered, only about one third of patients are likely to achieve more than 50% pain relief. Further research to improve the diagnosis and management of DPNP is needed.

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Aging Male. 2006 Sep;9(3):139-47.
Diabetes mellitus in older men.
Kim MJ, Rolland Y, Cepeda O, Gammack JK, Morley JE.
Division of Geriatric Medicine, Saint Louis University School of Medicine, St. Louis, Missouri, USA.

Most persons with diabetes mellitus are over the age of 60 years. Males develop diabetes more commonly than females. Older diabetics tend to have both impaired insulin release as well as insulin resistance. In older persons diabetes mellitus is associated with decreased functional status and cognitive dysfunction. In general, older persons with diabetes are inclined to be underdiagnosed and undertreated. Managing diabetes in older persons requires special considerations because of their differences in pathophysiology of diabetes and strong association with functional, cognitive impairments and comorbidities. The use of strict therapeutic diets is not recommended in older persons. Treatment of hypertension and hyperglycemia can improve outcomes in older persons. The interdisciplinary team approach is important for care of older diabetic persons.

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Int J Clin Pract. 2006 Jul;60(7):783-90.
Beta-cell response to metformin-glibenclamide combination tablets (Glucovance) in patients with type 2 diabetes.
Bruce S, Park JS, Fiedorek FT, Howlett HC.
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ, USA.

This exploratory double-blind, randomised, 20-week study evaluated the mechanism of action of metformin-glibenclamide combination tablets (Glucovance((R))) vs. metformin and glibenclamide in 50 type 2 diabetes patients inadequately controlled by diet and exercise. A glycaemic target of HbA(1C) 7.0% was used. Final HbA(1C), fasting glucose and post-oral glucose tolerance test (OGTT) glucose were similar between groups, although average doses of metformin and glibenclamide from combination tablets (708 and 3.5 mg) were lower than monotherapy doses (1500 and 6.6 mg). Second-phase insulin during a hyperglycaemic clamp increased by 93% with combination tablets, 36% with metformin and 46% with glibenclamide. The insulin response post-OGTT was more rapid with the combination tablets vs. glibenclamide. First-phase insulin responses improved modestly in all groups, possibly due to reduced glucotoxicity. Changes in insulin sensitivity were minor. Larger beta-cell responses between combination tablets and glibenclamide may reflect more rapid glibenclamide absorption.

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Ann Intern Med. 2006 Jul 18;145(2):125-34.
Narrative review: a rational approach to starting insulin therapy.
Mooradian AD, Bernbaum M, Albert SG.
St. Louis University School of Medicine, St. Louis, Missouri, USA. arshag.mooradian@jax.ufl.edu

BACKGROUND: The emergence of multiple insulin products has provided new opportunities to achieve diabetes control. However, the number of options has raised concerns about the optimal choices of products. PURPOSE: To briefly review the pharmacologic characteristics of currently available insulin products and to suggest an initial insulin regimen based on common blood glucose profiles among patients with diabetes. DATA SOURCES: Relevant manuscripts were identified through a MEDLINE search (1996 to 25 February 2006) of the English-language literature. The key phrase used was therapeutic use of insulin. The literature search was limited to core clinical journals that have accessible full texts. STUDY SELECTION: Clinical trials and authoritative reviews published between 1996 and February 2006 were selected. A total of 420 manuscripts was reviewed. DATA EXTRACTION: The authors independently reviewed the relevant available literature. This literature, along with the authors' clinical experience, was used to construct practical suggestions. DATA SYNTHESIS: Several new insulin and insulin analogue preparations are now available for clinical use. Used as prandial insulin (for example, insulin lispro, insulin aspart, or insulin glulisine) and basal insulin (for example, insulin glargine or insulin detemir), the analogues simulate physiologic insulin profiles more closely than the older conventional insulins. There is currently no strong rationale favoring glargine, neutral protamine Hagedorn insulin, insulin detemir, or fixed-ratio insulin preparations as the preferred agent for initiating insulin therapy. LIMITATIONS: This was a retrospective review of previously published manuscripts chosen at the authors' discretion. CONCLUSIONS: The advent of recombinant DNA technology made it possible to overcome limitations in the time-action profiles of conventional insulins. Insulin therapy must be individualized. Nevertheless, certain subgroups of patients with diabetes can be differentiated from each other according to the pattern of blood glucose changes during the day. On the basis of the blood glucose profile, the authors suggest an initial insulin regimen that can be used to evaluate individual responsiveness and plan a long-term regimen.

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Am J Med Sci. 2006 Jul;332(1):24-31.
Basal-prandial insulin therapy: scientific concept review and application.
Leahy JL.
>From the University of Vermont College of Medicine, Burlington, Vermont.

The majority of patients with type 2 diabetes mellitus (T2DM) eventually require the addition of basal insulin to existing oral therapy to achieve the glycemic goals set forth by the American Diabetes Association (A1C, <7.0%). In many patients with T2DM, insulin is the only option for achieving glycemic control and may be used successfully to attain glycemic targets in regimens that combine basal insulin with oral antidiabetic agents, or in regimens that combine basal insulin with mealtime (prandial) insulin. Basal-prandial insulin regimens that use a long-acting insulin analogue to control the fasting plasma glucose level and a short-acting insulin analogue for post-meal glucose excursions replace insulin in a manner that most closely approximates normal physiologic patterns. The current body of evidence demonstrates that such regimens will prove to be the optimal strategy for achieving glycemic control in patients with T2DM who require both basal and prandial insulin replacement. Here, we review current findings in the published literature on the efficacy of basal-prandial insulin, with a focus on practical information that might help to provide an evidence-based guide for progressing to basal-prandial insulin therapy in appropriate patients with T2DM.

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Diabet Med. 2006 Jul;23(7):743-9.
Comparison of insulin lispro mixture 25/75 with insulin glargine during a 24-h standardized test-meal period in patients with Type 2 diabetes.
Roach P, Malone JK.
Indiana University School of Medicine and Eli Lilly and Company, Indianapolis, IN, USA.

Aim:To compare insulin lispro mixture (25% insulin lispro and 75% NPL; Mix 25/75) twice-daily plus oral glucose-lowering medications (metformin and/or sulphonylurea) with once-daily insulin glargine plus oral agents with respect to postprandial glycaemic control and other glucose and lipid parameters in patients with Type 2 diabetes inadequately controlled with insulin and/or oral glucose-lowering agents. This was a randomized, open-label, crossover study. Prestudy oral agents were continued and patients not already on oral agents were treated with metformin. Mix 25/75 and insulin glargine were adjusted over 3 months to attain premeal plasma glucose (PG) < 6.0 mmol/l and were then given during a 24-h in-patient test meal period with frequent PG, serum triglyceride (TG) and free fatty acid (FFA) measurements. Twenty patients (10 F/10 M; mean +/-sd age 54.0 +/- 10.7 years, body mass index 37.0 +/- 8.6 kg/m(2), HbA(1c) 8.4 +/- 1.01%) participated. Mean doses were 23 U before the morning and 37 U before the evening meal for Mix 25/75 and 44 U for insulin glargine. The combined 2-h morning and evening meal postprandial plasma glucose (PPG) was not different between groups (9.2 +/- 2.04 vs. 9.9 +/- 1.66 mmol/l, P = 0.161). Mix 25/75 was associated with a lower mean 2-h PPG for all meals combined (9.0 +/- 1.88 vs. 9.9 +/- 1.80 mmol/l, P < 0.05) and lower mean 24-h PG (6.7 +/- 1.00 vs. 7.5 +/- 1.32 mmol/l, P < 0.01). Eight patients experienced mild hypoglycaemia (PG < 3.5 mmol/l) with Mix 25/75 and 3 with insulin glargine. The endpoint HbA(1c) was lower with Mix 25/75 (6.9 +/- 0.52% vs. 7.3 +/- 0.81%, P < 0.05). In a 24-h test-meal setting in 20 patients, Mix 25/75 insulin plus oral glucose-lowering agents was associated with lower mean PPG and 24-h PG, more mild hypoglycaemia and similar TG, FFA and fasting PG concentrations. HbA(1c) was lower with Mix 75/25 plus oral agents, although it may not have reached steady state due to ongoing dose adjustment.

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Diabet Med. 2006 Jul;23(7):736-42.
A randomized trial of adding insulin glargine vs. avoidance of insulin in people with Type 2 diabetes on either no oral glucose-lowering agents or submaximal doses of metformin and/or sulphonylureas. The Canadian INSIGHT (Implementing New Strategies with Insulin Glargine for Hyperglycaemia Treatment) Study.
Gerstein HC, Yale JF, Harris SB, Issa M, Stewart JA, Dempsey E.
McGill Nutrition and Food Science Centre, McGill University, Montreal Quebec, Canada.

Insulin is generally withheld until people with Type 2 diabetes are unresponsive to other therapies. However, its potential advantages suggest that it could be added earlier to achieve glycaemic goals; this possibility was tested in a clinical trial. Consenting adults aged 18-80 years with Type 2 diabetes for at least 6 months, HbA(1c) of 7.5-11%, and on 0, 1 or 2 oral agents, were randomized to one of two therapeutic approaches for 24 weeks: evening insulin glargine plus self-titration by 1 unit/day if the fasting plasma glucose (FPG) was > 5.5 mmol/l; or conventional therapy with physician adjustment of oral glucose-lowering agents if capillary FPG levels were > 5.5 mmol/l. The primary outcome was the first achievement of two consecutive HbA(1c) levels </= 6.5%. Two hundred and six participants were allocated to glargine and 199 to oral agents. Compared with control subjects, participants receiving glargine: (i) were 1.68 times more likely to achieve two consecutive HbA(1c) levels </= 6.5% (95% CI 1.00-2.83; P = 0.049); (ii) reduced their HbA(1c) by 1.55 vs. 1.25% (P = 0.005), achieving adjusted means of 7.0 vs. 7.2% (P = 0.0007); (iii) had lower FPG (P = 0.0001), non-high-density lipoprotein (HDL) cholesterol (P = 0.02) and triglycerides (P = 0.02); (iv) had greater increases in treatment satisfaction (P = 0.045); and (v) had a 1.9-kg greater increase in weight (P < 0.0001). No differences in hypoglycaemia were noted. Adding insulin glargine is more likely to achieve a lower HbA(1c) level than conventional therapy with oral agents.

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Diabet Med. 2006 Jul;23(7):729-35.
Insulin detemir lowers the risk of hypoglycaemia and provides more consistent plasma glucose levels compared with NPH insulin in Type 1 diabetes.
Kolendorf K, Ross GP, Pavlic-Renar I, Perriello G, Philotheou A, Jendle J, Gall MA, Heller SR.
The Diabetes Centre, Royal Prince Alfred Hospital, Sydney, Australia.

Hypoglycaemia remains a major barrier preventing optimal glycaemic control in Type 1 diabetes due to the limitations of conventional insulin preparations. We investigated whether basal-bolus therapy with insulin detemir (detemir), a new soluble basal insulin analogue, was more effective in reducing the risk of hypoglycaemia compared with NPH insulin (NPH). In this multinational, open-label, cross-over trial, 130 individuals with Type 1 diabetes received detemir and NPH twice daily in a randomized order in combination with premeal insulin aspart (IAsp) during two 16-week treatment periods. Risk of hypoglycaemia was based on self-measured plasma glucose (SMPG) and self-reported episodes during the last 10 weeks of each period. Risk of nocturnal and overall hypoglycaemia was, respectively, 50% and 18% lower with detemir than with NPH (P < 0.001). A total of 19 severe hypoglycaemic episodes occurred during treatment with detemir compared with 33 with NPH (NS). HbA(1c) decreased by 0.3% point with both treatments and was comparable at 7.6% (+/- sem 0.06%, 95% confidence interval -0.106, 0.108) after 16 weeks with similar doses of basal insulin. Within-person variation in mean plasma glucose was lower with detemir than with NPH (sd 3.00 vs. 3.33, P < 0.001), as was prebreakfast SMPG (P < 0.0001). Detemir was associated with a significantly lower risk of hypoglycaemia compared with NPH at similar HbA(1c) when used in combination with mealtime IAsp. The more consistent plasma glucose levels observed with detemir may allow people to aim for tighter glycaemic control without an increased risk of hypoglycaemia.

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Curr Med Res Opin. 2006 Jun;22(6):1211-5.
Glycemic control and treatment failure with pioglitazone versus glibenclamide in type 2 diabetes mellitus: a 42-month, open-label, observational, primary care study.
Hanefeld M, Pfutzner A, Forst T, Lubben G.
Centre for Clinical Studies, GWT Technical University, Dresden, Germany. hanefeld@gwtonline-zks.de

BACKGROUND: Insulin resistance and declining beta-cell function are the core defects in type 2 diabetes mellitus. It has been suggested that deteriorating glycemic control is related to baseline hemoglobin A(1c) (HbA(1c)) values and remaining beta-cell function. PATIENTS AND METHODS: We report glycemic data from a 3.5-year, open-label, observational, primary care study comparing 30 mg/day pioglitazone with 3.5 mg/day glibenclamide add-on to stable metformin monotherapy in 500 patients with type 2 diabetes. Insulin commencement was considered for patients with HbA(1c) > or = 8.0% or when vascular complications occurred. The change in HbA(1c) compared with baseline and the difference in time to failure to maintain glycemic control were calculated. RESULTS: At endpoint, HbA(1c) had decreased by 1.0% in the pioglitazone group (p < 0.005) and by 0.6% in the glibenclamide group (p < 0.05). Annual progression rates to insulin treatment were 6.6% (pioglitazone) and 16.4% (glibenclamide; p < 0.001 between-group difference). Mean weight increases of 3.5 +/- 0.42 kg in the pioglitazone group and 3.3 +/- 0.38 kg in the glibenclamide group were noted. Overall, both treatments were well tolerated. CONCLUSIONS: Pioglitazone add-on to metformin revealed significant benefits in long-term glycemic control compared with glibenclamide. This difference may be explained by a large between-group difference in HOMA-S, which was shown to correlate significantly to the change in HbA(1c). This suggests that a strategy to reduce insulin resistance to lower the burden of the beta-cell is superior to treatment with glibenclamide.

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Drugs Today (Barc). 2006 Jun;42(6):405-24.
Noninjectable methods of insulin administration.
Cernea S, Raz I.
Division of Endocrinology, Department of Medicine, Columbia University, New York, New York, USA. ntv502@netvision.net.il.

Optimal glycemic control is essential for the prevention of diabetes-related complications, and the intensive insulin regimens that best resemble physiological insulin secretion are most likely to attain it. However, there are many limitations that preclude the early use of insulin by patients with type 2 diabetes or wider implementation of the intensive regimens in type 1 diabetes. More acceptable alternative routes of insulin administration and effective, noninvasive, patient-friendly delivery systems that alleviate the burden of insulin injections have been researched over the years. To date, only pulmonary inhalation of insulin has become a feasible alternative; it has proved to be as effective and well tolerated as the subcutaneously injected regular insulin and it has a pharmacodynamic profile well suited for mealtime insulin therapy. Several pulmonary insulin delivery systems are in different stages of development, and one (Exubera(R), Nektar Therapeutics/Pfizer Inc.-Sanofi-Aventis Group) has already become clinically available in the United States and Europe for patients with diabetes. Other noninjectable methods of insulin administration are reviewed. (c) 2006 Prous Science. All rights reserved.

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Am J Transplant. 2006 Apr;6(4):842-6.
Repaglinide in the management of new-onset diabetes mellitus after renal transplantation.
Turk T, Pietruck F, Dolff S, Kribben A, Janssen OE, Mann K, Philipp T, Heemann U, Witzke O.
Department of Nephrology and Hypertension, School of Medicine, University of Diusburg-Essen, Hufelandstrasse 55, D-45122 Essen, Germany.

The purpose of this study was to investigate the use of the short-acting insulin secretion drug repaglinide in new-onset diabetes mellitus (NODM) after renal transplantation. Twenty-three Caucasian patients with NODM after renal transplantation were selected to receive repaglinide therapy and were followed for at least 6 months. A control group treated with rosiglitazone was chosen for comparison. Successful repaglinide treatment was defined as a significant improvement of blood glucose concentrations and HbA1c <7% in the absence of glucosuria and without the need for the addition of further anti-diabetic agents. After 6 months of treatment with repaglinide, 14 of the 23 patients were successfully treated. Mean HbA1c decreased from 7.6 +/- 0.6% to 5.8 +/- 0.6% in 14 patients treated successfully. In nine patients, hyperglycemia persisted, and they were switched to insulin treatment (HbA1c 8.5 +/- 2.9% at the beginning to 7.4 +/- 2.2%). Mean serum creatinine levels, cyclosporine A and tacrolimus blood levels did not change significantly following institution of repaglinide therapy. The rate of successful treatment and the degree of HbA1c decrease were similar compared to rosiglitazone-treated control patients. The data from our observational study indicate that repaglinide can be an effective treatment option in Caucasian patients with NODM after renal transplantation.

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Internist (Berl). 2006 Mar 8; [Epub ahead of print]
[Pharmacotherapy of diabetes mellitus type 2: from the glucocentric tradition towards cardiovascular risk management.]
[Article in German]
Jacob S, Marx N.
Abteilung fur Innere Medizin II, Medizinische Univ.-Klinik und Poliklinik Ulm, .

Patients with diabetes type 2 are not directly endangered by dysglycemia but they suffer vascular complications. The diabetic patient with existing cardiovascular disease has a particularly high risk for further cardiovascular complications and therefore requires specific attention. This is not only due to the hyperglycemia, but due to the coexistence of further cardiovascular risk factors, such as hypertension, dyslidemia, visceral fat accumulation, chronic inflammation and coagulopathy, also clinically described as the metabolic syndrome. These patients need an intense and multi-modal therapeutic approach, not only for improvement of glycemic control. Also other vascular risk factors should be handled aggressively, such as blood pressure, coagulopathy and dyslipidemia. Recent studies - as STENO 2 - indicate that a multi-modal and aggressive approach in diabetic patients can markedly improve their prognosis. Therefore, the current practice of a glucocentric approach should be changed towards a more vascular approach.

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Med J Aust. 2006 Mar 6;184(5):221-5.
Clinical islet transplantation in type 1 diabetes mellitus: results of Australia's first trial.
O'Connell PJ, Hawthorne WJ, Holmes-Walker DJ, Nankivell BJ, Gunton JE, Patel AT, Walters SN, Pleass HC, Allen RD, Chapman JR.
National Pancreas Transplant Unit, University of Sydney at Westmead Hospital, Darcy Road, Westmead, NSW 2145, Australia. philip_oconnell@wsahs.nsw.gov.au

OBJECTIVE: To determine whether pancreatic islet transplantation can control diabetes and prevent severe life-threatening hypoglycaemia. DESIGN, SETTING AND PARTICIPANTS: A single-arm observation study of six patients undergoing islet transplantation. All patients had had type 1 diabetes mellitus for over 5 years and documented episodes of repeated severe hypoglycaemia. Islets were isolated from donor pancreases digested by Liberase. Separated islets were infused into the recipient's liver via the portal vein. Patients were immunosuppressed with daclizumab, sirolimus and tacrolimus. The transplants were performed at Westmead Hospital, NSW, between October 2002 and February 2005. MAIN OUTCOME MEASURES: Normal blood glucose control without administration of exogenous insulin; demonstration of islet function and abolition of hypoglycaemia. RESULTS: Five of the patients received two islet infusions, and the sixth was withdrawn after one infusion following a portal vein thrombosis. Three patients became insulin-independent, with excellent glycaemic control. Two had islet function with circulating C-peptide, improved glycaemic control, reduced insulin requirement and abolition of severe hypoglycaemia. However, over a 2-year period, graft function deteriorated. Recipients who were initially insulin free remained C-peptide positive but required supplemental insulin. Complications included one postoperative bleed, two portal vein thromboses (which resolved completely), presumed recurrence of tuberculosis in one patient, and deterioration in renal function in one patient. CONCLUSIONS: Islet transplantation is effective at improving glycaemic control and hypoglycaemia unawareness in the short to medium term. However, problems with long-term safety of immunosuppression, islet-induced thrombosis and early detection of loss of islet function remain to be addressed.

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Expert Opin Pharmacother. 2006 Mar;7(4):463-76.
Pioglitazone: an antidiabetic drug with the potency to reduce cardiovascular mortality.
Pfutzner A, Forst T.
Institut fur Klinische Forschung und Entwicklung IKFE, Institute for Clinical Research and Development, Parcusstr. 8, D-55116 Mainz, Germany. AndreasP@ikfe.de

Pioglitazone is an antidiabetic drug known to decrease peripheral, hepatic and vascular insulin resistance by the stimulation of PPARgamma. In clinical trials, pioglitazone as monotherapy or in combination with other oral antidiabetic drugs or insulin has demonstrated to effectively improve blood glucose levels, long-term glucose control and the lipid profile. The vascular effects of pioglitazone include improvement of endothelial function and microcirculation, reduction of blood pressure and inflammatory surrogate markers of atherosclerosis, and a reduction of a composite measure of macrovascular events (death, stroke and myocardial infarctions). The drug is well tolerated and has an acceptable side effect profile. Because of its additional microvascular and macrovascular effects, pioglitazone is an attractive and effective treatment option for the management of Type 2 diabetes mellitus.

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Expert Opin Investig Drugs. 2006 Mar;15(3):243-50.
Recent findings concerning thiazolidinediones in the treatment of diabetes.
Boden G, Zhang M.
Division of Endocrinology/Diabetes/Metabolism, Temple University School of Medicine, Philadelphia, PA, USA. bodengh@tuhs.temple.edu

Thiazolidinediones (TZDs) are peroxisomal proliferator-activated receptor (PPAR)-gamma agonists. They increase insulin action through several mechanisms including: stimulation of the expression of genes that increase fat oxidation and lower plasma free fatty acid levels; increased expression, synthesis and release of adiponectin; and stimulation of adipocyte differentiation resulting in more and smaller fat cells. TZDs lower blood sugar comparably to sulfonylureas and metformin. The clinical use of TZDs is limited due to the long duration of time required before they reach their full blood sugar-lowering action (3-4 months) and adverse effects such as fluid retention, resulting in excessive weight gain and occasionally in peripheral and/or pulmonary oedema and congestive heart failure. Troglitazone, a TZD that has since been removed from the market because of hepatoxicity, has been demonstrated to decrease the progression from normal or impaired glucose tolerance to overt Type 2 diabetes mellitus. Pioglitazone, another TZD, marginally decreased the incidence of cardiovascular complications in patients with Type 2 diabetes mellitus (PROactive trial). Other, as yet, unapproved uses of TZDs include: non-alcoholic fatty liver disease, in which TZDs reduced hepatic fat accumulation and improved liver function tests; polycystic ovary syndrome, where TZDs improved ovulation, hirsutism and endothelial dysfunction; and lipodystrophies, where TZDs increased body fat (marginally) and decrease liver size. Lastly, because PPAR-alpha and -gamma agonists improve atherosclerotic vascular disease and insulin sensitivity, respectively, dual PPAR-alpha/gamma agonists, which are currently undergoing clinical trials, may be useful in treating patients with the metabolic syndrome.

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Endocr J. 2006 Feb;53(1):67-72.
Therapeutic efficacy of mitiglinide combined with once daily insulin glargine after switching from multiple daily insulin regimen of aspart insulin and glargine in patients with type 2 diabetes mellitus.
Yoshihara T, Kumashiro N, Kanazawa Y, Mita T, Sakurai Y, Kawai J, Abe M, Motojima K, Hara K, Yamazaki Y, Kanazawa A, Miwa S, Sato F, Kanno R, Shimizu T, Sakai K, Uchino H, Watada H, Tanaka Y, Kawamori R, Hirose T.
Department of Medicine, Metabolism and Endocrinology, Juntendo University, School of Medicine.

Mitiglinide is novel class of rapid-acting insulin secretagogues, which have been widely used alone or in combination with other oral hypoglycemic drugs to improve postprandial hyperglycemia in early type 2 diabetes. While mitiglinide enhances postprandial requirement of insulin, the efficacy of mitiglinide combined with insulin has yet to be established. We investigated the efficacy of mitiglinide combined with insulin glargine, the first soluble insulin analog that has a flat and prolonged effect. After control with the intensive regimen (daily aspart insulin and glargine), 30 inpatients with type 2 diabetes were switched to premeal mitiglinide combined with once daily insulin glargine (mitiglinide regimen), and daily profiles of blood glucose level were compared under each regimen. Fifteen patients showed similar control of hyperglycemia with mitiglinide regimen and intensive insulin regimen, assessed by M value (<32), while the remaining 15 showed worsening under the mitiglinide regimen. The patients who were well controlled with mitiglinide regimen were significantly younger (51.9 +/- 16.0 years, p<0.005) and heavier (body mass index: 25.7 +/- 3.3 kg/m(2), p<0.05) than those who were not (67.9 +/- 8.7 and 23.0 +/- 3.1, respectively). Moreover, insulin doses of aspart per body weight were significantly fewer in effective group than in ineffective group. Duration of diabetes was shorter in the effective group, albeit insignificantly. Previous treatment before starting intensive insulin regimen, such as insulin and sulfonylurea, was not different between the two groups. Our results suggest that mitiglinide plus insulin glargine combination therapy is useful for lowering both fasting and postprandial hyperglycemia in a subpopulation of type 2 diabetes. The long-term effects of such treatment need to be established in future studies.

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Diabetologia. 2006 Feb 28; [Epub ahead of print]
Efficacy and safety of preprandial human insulin inhalation powder versus injectable insulin in patients with type 1 diabetes.
Garg S, Rosenstock J, Silverman BL, Sun B, Konkoy CS, de la Pena A, Muchmore DB.
Department of Medicine and Paediatrics, Barbara Davis Center for Diabetes at the University of Colorado Health Sciences Center, Mail stop A140, P.O. Box 6511, Aurora, CO, 80045, USA, satish.garg@uchsc.edu.

AIMS/HYPOTHESIS: The efficacy and safety of human insulin inhalation powder (HIIP) plus insulin glargine were compared to subcutaneously injected insulin (SC insulin) plus insulin glargine in patients with type 1 diabetes. METHODS: This was a randomised, open-label crossover study in which one group of patients received preprandial HIIP plus insulin glargine for 12 weeks, followed by the same duration with preprandial SC insulin (lispro or regular) plus insulin glargine. Another group of patients received the reverse treatment sequence. The trial was designed as a non-inferiority comparison of the two treatments for effect on HbA(1c); blood glucose levels were also monitored. Safety assessments included adverse event reporting and hypoglycaemic events. RESULTS: HbA(1c) at endpoint was 7.95+/-0.12% for the HIIP treatment and 8.06+/-0.12% for the SC insulin treatment; mean changes from baseline to endpoint were -0.08 and 0.00%, respectively, (p=NS). The upper limit of the 95% CI of mean difference in HbA(1c) between the two treatments was 0.02%, indicating that HIIP was not inferior relative to SC insulin, as measured against the pre-defined margin of 0.3%. Fasting blood glucose was significantly lower for HIIP treatment (8.09+/-0.33 mmol/l; n=117) than for SC insulin treatment (9.05+/-0.33 mmol/l; n=111) (p=0.01). Safety profiles were comparable between the two treatments. The rate of any hypoglycaemia (least-squares mean adjusted for 30 days+/-SE) was 8.9+/-0.7 and 8.2+/-0.8 for HIIP and SC insulin treatments, respectively, (p=0.29). The rate of nocturnal hypoglycaemia was greater for HIIP (4.2+/-0.4) than for SC insulin (2.7+/-0.4; p<0.001). CONCLUSIONS/INTERPRETATION: HIIP was similar in efficacy to SC insulin for glycaemic control in type 1 diabetes mellitus. The two treatments had comparable safety profiles.

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Endocr J. 2006 Feb;53(1):67-72.
Therapeutic efficacy of mitiglinide combined with once daily insulin glargine after switching from multiple daily insulin regimen of aspart insulin and glargine in patients with type 2 diabetes mellitus.
Yoshihara T, Kumashiro N, Kanazawa Y, Mita T, Sakurai Y, Kawai J, Abe M, Motojima K, Hara K, Yamazaki Y, Kanazawa A, Miwa S, Sato F, Kanno R, Shimizu T, Sakai K, Uchino H, Watada H, Tanaka Y, Kawamori R, Hirose T.
Department of Medicine, Metabolism and Endocrinology, Juntendo University, School of Medicine.

Mitiglinide is novel class of rapid-acting insulin secretagogues, which have been widely used alone or in combination with other oral hypoglycemic drugs to improve postprandial hyperglycemia in early type 2 diabetes. While mitiglinide enhances postprandial requirement of insulin, the efficacy of mitiglinide combined with insulin has yet to be established. We investigated the efficacy of mitiglinide combined with insulin glargine, the first soluble insulin analog that has a flat and prolonged effect. After control with the intensive regimen (daily aspart insulin and glargine), 30 inpatients with type 2 diabetes were switched to premeal mitiglinide combined with once daily insulin glargine (mitiglinide regimen), and daily profiles of blood glucose level were compared under each regimen. Fifteen patients showed similar control of hyperglycemia with mitiglinide regimen and intensive insulin regimen, assessed by M value (<32), while the remaining 15 showed worsening under the mitiglinide regimen. The patients who were well controlled with mitiglinide regimen were significantly younger (51.9 +/- 16.0 years, p<0.005) and heavier (body mass index: 25.7 +/- 3.3 kg/m(2), p<0.05) than those who were not (67.9 +/- 8.7 and 23.0 +/- 3.1, respectively). Moreover, insulin doses of aspart per body weight were significantly fewer in effective group than in ineffective group. Duration of diabetes was shorter in the effective group, albeit insignificantly. Previous treatment before starting intensive insulin regimen, such as insulin and sulfonylurea, was not different between the two groups. Our results suggest that mitiglinide plus insulin glargine combination therapy is useful for lowering both fasting and postprandial hyperglycemia in a subpopulation of type 2 diabetes. The long-term effects of such treatment need to be established in future studies.

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Ned Tijdschr Geneeskd. 2006 Feb 18;150(7):361-6.
[Treatment of patients with diabetes mellitus type 2 and coronary artery disease]
[Article in Dutch]
Wiersma JJ, Trip MD, Piek JJ.
Universiteit van Amsterdam, afd. Cardiologie, B2-224, Meibergdreef 9, 1105 AZ Amsterdam. j.j.wiersma@amc.uva.nl

Of all patients presenting with coronary, artery disease, 20-30% already have a diagnosis of diabetes mellitus type 2. Of the remaining patients, another 15-20% are found at presentation to have diabetes mellitus and 30% have glucose intolerance. Both conditions are major risk factors for the recurrence of coronary artery disease and mortality. The treatment of patients with diabetes mellitus type 2 always includes improvement in lifestyle, adequate blood-glucose control, cholesterol-lowering therapy and blood-pressure control. Furthermore, if one or more other traditional cardiovascular risk factors are present, or if the patient is over 40 years of age, acetylsalicylic acid must be added. Finally, with a prior history of coronary-artery disease, patients must be given an angiotensin converting enzyme (ACE) inhibitor. During percutaneous coronary interventions, patients with diabetes mellitus type 2 are preferably treated with a drug-eluting stent in combination with clopidogrel, and in case of an acute coronary syndrome, glycoprotein (GP) IIb/IIIa receptor antagonists are added to the standard treatment.

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Nepal Med Coll J. 2005 Dec;7(2):145-7.
The beneficial effect of yoga in diabetes.
Malhotra V, Singh S, Tandon OP, Sharma SB.
Department of Physiology, University College of Medical Sciences and Guru Tegh Bahadur Hospital, Delhi. dr_varun@yahoo.com

Twenty NIDDM subjects (mild to moderate diabetics) in the age group of 30-60 years were selected from the out patient clinic of G.T.B. hospital. They were on a 40 days yoga asana regime under the supervision of a yoga expert. 13 specific Yoga asanas < or = done by Type 2 Diabetes Patients included. Surya Namaskar, Trikonasana, Tadasana, Sukhasana, Padmasana, Bhastrika Pranayama, Pashimottanasana, Ardhmatsyendrasana, Pawanmuktasana, Bhujangasana, Vajrasana, Dhanurasana and Shavasana are beneficial for diabetes mellitus. Serum insulin, plasma fasting and one hour postprandial blood glucose levels and anthropometric parameters were measured before and after yoga asanas. The results indicate that there was significant decrease in fasting glucose levels from basal 208.3 +/- 20.0 to 171.7 +/- 19.5 mg/dl and one hour postprandial blood glucose levels decreased from 295.3 +/- 22.0 to 269.7 +/- 19.9 mg/dl. The exact mechanism as to how these postures and controlled breathing interact with somatoendocrine mechanism affecting insulin kinetics was worked out. A significant decrease in waist-hip ratio and changes in insulin levels were also observed, suggesting a positive effect of yoga asanas on glucose utilisation and fat redistribution in NIDDM. Yoga asanas may be used as an adjunct with diet and drugs in the management of Type 2 diabetes.

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Med J Malaysia. 2005 Dec;60(5):578-84.
Management of type 2 diabetes mellitus: is it in accordance with the guidelines?
Chan GC, Ghazali O, Khoo EM.
Family Medicine Specialist, Poliklinik Komuniti Peringgit, Jalan Pantai Peringgit, 75400 Melaka.

A cross-sectional study was conducted among 517 patients with diabetes mellitus at all health centres in Melaka Tengah District to examine whether these patients and their associated cardiovascular risk factors were managed according to current guidelines. All patients had Type 2 diabetes mellitus with mean age of 57.9 +/- 10.5 years and the mean duration of diabetes was 7.2 +/- 6.0 years. The glycaemic control was poor with 53.6% of the patients having HbAlc above 8% (mean = 8.5%) and 24% of them had microalbuminuria. Among these patients with poor glycaemic control, about 47.6% of them were on monotherapy. Three hundred and fifty (67.7%) patients had hypertension but only 11 (3.1%) achieved target blood pressure of less than 130/80 mmHg. Only 18.3% of the diabetics with hypertension were prescribed angiotensin converting enzyme inhibitors and 0.3% with angiotensin receptor blockers. Nearly two-third of them had low-density lipoprotein cholesterol greater than 2.6 mmol/l (mean = 3.4 mmol/l) but only 6.8% were prescribed lipid-lowering agents. Aspirin was prescribed to 8.2% of diabetics aged above 40 years. Sixteen percent of the patients smoked, 53% did not do any exercise, and the mean BMI was 26.8 kg/mn. The management of diabetes mellitus and its associated cardiovascular risk factors was suboptimal on the basis of current clinical guidelines. A greater effort in educating doctors in the health centres about these management and adherence to the guidelines is important in reducing patients' risk of cardiovascular disease and its associated morbidity and mortality.

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J Pediatr Psychol. 2005 Dec;30(8):683-688. Epub 2005 Mar 3.
Brief Report: In-Home Family Therapy for Adolescents with Poorly Controlled Diabetes:
Failure to Maintain Benefits at 6-Month Follow-Up.
Harris MA, Harris BS, Mertlich D.
Patient Oriented Research Unit, Campus Box 8208, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110. harris_ma@kids.wustl.edu.

OBJECTIVE: To examine 6-month follow-up data on the effectiveness of in-home Behavioral Family Systems Therapy (BFST) for adolescents with poorly controlled diabetes, using a pilot and feasibility study. METHODS: Eighteen adolescents with poorly controlled diabetes received ten 90-min sessions of in-home BFST. Diabetes-related functioning, general family functioning, and health status were assessed at baseline, immediately following treatment and 6-months after the treatment. RESULTS: Although the initial posttreatment follow-up evaluation indicated decreases in general family conflict, diabetes-related family conflict, and behavior problems, evaluation at a 6-month follow-up (N = 17) demonstrated that initial posttreatment improvements were no longer present for any of the variables assessed. Metabolic control remained unchanged from baseline to initial posttreatment as well as at 6-month follow-up. CONCLUSIONS: A plausible explanation for this finding is that participating families were experiencing distress that required longer-term treatment for enduring results, beyond what was employed in this study. Further research is necessary before in-home BFST can be considered an effective psychosocial intervention for adolescents with poorly controlled diabetes.

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J Pediatr Psychol. 2005 Dec;30(8):656-666. Epub 2005 Mar 3.
Multisystemic Treatment of Poorly Controlled Type 1 Diabetes: Effects on Medical Resource Utilization.
Ellis DA, Naar-King S, Frey M, Templin T, Rowland M, Cakan N.
Children's Hospital of Michigan, Department of Child Psychitary and Psychology, 3901 Beaubien, Detroit, MI 48201. dellis@med.Wayne.edu.

OBJECTIVE: To determine whether multisystemic therapy (MST), an intensive, home-based psychotherapy, could decrease rates of hospital utilization and related costs of care among adolescents with poorly controlled type diabetes. METHODS: Thirty-one adolescents were randomly assigned to receive either MST or standard care. MST lasted approximately 6 months, and all participants were followed for 9 months. Rates of inpatient admissions and emergency room (ER) visits were calculated for a 9-month prestudy period and during the 9 months of study participation. The relationship between changes in inpatient admissions and changes in metabolic control was also investigated. RESULTS: Intervention participants had a decreasing number of inpatient admissions from the baseline period to the end of the study, whereas the number of inpatient admissions increased for controls. Use of the emergency room did not differ. Related medical charges and direct care costs were significantly lower for adolescents receiving MST. Correlational analyses conducted with a subset of participants indicated that decreases in inpatient admissions were associated with improved metabolic control for MST but not control participants. CONCLUSIONS: Findings suggest that MST has the potential to decrease inpatient admissions among adolescents with poorly controlled type 1 diabetes.

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Expert Opin Pharmacother. 2005 Nov;6(14):2483-2491.
The use of orlistat in the treatment of obesity, dyslipidaemia and Type 2 diabetes.
Nelson RH, Miles JM.
Endocrine Research Unit, Mayo Clinic, Rochester, MN 55905, USA. miles.john@mayo.edu.

Orlistat (tetrahydrolipstatin) is an inhibitor of gastrointestinal lipases, especially pancreatic lipase. It is used as an adjunct to diet and exercise in order to achieve weight loss in obese individuals (body mass index > 30 kg/m(2)) or in overweight individuals (body mass index > 27 kg/m(2)) with other risk factors for atherosclerotic vascular disease, such as hypertension, dyslipidaemia or diabetes. Short- and long-term studies of up to 4 years duration have shown the drug to have significant benefits in weight loss, as well as in the reduction in lipids, glucose and haemoglobin A1c, and in time to onset of Type 2 diabetes compared with diet alone or placebo groups. The incremental amount of weight loss that orlistat produces is modest, but sufficient to result in improvement in obesity comorbidities such as elevated blood pressure, dyslipidaemia and hyperglycaemia compared with diet and exercise alone. Orlistat should only be prescribed for individuals who are motivated to adhere to lifestyle modifications, especially dietary fat restriction.

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Diabetes Care. 2005 Nov;28(11):2728-32.
Effect of pitavastatin on urinary liver-type Fatty Acid-binding protein levels in patients with early diabetic nephropathy.
Nakamura T, Sugaya T, Kawagoe Y, Ueda Y, Osada S, Koide H.
Department of Medicine, Koto Hospital, 6-8-5 Ojima, Koto-ku, Tokyo 136-0072, Japan. hkoide@koto-hospital.or.jp.

OBJECTIVE: Liver-type fatty acid-binding protein (l-FABP) is expressed in renal proximal tubules and is reported to be a useful marker for progression of chronic glomerulonephritis. The aim of this study was to determine whether urinary l-FABP levels are altered at various stages of diabetic nephropathy and whether pitavastatin affects urinary l-FABP levels in early diabetic nephropathy. RESEARCH DESIGN AND METHODS: Fifty-eight patients with type 2 diabetes (34 men and 24 women, median age 52 years) and 20 healthy, age-matched subjects (group E) were recruited for the study. The diabetic patients included 12 patients without nephropathy (group A), 20 patients with microalbuminuria (group B), 14 patients with macroalbuminuria and normal renal function (group C), and 12 patients with chronic renal failure but not undergoing hemodialysis (blood creatinine >1.2 mg/dl; mean 2.5 mg/dl, group D). Twenty group B patients were randomly assigned to receive 1 mg/day pitavastatin (10 patients, group B1) or placebo (10 patients, group B2). Treatment was continued for 12 months. Urinary l-FABP levels were measured by enzyme-linked immunosorbent assay. Urinary 8-hydroxydeoxyguanosine and serum free fatty acids (FFAs) were also measured in group B. RESULTS: Urinary l-FABP levels in groups A-D were 6.2 +/- 4.6 mug/g creatinine, 19.6 +/- 13.5 mug/g creatinine, 26.8 +/- 20.4 mug/g creatinine, and 52.4 +/- 46.8 mug/g creatinine, respectively. Urinary l-FABP levels in groups B-D were significantly higher than those in healthy subjects (group E, 5.8 +/- 4.0 mug/g creatinine) (group B, P < 0.05; group C, P < 0.01; group D, P < 0.01). In group B1, urinary albumin excretion (UAE) and urinary l-FABP levels were decreased after pitavastatin treatment (UAE before, 110 +/- 74 mug/min; 6 months, 88 +/- 60 mug/min, P < 0.05; 12 months, 58 +/- 32 mug/min, P < 0.01; l-FABP before, 18.6 +/- 12.5 mug/g creatinine; 6 months, 12.2 +/- 8.8 mug/g creatinine, P < 0.05; 12 months, 8.8 +/- 6.4 mug/g creatinine, P < 0.01). In group B2, UAE and l-FABP levels showed little change during the experimental period. In group B1, urinary 8-hydroxydeoxyguanosine was decreased 12 months after pitavastatin treatment (before 32.5 +/- 19.5 ng/mg creatinine, after 18.8 +/- 14.5 ng/mg creatinine, P < 0.01), but in group B2, these showed little difference during the experimental period. In both groups B1 and B2, serum FFAs showed little difference during the experimental period. CONCLUSIONS: Urinary l-FABP levels appear to be associated with the progression of diabetic nephropathy, and pitavastatin may be effective in ameliorating tubulointerstitial damage in early diabetic nephropathy.

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Diabet Med. 2005 Nov;22(11):1465-75.
Fat food for a bad mood. Could we treat and prevent depression in Type 2 diabetes by means of omega-3 polyunsaturated fatty acids? A review of the evidence.
Pouwer F, Nijpels G, Beekman AT, Dekker JM, Dam RM, Heine RJ, Snoek FJ.
Vrije Universiteit Medical Centre, Department of Medical Psychology, EMGO Institute, Amsterdam, the Netherlands.

Abstract Aims Evidence strongly suggests that depression is a common complication of Type 2 diabetes mellitus. However, there is considerable room to improve the effectiveness of pharmacological antidepressant agents, as in only 50-60% of the depressed subjects with diabetes does pharmacotherapy lead to remission of depression. The aim of the present paper was to review whether polyunsaturated fatty acids (PUFA) of the omega-3 family could be used for the prevention and treatment of depression in Type 2 diabetes. Methods MEDLINE database and published reference lists were used to identify studies that examined the associations between omega-3 PUFA and depression. To examine potential side-effects, such as on glycaemic control, studies regarding the use of omega-3 supplements in Type 2 diabetes were also reviewed. Results Epidemiological and clinical studies suggest that a high intake of omega-3 PUFA protects against the development of depression. There is also some evidence that a low intake of omega-3 is associated with an increased risk of Type 2 diabetes, but the results are less conclusive. Results from randomized controlled trials in non-diabetic subjects with major depression show that eicosapentaenoic acid is an effective adjunct treatment of depression in diabetes, while docosahexanoic acid is not. Moreover, consumption of omega-3 PUFA reduces the risk of cardiovascular disease and may therefore indirectly decrease depression in Type 2 diabetes, via the reduction of cardiovascular complications. Conclusions Supplementation with omega-3 PUFA, in particular eicosapentaenoic acid, may be a safe and helpful tool to reduce the incidence of depression and to treat depression in Type 2 diabetes. Further studies are now justified to test these hypotheses in patients with Type 2 diabetes. Diabet. Med, 22, 1465-1475 (2005).

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Diabetes Care. 2005 Nov;28(11):2697-702.
A Randomized Controlled Trial of the Effect of Real-Time Telemedicine Support on Glycemic Control in Young Adults With Type 1 Diabetes (ISRCTN 46889446).
Farmer AJ, Gibson OJ, Dudley C, Bryden K, Hayton PM, Tarassenko L, Neil A.
Address correspondence and reprint requests to Dr. Andrew J. Farmer. andrew.farmer@dphpc.ox.ac.uk.

OBJECTIVE: To determine whether a system of telemedicine support can improve glycemic control in type 1 diabetes. RESEARCH DESIGN AND METHODS: A 9-month randomized trial compared glucose self-monitoring real-time result transmission and feedback of results for the previous 24 h in the control group with real-time graphical phone-based feedback for the previous 2 weeks together with nurse-initiated support using a web-based graphical analysis of glucose self-monitoring results in the intervention group. All patients aged 18-30 years with HbA(1c) (A1C) levels of 8-11% were eligible for inclusion. RESULTS: A total of 93 patients (55 men) with mean diabetes duration (means +/- SD) 12.1 +/- 6.7 years were recruited from a young adult clinic. In total, the intervention and control groups transmitted 29,765 and 21,400 results, respectively. The corresponding median blood glucose levels were 8.9 mmol/l (interquartile range 5.4-13.5) and 10.3 mmol/l (6.5-14.4) (P < 0.0001). There was a reduction in A1C in the intervention group after 9 months from 9.2 +/- 1.1 to 8.6 +/- 1.4% (difference 0.6% [95% CI 0.3-1.0]) and a reduction in A1C in the control group from 9.3 +/- 1.5 to 8.9 +/- 1.4% (difference 0.4% [0.03-0.7]). This difference in change in A1C between groups was not statistically significant (0.2% [-0.2 to 0.7, P = 0.3). CONCLUSIONS: Real-time telemedicine transmission and feedback of information about blood glucose results with nurse support is feasible and acceptable to patients, but to significantly improve glycemic control, access to real-time decision support for medication dosing and changes in diet and exercise may be required.

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Diabetes Care. 2005 Nov;28(11):2703-9.
Laparoscopic Gastric Banding Prevents Type 2 Diabetes and Arterial Hypertension and Induces Their Remission in Morbid Obesity: A 4-year case-controlled study.
Pontiroli AE, Folli F, Paganelli M, Micheletto G, Pizzocri P, Vedani P, Luisi F, Perego L, Morabito A, Bressani Doldi S.
Universita Degli Studi di Milano, Cattedra di Medicina Interna, Ospedale San Paolo, via a di Rudini, 8, 20142 Milano, Italy. antonio.pontiroli@unimi.it.

OBJECTIVE: Lifestyle modifications and pharmacological interventions can prevent type 2 diabetes in obese subjects with impaired glucose tolerance. The aim of this study was to compare laparoscopic adjustable gastric banding (LAGB) and conventional diet (No-LAGB) in the prevention (primary intervention study; 56 vs. 29 patients) and remission (secondary intervention study; 17 vs. 20 patients) of type 2 diabetes and hypertension in grade 3 obesity in a 4-year study. RESEARCH DESIGN AND METHODS: The subjects (n = 122; age 48.5 +/- 1.05 years; BMI 45.7 +/- 0.67 kg/m(2)) underwent a diagnostic workup, including psychological and psychiatric assessments, in preparation for the LAGB procedure. Of the 122 subjects, 73 had the surgery (LAGB group). The control group (No-LAGB group) consisted of the 49 subjects who refused the surgery but agreed to be followed up; 6 of these subjects dropped out by the 2nd year of the study, so that the final number of patients was 73 and 43 in the LAGB and No-LAGB groups, respectively. All patients had a yearly visit and oral glucose tolerance test. RESULTS: From baseline to the end of the 4-year follow-up, BMI decreased from 45.9 +/- 0.89 at baseline to 37.7 +/- 0.71 kg/m(2) in the LAGB group and remained steady in the No-LAGB group (from 45.2 +/- 1.04 to 46.5 +/- 1.37 kg/m(2)), with no significant differences between the primary and secondary intervention groups. In the primary intervention study, five of the No-LAGB subjects (17.2%) and none of the LAGB subjects (0.0%; P = 0.0001) progressed to type 2 diabetes; in the secondary intervention study, type 2 diabetes remitted in one No-LAGB patient (4.0%) and seven LAGB patients (45.0%; P = 0.0052). Hypertension occurred in 11 No-LAGB patients (25.6%) and 1 LAGB patient (1.4%; P = 0.0001) and remitted in 1 No-LAGB (2.3%) and 15 LAGB patients (20.5%; P = 0.0001). A study of body mass composition revealed a significant reduction of fat mass and a transitory, but not significant, decrease of fat-free mass in LAGB patients. CONCLUSIONS: In morbid obesity, sustained and long-lasting weight loss obtained through LAGB prevents the occurrence of type 2 diabetes and hypertension and decreases the prevalence of these disorders.

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Diabetes Care. 2005 Nov;28(11):2686-90.
The effect of ruboxistaurin on nephropathy in type 2 diabetes.
Tuttle KR, Bakris GL, Toto RD, McGill JB, Hu K, Anderson PW.
Research Department, 122 W. 7th Ave., Suite 230, Spokane, WA 99204-2340. ktuttle@this.org.

OBJECTIVE: Ruboxistaurin selectively inhibits protein kinase C-beta and ameliorates kidney disease in animal models of diabetes. The purpose of this study was to evaluate the effects of ruboxistaurin on diabetic nephropathy in humans. RESEARCH DESIGN AND METHODS: A randomized, double-blind, placebo-controlled, multicenter, pilot study was performed to evaluate the effects of 32 mg/day ruboxistaurin for 1 year in persons (n = 123) with type 2 diabetes and persistent albuminuria (albumin-to-creatinine ratio [ACR] 200-2,000 mg/g), despite therapy with renin-angiotensin system inhibitors. The primary end point was a change in the ACR. Estimated glomerular filtration rate (eGFR) (four-component equation from the Modification of Diet in Renal Disease study) was also calculated. RESULTS: At baseline, urinary ACR was 764 +/- 427 mg/g (means +/- SD), and eGFR was 70 +/- 24 ml/min per 1.73 m(2). Systolic and diastolic blood pressures were 135 +/- 14 and 75 +/- 9 mmHg, respectively. HbA(1c) was 8.0 +/- 1.2%. After 1 year, urinary ACR decreased significantly (-24 +/- 9%) in participants treated with ruboxistaurin (P = 0.020) and nonsignificantly (-9 +/- 11%) in the placebo group (P = 0.430). The ACR-lowering effect of ruboxistaurin appeared by 1 month. eGFR did not decline significantly in the ruboxistaurin group (-2.5 +/- 1.9 ml/min per 1.73 m(2)) (P = 0.185), whereas the placebo group lost significant eGFR over 1 year (-4.8 +/- 1.8 ml/min per 1.73 m(2)) (P = 0.009). Between-group differences for changes in ACR and eGFR were not statistically significant, but this pilot study was underpowered to determine such differences. CONCLUSIONS: In persons with type 2 diabetes and nephropathy, treatment with ruboxistaurin reduced albuminuria and maintained eGFR over 1 year. Ruboxistaurin may add benefit to established therapies for diabetic nephropathy.

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J Lipid Res. 2005 Oct 28; [Epub ahead of print]
The effect of high dose simvastatin on triglyceride rich lipoprotein metabolism in patients with type 2 diabetes mellitus.
Isley WL, Miles JM, Patterson BW, Harris WS.

Statins decrease triglycerides in addition to lowering low-density lipoprotein cholesterol. While the mechanism for the latter effect is well understood, it is still unclear how triglyceride lowering is achieved with statin therapy. Since hypertriglyceridemia is common in obese patients with type 2 diabetes mellitus, we studied triglyceride rich lipoprotein triglyceride (TRL-TG) turnover in twelve such subjects using stable isotopically-labeled glycerol. The diabetic subjects were studied after twelve weeks of placebo and after a similar course of therapy with simvastatin 80 mg daily in a single blind design. The results were compared to those from six non-obese non-diabetic control subjects. Simvastatin therapy reduced serum triglycerides by 35% in the diabetic subjects. Compared to the control subjects, TRL-TG secretion was almost two-fold higher in the diabetic subjects (45.4{plusmn}4.9 vs 24.4{plusmn}1.9 mumol/min, p<0.002), and was unaffected by simvastatin therapy. However, TRL-TG clearance was significantly increased in the diabetic subjects during simvastatin treatment compared to placebo (0.25{plusmn}0.03 vs 0.16{plusmn}0.02 pools/hr, p<0.002). This change was accompanied by a 49% increase in pre-heparin plasma lipase activity (p<0.03) and a 21% increase in post-heparin lipoprotein lipase (LPL) activity (p<0.01). Taken together, these findings provide strong evidence that the effect of statins on serum triglycerides is related to an increase in LPL activity, resulting in accelerated delipidation of TRL particles.

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J Am Soc Nephrol. 2005 Oct 26; [Epub ahead of print]
Effect of Pravastatin in People with Diabetes and Chronic Kidney Disease.
Tonelli M, Keech A, Shepherd J, Sacks F, Tonkin A, Packard C, Pfeffer M, Simes J, Isles C, Furberg C, West M, Craven T, Curhan G.
Divisions of *Nephrology and Critical Care Medicine, University of Alberta, Edmonton, Alberta, Canada; Institute of Health Economics, Edmonton, Alberta, Canada; NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia; ||University of Glasgow, Glasgow, Scotland, United Kingdom; Departments of paragraph signNutrition and paragraph sign paragraph signEpidemiology, Harvard School of Public Health, Boston, Massachusetts; #Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia; *Department of Pathological Biochemistry, Glasgow Royal Infirmary, Glasgow, Scotland, United Kingdom; Cardiovascular Division and ##Renal Division and Channing Laboratory, Brigham and Women's Hospital, Boston, Massachusetts; Department of Medicine, Dumfries and Galloway Royal Infirmary, Dumfries, Scotland, United Kingdom; and Wake Forest University School of Medicine, Winston-Salem, North Carolina; ||||Department of Medicine, University of Queensland, Brisbane, Australia.

Although diabetes is a major cause of chronic kidney disease (CKD), limited data describe the cardiovascular benefit of hydroxymethyl glutaryl CoA reductase inhibitors (statins) in people with both of these conditions. This study sought to determine whether pravastatin reduced the incidence of first or recurrent cardiovascular events in people with non-dialysis-dependent CKD and concomitant diabetes, using data from three randomized trials of pravastatin 40 mg daily versus placebo. CKD was defined by estimated GFR <60 or 60 to 89.9 ml/min per 1.73 m(2) with proteinuria. Of 19,737 patients, 4099 (20.8%) had CKD but not diabetes at baseline, 873 (4.4%) had diabetes but not CKD, and 571 (2.9%) had both conditions. The primary composite outcome was time to myocardial infarction, coronary death, or percutaneous/surgical coronary revascularization. Median follow-up was 64 mo. After adjustment for trial and random treatment assignment, the incidence of the primary outcome was lowest in individuals with neither CKD nor diabetes (15.2%), intermediate in individuals with only CKD (18.6%) or only diabetes (21.3%), and highest in individuals with both characteristics (27.0%). Pravastatin reduced the relative likelihood of the primary outcome to a similar extent in subgroups defined by the presence or absence of CKD and diabetes. For example, pravastatin was associated with a significant reduction in the relative risk of the primary outcome by 25% in patients with CKD and concomitant diabetes and by 24% in individuals with neither characteristic. However, the absolute reduction in the risk of the primary outcome as a result of pravastatin use was highest in patients with both CKD and diabetes (6.4%) and lowest in individuals with neither characteristic (3.5%). In conclusion, stage 2 or early stage 3 CKD and diabetes both are associated with higher cardiovascular risk, and pravastatin reduces cardiovascular event rates in people with neither, one, or both characteristics. Given the high absolute benefit of pravastatin in patient with diabetes and stage 2 or early stage 3 CKD, this population in particular should be targeted for widespread use of statins. Additional studies are needed to determine whether these benefits apply to patients with more severe CKD, and recruitment to such studies should be given high priority.

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Curr Pharm Biotechnol. 2005 Oct;6(5):387-95.
Advanced approaches in insulin delivery.
Shaikh IM, Jadhav KR, Ganga S, Kadam VJ, Pisal SS.
Department of Pharmaceutics, Bharati Vidyapeeth's College of Pharmacy, CBD Belapur, Sector-8, Navi- Mumbai-400614, India. shaikhpeer@rediffmail.com.

Diabetes is a syndrome of disordered metabolism and inappropriate hyperglycemia resulting from a deficiency of insulin secretion or insulin resistance. Insulin, a pancreatic hormone, helps to lower the blood sugar levels. The structural features of insulin and insulin receptors are summarized. Diabetic patients use insulin in the form of injections, which involves lots of pain, and a need for non-invasive, alternative mode of insulin administration is desired. These challenges have lead to attempts in insulin therapy using oral, nasal, pulmonary, rectal, transdermal, buccal, gene therapy, islet cell transplantation and diabetes vaccine. Among all the approaches pulmonary administration has achieved some clinical significance. Future approaches that can be exploited for insulin therapy in Insulin Dependent Diabetes Mellitus [IDDM] have been summarized. Insulin inhalers or tablets for IDDM are interesting alternatives.

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Cochrane Database Syst Rev. 2005 Jul 20;(3):CD002966.
Metformin monotherapy for type 2 diabetes mellitus.
Saenz A, Fernandez-Esteban I, Mataix A, Ausejo M, Roque M, Moher D.
Centro de Salud Pozuelo 1, INSALUD - Madrid, Emisora s/n, Pozuelo de Alarcon, Madrid, SPAIN, 28224.

BACKGROUND: Metformin is an anti-hyperglycaemic agent used for the treatment of type 2 diabetes mellitus. Type 2 diabetes may present long-term complications: micro- (retinopathy, nephropathy and neuropathy) and macrovascular (stroke, myocardial infarction and peripheral vascular disease). Two meta-analyses have been published before, although only secondary outcomes were assessed. OBJECTIVES: To assess the effects of metformin monotherapy on mortality, morbidity, quality of life, glycaemic control, body weight, lipid levels, blood pressure, insulinaemia, and albuminuria in patients with type 2 diabetes mellitus. SEARCH STRATEGY: Studies were obtained from computerised searches of multiple electronic databases and hand searches of reference lists of relevant trials identified. Date of last search: September 2003. SELECTION CRITERIA: Trials fulfilling the following inclusion criteria: Diabetes mellitus type 2, metformin versus any other oral intervention, assessment of relevant clinical outcome measures, use of random allocation. DATA COLLECTION AND ANALYSIS: Two reviewers extracted data, using a standard data extraction form. Data were summarised under a random effects model. Dichotomous data were expressed as relative risk. We calculated the risk difference (RD), and the Number Needed to Treat, when it was possible. We collected data of mean and standard deviation from changes to baseline. However many trials reported end point data. This limitation lead to the expression of the results as standardised mean differences (SMD) and an overall SMD was calculated. Heterogeneity was tested for using the Z score and the I-squared statistic. Subgroup, sensitivity analysis and meta-regression were used to explore heterogeneity. MAIN RESULTS: We included for analysis 29 trials with 37 arms (5259 participants), comparing metformin (37 arms and 2007 participants) with sulphonylureas (13 and 1167), placebo (12 and 702), diet (three and 493), thiazolidinediones (three and 132), insulin (two and 439), meglitinides (two and 208), and glucosidase inhibitors (two and 111). Nine studies reported data on primary outcomes. Obese patients allocated to intensive blood glucose control with metformin showed a greater benefit than chlorpropamide, glibenclamide, or insulin for any diabetes-related outcomes (P = 0.009), and for all-cause mortality (P = 0.03). Obese participants assigned to intensive blood glucose control with metformin showed a greater benefit than overweight patients on conventional treatment for any diabetes-related outcomes (P = 0.004), diabetes-related death (P = 0.03), all-cause mortality (P = 0.01), and myocardial infarction (P = 0.02). Patients assigned to metformin monotherapy showed a significant benefit for glycaemia control, weight, dyslipidaemia, and diastolic blood pressure. Metformin presents a strong benefit for HbA1c when compared with placebo and diet; and a moderated benefit for: glycaemia control, LDL cholesterol, and BMI or weight when compared with sulphonylureas. AUTHORS' CONCLUSIONS: Metformin may be the first therapeutic option in the diabetes mellitus type 2 with overweight or obesity, as it may prevent some vascular complications, and mortality. Metformin produces beneficial changes in glycaemia control, and moderated in weight, lipids, insulinaemia and diastolic blood pressure. Sulphonylureas, alpha-glucosidase inhibitors, thiazolidinediones, meglitinides, insulin, and diet fail to show more benefit for glycaemia control, body weight, or lipids, than metformin.

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N Engl J Med. 2005 Jul 21;353(3):238-48.
Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis.
Wanner C, Krane V, Marz W, Olschewski M, Mann JF, Ruf G, Ritz E; German Diabetes and Dialysis Study Investigators.
Division of Nephrology, Department of Medicine, University of Wurzburg, Wurzburg, Germany. wanner_c@medizin.uni-wuerzburg.de

BACKGROUND: Statins reduce the incidence of cardiovascular events in persons with type 2 diabetes mellitus. However, the benefit of statins in such patients receiving hemodialysis, who are at high risk for cardiovascular disease and death, has not been examined. METHODS: We conducted a multicenter, randomized, double-blind, prospective study of 1255 subjects with type 2 diabetes mellitus receiving maintenance hemodialysis who were randomly assigned to receive 20 mg of atorvastatin per day or matching placebo. The primary end point was a composite of death from cardiac causes, nonfatal myocardial infarction, and stroke. Secondary end points included death from all causes and all cardiac and cerebrovascular events combined. RESULTS: After four weeks of treatment, the median level of low-density lipoprotein cholesterol was reduced by 42 percent among patients receiving atorvastatin, and among those receiving placebo it was reduced by 1.3 percent. During a median follow-up period of four years, 469 patients (37 percent) reached the primary end point, of whom 226 were assigned to atorvastatin and 243 to placebo (relative risk, 0.92; 95 percent confidence interval, 0.77 to 1.10; P=0.37). Atorvastatin had no significant effect on the individual components of the primary end point, except that the relative risk of fatal stroke among those receiving the drug was 2.03 (95 percent confidence interval, 1.05 to 3.93; P=0.04). Atorvastatin reduced the rate of all cardiac events combined (relative risk, 0.82; 95 percent confidence interval, 0.68 to 0.99; P=0.03, nominally significant) but not all cerebrovascular events combined (relative risk, 1.12; 95 percent confidence interval, 0.81 to 1.55; P=0.49) or total mortality (relative risk, 0.93; 95 percent confidence interval, 0.79 to 1.08; P=0.33). CONCLUSIONS: Atorvastatin had no statistically significant effect on the composite primary end point of cardiovascular death, nonfatal myocardial infarction, and stroke in patients with diabetes receiving hemodialysis.

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Ther Umsch. 2005 Jul;62(7):481-6.
[Islet transplantation in type I diabetes mellitus]
[Article in German]
Lehmann R, Pavlicek V, Spinas GA, Weber M.
Abteilung Endokrinologie und Diabetologie, Departement fur Innere Medizin Universitatsspital Zurich, Zurich. Roger.Lehmann@usz.ch

Type 1 diabetes mellitus results from autoimmune destruction of the insulin-secreting cells in the pancreas. The dramatic breakthrough in 2000 with the "Edmonton protocol" for successful solitary islet transplantation has restored optimism for the application of islet transplantation as a treatment for type I diabetes. Due to the recent successes, islet transplantation has evolved from a theoretical concept to its current status as a therapeutic option for patients with type 1 diabetes. Islet transplantation has shown to normalize metabolic control in a way that has been virtually impossible to achieve with exogenous insulin. The less invasive procedure of islet transplantation as compared to whole pancreas transplantation in patients with type 1 diabetes mellitus would be expected to be safer and much less costly. However, this procedure also requires lifetime immunosuppression with drugs. The limited availability of donor organs and the necessity of transplantation of several pancreata in order to achieve insulin independence limit this procedure to a small minority of patients. Unlike the North American centers, the European centers concentrated their efforts on islet after kidney and simultaneous islet kidney transplantation. The two Swiss islet transplantation programs have been pioneers in applying the steroid-free "Edmonton protocol" to simultaneous islet-kidney and islet after kidney transplantation. The long term follow-up showed that islet function decreases over time. In order to maintain insulin independence repeated islet transplants would have to be given to the patients. Therefore, there has been a change in paradigm over time. The major goal of islet transplantation focuses now on achieving a good blood glucose control and avoidance of severe hypoglycaemic episodes rather than only insulin-independence. Thus, due to the limited supply of donor organs, more patients can benefit from islet transplantation. Small insulin doses of exogenous insulin prevent stress on the islet in particular after meals and might help to maintain the transplanted islet mass over time. Due to the severe limitations of immunosuppression solitary islet transplantation is limited to a very small number of patients with type 1 diabetes. The most common indication for islet transplantation in Switzerland is terminal kidney failure in patients with type I diabetes. A simultaneous islet-kidney or pancreas-kidney transplantation should be offered to these patients. The choice between islet or pancreas transplantation is a matter of age and diabetic complications because the perioperative risk is considerably higher in pancreas transplantation.

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Treat Endocrinol. 2005;4(4):205-20.
Thiazolidinediones and insulin: rationale for use and role of combination therapy in type 2 diabetes mellitus.
Huang A, Raskin P.
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8858, USA.

The range of therapeutic modalities to treat type 2 diabetes mellitus has broadened in recent years. Biguanides and thiazolidinediones are the two currently available classes of anti-hyperglycemic agents with insulin-sensitizing properties. Thiazolidinediones, in particular, have received much attention, not only for the well documented hepatotoxicity of troglitazone that led to its removal from the market in 2000, but also for the emerging data that support the beneficial effects of the thiazolidinedione class of drugs on beta-cell rejuvenation and cardiovascular risk reduction. In the US, thiazolidinediones are indicated either as monotherapy or in combination with a sulfonylurea, metformin, or insulin in cases where diet, exercise, and a single drug fail. In contrast, the UK National Institute for Clinical Excellence included in its re-appraisal of 'glitazones' in August 2003 the continued exclusion from licensed use in the UK of combination therapy with thiazolidinediones and insulin. When added to insulin therapy, thiazolidinediones appear to effectively lower glucose levels and reduce insulin dosage in clinical trials involving individuals with poorly controlled type 2 diabetes. However, weight gain, hypoglycemia, and fluid retention pose problems in certain patients. The fluid retention may exacerbate or even precipitate congestive heart failure, which usually necessitates discontinuation of the drug. Risk stratification and careful management of patients at risk for heart failure, including those taking insulin concomitantly, allow healthcare providers to safely administer combination therapy with thiazolidinediones in patients with type 2 diabetes. Hepatic toxicity with currently available thiazolidinediones has been found to be minimal overall.

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Clin Nephrol. 2005 Jul;64(1):1-11.
Effect of soy protein-rich diet on renal function in young adults with insulin-dependent diabetes mellitus.
Stephenson TJ, Setchell KD, Kendall CW, Jenkins DJ, Anderson JW, Fanti P.
Division of Nutritional Science, College of Agriculture, University of Kentucky, USA.

BACKGROUND: Diabetic nephropathy is the most frequent cause of end-stage renal disease in the Western world. Dietary intake, including protein amount and type, seems to affect the progression of renal disease. This pilot study tested the hypothesis that substituting soy protein for animal protein in the diets of diabetics would help correct glomerular hyperfiltration. METHODS: Twelve young adults (aged 29.9 +/- 2.4 years) with type 1 diabetes mellitus (duration of diabetes 15.1 +/- 2.3 years) and hyperfiltration (glomerular filtration rate, GFR > 120 ml/min/1.73 m2) completed a crossover, dietary intervention trial. After a four-week assessment of baseline characteristics and dietary habits, subjects were assigned to either a control or soy diet for eight weeks after which each subject was crossed over to the alternative diet for another eight-week period. RESULTS: Mean GFR was significantly reduced (p < 0.02) after eight weeks on the soy diet (143 +/- 7.4 ml/min/1.73 m2) compared with baseline (159 +/- 7.7 ml/min/ 1.73 m2) and control diets (161 +/- 10.0 ml/min/1.73 m2). Urinary excretion of the soy isoflavones was significantly higher (p < 0.01) at the end of the soy diet (genistein 1,014.6 +/- 274.1 nmol/h, daidzein 2,645.1 +/- 989.6 nmol/h) compared with baseline (genistein 53.7 +/- 31.1 nmol/h, daidzein 151.1 +/- 74.1 nmol/h) and control diets (genistein 41.1 +/- 13.3 nmol/h, daidzein 127.5 +/- 54.0 nmol/h). The soy diet significantly reduced total and LDL cholesterol by 7% and 9%, respectively. CONCLUSIONS: Implementation of a soy-based diet appears to reduce the GFR and total and LDL cholesterol of young adults with type 1 diabetes and glomerular hyperfiltration, thus affecting positively their clinical profile.

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Nephrol Dial Transplant. 2005 Jul 26; [Epub ahead of print]
Effects of smoking on renal function in patients with type 1 and type 2 diabetes mellitus.
Orth SR, Schroeder T, Ritz E, Ferrari P.
Klinik und Poliklinik fur Innere Medizin II - Nephrologie, University of Regensburg, Regensburg, Germany.

BACKGROUND: Smoking increases the risk of end-stage renal failure in patients with primary renal disease. Whether and to what extent smoking affects the kidneys in diabetic patients with normal renal function and variable degrees of proteinuria has not been fully studied. METHODS: We followed 185 patients with type 1 or 2 diabetes mellitus and with or without signs of overt renal disease for at least 3 years, median 5.1 (3-6.8) years. Each patient had a baseline visit and at least four follow-up visits (average 4.8+/-0.3). Cases were patients who were smoking (n = 44) at the time the survey was started. Controls were patients who had never smoked (n = 141). Glomerular filtration rate (GFR) was estimated using the MDRD formula. Multiple logistic regression was used to correct for confounding factors. RESULTS: At baseline, smokers were younger (47+/-14 vs 54+/-16 years, P<0.01), and had a lower GFR (95+/-26 ml/min) than non-smokers (107+/-33 ml/min, P<0.05). Mean GFR remained constant during follow-up in non-smokers (106+/-31 ml/min), but decreased significantly in smokers (83+/-22 ml/min, P<0.0001), and this relationship persisted when adjusted for retinopathy, glycaemic control, age, body habitus, ACE-inhibitor treatment, blood pressure control or severity of proteinuria. The effect of smoking on GFR decline was stronger in patients with type 1 diabetes or male gender. CONCLUSIONS: Cigarette smoking causes a decrease in GFR in diabetic patients with normal or near-normal renal function, independent of confounding factors including severity of proteinuria. The latter finding suggests a mechanism independent of glomerular damage.

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Am Fam Physician. 2005 Jul 1;72(1):96-9.
Diabetic nephropathy: common questions.
Thorp ML.
Lake Road Nephrology Clinic, Milwaukie, Oregon 97267, USA. micahthorp@comcast.net

Diabetic nephropathy, or diabetic kidney disease, affects 20 to 30 percent of patients with diabetes. It is a common cause of kidney failure. Diabetic nephropathy presents in its earliest stage with low levels of albumin (microalbuminuria) in the urine. The most practical method of screening for microalbuminuria is to assess the albumin-to-creatinine ratio with a spot urine test. Results of two of three tests for microalbuminuria should be more than 30 mg per day or 20 mcg per minute in a three- to six-month period to diagnose a patient with diabetic nephropathy. Slowing the progression of diabetic nephropathy can be achieved by optimizing blood pressure (130/80 mm Hg or less) and glycemic control, and by prescribing an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Patients with diabetes and isolated microalbuminuria or hypertension benefit from angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. In the event that these medications cannot be prescribed, a nondihydropyridine calcium channel blocker may be considered. Serum creatinine and potassium levels should be monitored carefully for patients receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. These medications should be stopped if hyperkalemia is pronounced.

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Rev Med Liege. 2005 May-Jun;60(5-6):433-8.
[The care of the older person with diabetes mellitus]
[Article in French]
Smitz S.
Departement de Medecine Interne generale, Universite et CHU de Liege.

The care of the older adult with diabetes mellitus should be individualized, taking into consideration the patient's functional status and coexistent illnesses, as well as his or her preferences and life expectancy. The overall goal of care is to improve both the clinical status and the quality of life. Components of care are education, glycaemic control, cardiovascular risk factor management, eye and foot care and management of nephropathy and geriatric syndromes. A team approach is recommended. Glycaemic control and cardiovascular risk factor modification can reduce the risk of complications and improve the quality of life. However, the risk of severe or fatal hypoglycaemia associated with the use of anti-hyperglycaemic drugs increases with age and comorbidity. Targets for glycaemic control and HbA1c should be realistic, dynamic and tailored to the characteristics of each individual patient. Since cardiovascular complications are the main cause of morbidity and mortality, managing cardiovascular risk factors is mandatory. Hypertension should be treated gradually. The therapeutic approach comprises lifestyle modifications and anti-hyperglycaemic drugs. Older persons should be evaluated regularly to assess and review the medication being used. An appropriate physical activity, especially walking can forestall functional decline and decrease all-causes and cardiovascular mortality. Identifying and managing such geriatric syndromes as dehydration, cognitive dysfunction and depression may improve the quality of life.

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Rev Med Liege. 2005 May-Jun;60(5-6):374-82.
[Obesity and type 2 diabetes]
[Article in French]
Rorive M, Letiexhe MR, Scheen AJ, Ziegler O.
Universite de Liege, Centre de l'Obesite, CHU Ourthe-Ambleve, Esneux et Service de Diabetologie, Nutrition et Maladies metaboliques, CHU Sart Tilman, Liege.

Obesity is an epidemic disease associated with numerous cardiovascular risk factors as diabetes mellitus, dyslipidemia, hypertension. Insulin resistance seems to be an important promoter for the development of most of these abnormalities. Besides genetic background, obesity, especially abdominal adiposity, is by far the most important factor for the development of type 2 diabetes. The treatment of a diabetic obese subject begins with diet and regular physical activity, eventually with a psychological support. In case of failure of such lifestyle approach alone, addition of drug therapy should be considered. It may include pharmacological agents able to promote weight loss (orlistat, sibutramine, possibly rimonabant) and/or antihyperglycaemic compounds capable of reducing insulin resistance (metformin, glitazones, acarbose). In case of severe/morbid obesity complicated with type 2 diabetes not well controlled with medical means, bariatric surgery is the only treatment that can induce an important and sustained weight loss, associated with marked improvement of metabolic control and amelioration of overall prognosis.

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Rev Med Liege. 2005 May-Jun;60(5-6):329-34.
[Continuous subcutaneous insulin infusion with portable pumps]
[Article in French]
Radermecker RP, Hermans MP, Legrand DA, Scheen AJ.
Universite de Liege, Service de Diabetologie, Nutrition et Maladies metaboliques, Departement de Medecine, CHU Sart Tilman. Regis.Radermecker@ulg.ac.be

Type I diabetes mellitus requires an exogenous supply of insulin that ideally mimics physiological insulin secretion. The treatment goal is to achieve normoglycaemia in order to prevent or delay chronic complications, while limiting the risk of hypoglycaemia. Numerous advances have been performed in the last 10 years, as far as nature of insulin formulations, home blood glucose monitoring devices and modes of insulin delivery. Among the latter, continuous subcutaneous insulin infusion (CSII) using portable pumps represents the most sophisticated treatment capable of best mimicking normal insulin secretion. Such treatment provides better glucose control and glucose stability as compared to conventional multiple injection insulin therapy. However, it is essential to respect well defined indications and to organize a structured management by a multidisciplinary team in order to get the best metabolic results. The present paper describes recommendations, advantages and limits as well as cost of CSII with portable pumps in type 1 diabetic patients.

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Ann Pharmacother. 2005 May;39(5):843-53. Epub 2005 Apr 12.
Inhaled insulin: exubera.
Odegard PS, Capoccia KL.
School of Pharmacy, University of Washington, Seattle, WA; Clinical Specialist and Diabetes Educator, Evergreen Community Health Care, Seattle.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of Exubera, a novel, dry-powder formulation of insulin for inhalation, and describe patient satisfaction and quality-of-life data. DATA SOURCES: A MEDLINE search (1966-November 2004) was conducted using the key words inhaled insulin and Exubera for clinical trials limited to human research published in English. BIOSIS Previews and the American Diabetes Association Scientific Abstracts were used for published abstract information. STUDY SELECTION AND DATA EXTRACTION: All available human studies of Exubera were selected for review. References of identified articles were used for additional citations. DATA SYNTHESIS: Exubera is a rapid-acting insulin administered by oral inhalation before meals with long-acting insulin administered subcutaneously once or twice daily for type 1 or 2 diabetes mellitus. Exubera provides similar efficacy and improved patient satisfaction compared with standard subcutaneous insulin therapy (ie, NPH twice daily with regular insulin before meals). Efficacy has also been demonstrated for Exubera when used as adjunctive therapy with oral medications for type 2 diabetes. The onset of Exubera is more rapid and its duration of action is similar to that of regular insulin. To date, Exubera administered before meals with a once-daily long-acting subcutaneous insulin (usually Ultralente) has been compared with standard subcutaneous NPH/regular insulin regimens. Comparison of premeal Exubera plus a basal long-acting insulin analog (eg, glargine) with a regimen of premeal subcutaneous rapid-acting insulin analog (eg, lispro or aspart) plus a basal long-acting insulin analog (eg, glargine) is needed to fully evaluate Exubera. Pulmonary safety appears to be maintained for up to 4 years, although there are no data, as of this writing, on the use of this agent in patients with pulmonary conditions. CONCLUSIONS: Exubera is an effective inhaled insulin for preprandial use in type 1 or 2 diabetes. Improved patient satisfaction over injected insulin increases its potential for use earlier in the treatment of type 2 diabetes.

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Am J Med. 2005 May;118 Suppl 5:14-20.
Making the transition from oral to insulin therapy.
Riddle MC.
Section of Diabetes, Division of Endocrinology, Diabetes, and Clinical Nutrition, Oregon Health & Science University, Portland, Oregon, USA.

The typically long delay in starting insulin for patients with type 2 diabetes mellitus may be due in part to uncertainty about how best to make the transition from oral therapy to insulin. Recent studies show that when appropriate glycemic targets are sought, with systematic titration of insulin dosage, several methods of beginning insulin may be successful. Notably, either starting with a single injection of basal insulin or starting with 3 injections of short-acting insulin at mealtimes can be effective. Studies also suggest that continuing oral therapies and using insulin analogues rather than human insulins may improve the effectiveness of insulin treatment relative to the rate of hypoglycemia and gain of weight typically seen in this setting. Starting with a single injection of insulin to control basal glycemia while continuing oral therapy is the simplest approach, and lends itself to stepwise addition of mealtime injections as needed to bring most patients to glycemic targets in a logical and practical way. Future studies should consider not only the ability of regimens to reach hemoglobin A(1c) targets but also the burden of adverse effects accompanying this effort with a given method.

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Am J Med. 2005 May;118 Suppl 5:4-13.
How to select and combine oral agents for patients with type 2 diabetes mellitus.
Chipkin SR.
Department of Exercise Science, School of Public Health and Health Sciences, University of Massachusetts, Amherst, Massachusetts, USA.

The increased number of oral agents available to treat patients with type 2 diabetes mellitus (DM) has presented clinicians with choices about how to combine them when monotherapy is not adequate to achieve glycemic targets. Initial studies focused on whether a combination of 2 active drugs was better than a single active agent plus placebo. Several factors need to be considered before results of combination regimens from a given protocol can be compared with results from a different study regimen. Some of these factors include population characteristics, baseline control and prior therapies, length of study, and outcomes (glycemic and nonglycemic). Additional factors to be considered are costs and side effects. These studies generally demonstrate that combination therapy is more likely than monotherapy to achieve glucose control in patients not at glycemic targets. The data also demonstrate that inadequate glucose control with a given medication does not necessarily indicate drug failure; indeed, adding a new agent to an existing regimen is typically better than using the new agent as monotherapy. More recent studies have begun to compare regimens each containing 2 drugs (usually with 1 medication in common). Outcomes beyond glycemic control have been measured, including traditional (e.g., lipid profiles, albuminuria) and nontraditional (e.g., high-sensitivity C-reactive protein, plasminogen activator inhibitor type-1) markers. However, modifying traditional markers with these medications has not yet been shown to improve outcomes; modifying nontraditional markers is even less certain. None of these trials have been extended long enough to report on hard clinical end points. Nonetheless, certain combinations may end up being preferable because they have better impact on nonglycemic end points while maintaining equivalent degrees of glucose control. Finally, the costs of multiple medications for DM need to be weighed in the decision-making process faced by clinicians.

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Cochrane Database Syst Rev. 2005 Apr 18;(2):CD003639.
Alpha-glucosidase inhibitors for type 2 diabetes mellitus.
Van de Laar F, Lucassen P, Akkermans R, Van de Lisdonk E, Rutten G, Van Weel C.
Department of General Practice and Family Medicine, 229 HAG, University Medical Centre Nijmegen, P.O. Box 9101, Nijmegen, NETHERLANDS, 6500 HB.

BACKGROUND: Alpha-glucosidase inhibitors such as acarbose or miglitol, have the potential to improve glycemic control in type 2 diabetes mellitus. The true value of these agents, especially in relation to diabetes related mortality and morbidity, has never been investigated in a systematic literature review and meta-analysis. OBJECTIVES: To assess the effects of alpha-glucosidase inhibitors s in patients with type 2 diabetes mellitus. SEARCH STRATEGY: We searched The Cochrane Library, MEDLINE, EMBASE, Current Contents, LILACS, databases of ongoing trials, reference lists of reviews on the topic of alpha-glucosidase inhibitors and we contacted experts and manufacturers for additional trials. Date of most recent search: December 2003 (Current Contents) and April 2003 (other databases). SELECTION CRITERIA: Randomised controlled trials of at least 12 weeks duration comparing alpha-glucosidase inhibitor monotherapy in patients with type 2 diabetes with any other intervention and that included at least one of the following outcomes: mortality, morbidity, quality of life, glycemic control, lipids, insulin levels, body weight, adverse events. DATA COLLECTION AND ANALYSIS: Two reviewers read all abstracts, assessed quality and extracted data independently. Discrepancies were resolved by consensus or by the judgement of a third reviewer. A statistician checked all extracted data entrance in the database. We attempted to contact all authors for data clarification. MAIN RESULTS: We included 41 trials (8130 participants), 30 investigated acarbose, seven miglitol, one trial voglibose and three trials compared different alpha-glucosidase inhibitors. Study duration was 24 weeks in most cases and only two studies lasted amply longer than one year. We found only few data on mortality, morbidity and quality of life. Acarbose had a clear effect on glycemic control compared to placebo: glycated haemoglobin -0.8% (95% confidence interval -0.9 to -0.7), fasting blood glucose -1.1 mmol/L (95% confidence interval -1.4 to -0.9), post-load blood glucose -2.3 mmol/L (95% confidence interval -2.7 to -1.9). The effect on glycated haemoglobin by acarbose was not dose-dependent. We found a decreasing effect on post-load insulin and no clinically relevant effects on lipids or body weight. Adverse effects were mostly of gastro-intestinal origin and dose dependent. Compared to sulphonylurea, acarbose decreased fasting and post-load insulin levels by -24.8 pmol/L (95% confidence interval -43.3 to -6.3) and -133.2 pmol/L (95% confidence interval -184.5 to -81.8) respectively and acarbose caused more adverse effects. AUTHORS' CONCLUSIONS: It remains unclear whether alpha-glucosidase inhibitors influence mortality or morbidity in patients with type 2 diabetes. Conversely, they have a significant effect on glycemic control and insulin levels, but no statistically significant effect on lipids and body weight. These effects are less sure when alpha-glucosidase inhibitors are used for a longer duration. Acarbose dosages higher than 50 mg TID offer no additional effect on glycated hemoglobin but more adverse effects instead. Compared to sulphonylurea, alpha-glucosidase inhibitors lower fasting and post-load insulin levels and have an inferior profile regarding glycemic control and adverse effects.

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Lancet. 2005 Apr;365(9467):1333-46.
Type 2 diabetes: principles of pathogenesis and therapy.
Stumvoll M, Goldstein BJ, van Haeften TW.
Third Medical Department, University of Leipzig, Leipzig, Germany.

Type 2 diabetes mellitus has become an epidemic, and virtually no physician is without patients who have the disease. Whereas insulin insensitivity is an early phenomenon partly related to obesity, pancreas beta-cell function declines gradually over time already before the onset of clinical hyperglycaemia. Several mechanisms have been proposed, including increased non-esterified fatty acids, inflammatory cytokines, adipokines, and mitochondrial dysfunction for insulin resistance, and glucotoxicity, lipotoxicity, and amyloid formation for beta-cell dysfunction. Moreover, the disease has a strong genetic component, but only a handful of genes have been identified so far: genes for calpain 10, potassium inward-rectifier 6.2, peroxisome proliferator-activated receptor gamma, insulin receptor substrate-1, and others. Management includes not only diet and exercise, but also combinations of anti-hyperglycaemic drug treatment with lipid-lowering, antihypertensive, and anti platelet therapy.

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Transplant Proc. 2005 Mar;37(2):1283-4.
Simultaneous Pancreas-Kidney Transplants in Type I and Type II Diabetic Patients With End-Stage Renal Disease: Similar 10-Year Outcomes.
Light JA, Barhyte DY.
Washington Hospital Center, Washington DC, USA.

INTRODUCTION: Herein we report 10- to 15-year results of simultaneous pancreas-kidney (SPK) transplants in 135 type I and type II insulin-dependent diabetes mellitus (IDDM) patients. METHODS: Diabetes type was defined by the absence (type I) or presence (type II) of C-peptide. The freedom from dialysis and need for insulin defined graft survival. Patient survival was verified by record review and the Social Security Death Registry. The mean follow-up exceeded 100 months. RESULTS: Type II IDDM present in 28% of the 135 cohort, predominately among African-Americans (AA). The type II group was two-thirds AA (43% of the total AA patients) and 17% of the non-African-American (nAA) group. The difference between the two groups by C-peptide level was significant (P = .001). Type II patients had a higher body mass index, were slightly older at the onset of DM, but had similar duration of IDDM before ESRD. At 5 and 10 years, pancreas survival for type 1 DM was 71% and 49%; for type II DM it was 67% and 56% (P = .52). Kidney survival for type I DM was 77% and 50%; for type II it was 72% and 56% (P = .65). Patient survival for type I DM was 85% and 63%; for type II DM it was 73% and 70% (P = .98). CONCLUSIONS: We conclude that the outcomes of SPK transplants are equivalent regardless of diabetes type. Accordingly, the decision whether to perform pancreas transplants in diabetic recipients of kidney allografts should be based on general acceptance criteria not diabetes type.

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Transplant Proc. 2005 Mar;37(2):1001-4.
Prospective, multicenter, randomized trial to compare incidence of new-onset diabetes mellitus and glucose metabolism in patients receiving cyclosporine microemulsion versus tacrolimus after de novo kidney transplantation.
Vincenti F, Tuncer M, Castagneto M, Klinger M, Friman S, Scheuermann EH, Wiecek A, Russ GR, Martinek A, Nonnast-Daniel B.
Kidney Transplant Service, UCSF, San Francisco, California, USA.

New-onset diabetes mellitus (NODM) is associated with increased risk of graft failure and death in renal transplant recipients. Some clinical studies have indicated that NODM risk is higher with tacrolimus than cyclosporine, but no comparative trial has used American Diabetic Association (ADA)/World Health Organization (WHO) criteria for diagnosis of diabetes mellitus. The Diabetes Incidence After Renal Transplantation, Neoral C(2) Monitoring Versus Tacrolimus (DIRECT) study is a 6-month open-label, multicenter trial comparing the impact of tacrolimus and Neoral (cyclosporine microemulsion) on glucose metabolism in 700 de novo kidney transplant recipients, based on ADA/WHO criteria. Patients are randomized to tacrolimus (C(0) monitoring) or Neoral (C(2) monitoring), stratified by baseline diabetic status and ethnicity. All patients receive basiliximab, corticosteroids, and mycophenolate mofetil or enteric-coated mycophenolate acid (myfortic). Pooled interim 3-month results from a subset of 115 patients receiving either tacrolimus or Neoral showed that the primary efficacy end-point (biopsy-proven acute rejection [BPAR], graft loss or death) occurred in 11 patients (10%). There were four graft losses and only one death, which occurred after graft loss. Eight patients experienced BPAR (7.3%). Among 99 patients who were nondiabetic at baseline, 14 developed NODM by month 3, 17 developed impaired fasting glucose or impaired glucose tolerance, and another 5 patients received hypoglycemic treatment for at least 14 consecutive days or at the month 3 visit, resulting in a 36% incidence of impaired glucose metabolism. At 3 months, median GFR (Nankivell) was 63.7 mL/min; median serum creatinine was 137 mumol/L. Full complete results are expected in December 2005.

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Transplant Proc. 2005 Mar;37(2):999-1000.
Immediate conversion from tacrolimus to cyclosporine in the treatment of posttransplantation diabetes mellitus.
Oberholzer J, Thielke J, Hatipoglu B, Testa G, Sankary HN, Benedetti E.
Division of Transplantation, University of Illinois at Chicago, Chicago, Illinois, USA.

Posttransplantation diabetes (PTDM) is a frequent complication of tacrolimus (TAC)-based immunosuppressive therapy after kidney transplantation. We investigated whether immediate conversion from TAC to Cyclosporine (CSA) could reverse or at least improve new-onset PTDM. Between February 2002 and February 2004, 28 adult kidney transplant recipients maintained on TAC were diagnosed with new-onset PTDM. Eight adult patients with new-onset PTDM were enrolled in the study and converted from TAC to CSA, the remaining 20 patients served as controls and were continued on the TAC-based immunosuppression. The conversion to CSA was performed immediately after establishing the diagnosis of PTDM at an average of 11 months posttransplantation. We did not document any episodes of acute rejection or worsening renal function after conversion. After conversion to CSA, among the 3 patients started on insulin, 1 has come completely off antidiabetic medications, whereas 1 required decreased doses of insulin, and the third has been converted to oral medications. Of the 5 patients originally on oral medications, 3 completely discontinued therapy, whereas the other 2 were well controlled on single-drug therapy at reduced doses. After a mean follow-up of 17 months, in the control group 9 of the 16 patients started on oral antidiabetics ultimately required insulin treatment and no patient could stop antidiabetic or insulin therapy. These findings indicate that conversion from TAC to CSA is a simple, safe, and efficacious way to reverse or at least improve PTDM.

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Diabetes Metab Res Rev. 2005 Jan-Feb;21(1):31-8.
Phlorizin: a review.
Ehrenkranz JR, Lewis NG, Ronald Kahn C, Roth J.
Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado, USA.

The dihydrochalcone phlorizin is a natural product and dietary constituent found in a number of fruit trees. It has been used as a pharmaceutical and tool for physiology research for over 150 years. Phlorizin's principal pharmacological action is to produce renal glycosuria and block intestinal glucose absorption through inhibition of the sodium-glucose symporters located in the proximal renal tubule and mucosa of the small intestine.This review covers the role phlorizin has played in the history of diabetes mellitus and its use as an agent to understand fundamental concepts in renal physiology as well as summarizes the physiology of cellular glucose transport and the pathophysiology of renal glycosuria. It reviews the biology and pathobiology of glucose transporters and discusses the medical botany of phlorizin and the potential effects of plant flavonoids, such as phlorizin, on human metabolism. Lastly, it describes the clinical pharmacology and toxicology of phlorizin, including investigational uses of phlorizin and phlorizin analogs in the treatment of diabetes, obesity, and stress hyperglycemia. Copyright (c) 2004 John Wiley & Sons, Ltd.

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JAMA. 2005 Jan 12;293(2):217-28.
Preventing foot ulcers in patients with diabetes.
Singh N, Armstrong DG, Lipsky BA.
Department of Medicine, Division of Endocrinology,Veterans Affairs Puget Sound Healthcare System and University of Washington School of Medicine, Seattle 98108, USA. Nalini.Singh2@med.va.gov

CONTEXT: Among persons diagnosed as having diabetes mellitus, the prevalence of foot ulcers is 4% to 10%, the annual population-based incidence is 1.0% to 4.1%, and the lifetime incidence may be as high as 25%. These ulcers frequently become infected, cause great morbidity, engender considerable financial costs, and are the usual first step to lower extremity amputation. OBJECTIVE: To systematically review the evidence on the efficacy of methods advocated for preventing diabetic foot ulcers in the primary care setting. DATA SOURCES, STUDY SELECTION, AND DATA EXTRACTION: The EBSCO, MEDLINE, and the National Guideline Clearinghouse databases were searched for articles published between January 1980 and April 2004 using database-specific keywords. Bibliographies of retrieved articles were also searched, along with the Cochrane Library and relevant Web sites. We reviewed the retrieved literature for pertinent information, paying particular attention to prospective cohort studies and randomized clinical trials. DATA SYNTHESIS: Prevention of diabetic foot ulcers begins with screening for loss of protective sensation, which is best accomplished in the primary care setting with a brief history and the Semmes-Weinstein monofilament. Specialist clinics may quantify neuropathy with biothesiometry, measure plantar foot pressure, and assess lower extremity vascular status with Doppler ultrasound and ankle-brachial blood pressure indices. These measurements, in conjunction with other findings from the history and physical examination, enable clinicians to stratify patients based on risk and to determine the type of intervention. Educating patients about proper foot care and periodic foot examinations are effective interventions to prevent ulceration. Other possibly effective clinical interventions include optimizing glycemic control, smoking cessation, intensive podiatric care, debridement of calluses, and certain types of prophylactic foot surgery. The value of various types of prescription footwear for ulcer prevention is not clear. CONCLUSIONS: Substantial evidence supports screening all patients with diabetes to identify those at risk for foot ulceration. These patients might benefit from certain prophylactic interventions, including patient education, prescription footwear, intensive podiatric care, and evaluation for surgical interventions.

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Diabetes Obes Metab. 2005 Jan;7(1):88-97.
Efficacy and safety of ezetimibe co-administered with simvastatin in thiazolidinedione-treated type 2 diabetic patients.
Gaudiani LM, Lewin A, Meneghini L, Perevozskaya I, Plotkin D, Mitchel Y, Shah S.
Marin Endocrine Associates, Greenbrae, CA, USA.

Aim: In patients with type 2 diabetes mellitus (T2DM), combination therapy is usually required to optimize glucose metabolism as well as to help patients achieve aggressive targets for low-density lipoprotein cholesterol (LDL-C) and other lipid parameters associated with cardiovascular risk. The thiazolidinediones (TZDs) are increasingly being used for both their blood glucose-lowering properties and their modest beneficial effects on triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C). Ezetimibe, an intestinal cholesterol absorption inhibitor, has a mechanism of action that differs from that of statins, which inhibit hepatic cholesterol synthesis. We compared the lipid-modifying efficacy and safety of adding ezetimibe to simvastatin, vs. doubling the dose of simvastatin, in TZD-treated T2DM patients. Methods: This was a randomized, double-blind, parallel group, multicentre study in T2DM patients, 30-75 years of age, who had been on a stable dose of a TZD for at least 3 months and had LDL-C > 2.6 mmol/l (100 mg/dl) prior to study entry. Other antidiabetic medications were also allowed. Following 6 weeks of open-label simvastatin 20 mg/day, patients were randomized to the addition of either blinded ezetimibe 10 mg/day (n = 104) or an additional blinded simvastatin 20 mg/day (total simvastatin 40 mg/day; n = 110) for 24 weeks. Patients were stratified according to TZD type and dose (pioglitazone 15-30 vs. 45 mg/day; rosiglitazone 2-4 vs. 8 mg/day). Results: LDL-C was reduced more (p < 0.001) by adding ezetimibe 10 mg to simvastatin 20 mg (-20.8%) than by doubling the dose of simvastatin to 40 mg (-0.3%). Ezetimibe plus simvastatin 20 mg also produced significant incremental reductions in non-HDL-C (p < 0.001), very low-density lipoprotein cholesterol (p < 0.05) and apolipoprotein B (p < 0.001) relative to simvastatin 40 mg. There were no differences between the groups with respect to changes in TG and HDL-C levels, and both treatments were well tolerated. Conclusions: Co-administration of ezetimibe with simvastatin, a dual inhibition treatment strategy targeting both cholesterol synthesis and absorption, is well tolerated and provides greater LDL-C-lowering efficacy than increasing the dose of simvastatin in T2DM patients taking TZDs.

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Clin Calcium. 2005 Jan;15(1):49-57.
[Therapeutic potential of vanadium in treating diabetes mellitus.]
[Article in Japanese]
Sakurai H.
Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University.

The patients suffered from diabetes mellitus (DM) are increasing year by year through the world. DM is classified into two groups, insulin-dependent type 1 and non-insulin-dependent type 2. Recent research has demonstrated that vanadate (VO(3)( - ), oxidation state + 5) and vanadyl (VO(2 + ), oxidation state + 4) both mimic various actions of insulin in cellular systems. In 1985, vanadate given orally as a drinking water to streptozotocin-induced hyperglycemic type 1 diabetic rats (STZ-rats) was found to reduce the high levels of blood glucose down to normal levels and ameliorated many of the aberrations induced by hyperglycemia. In 1990, we proposed first orally active vanadyl complexes such as vanadyl-cysteine methylester and vanadyl-oxalate complexes in STZ-rats. Since then, we have developed orally active vanadyl complexes with different coordination modes. Among them, vanadyl-picolinate complexes with VO (N(2)O(2)) coordination mode were found to be potent orally active insulin-mimetic agents, on the basis of the results on in vitro test using isolated rat adipocytes with respect to the inhibition of the release of free fatty acids (FFA) from the cells and in vivo evaluation (intraperitoneal injection and oral administration) in STZ-rats. Based on the results, the usefulness of vanadium complexes in treating and preventing DM has been revealed, proposing a possible action mechanism.

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Orv Hetil. 2004 Nov 21;145(47):2363-70.
[Current questions about the therapy of diabetes mellitus]
[Article in Hungarian]
Halmos T.
Orszagos Koranyi Tbc es Pulmonologiai Intezet, Metabolikus es Diabetes Ambulancia. fishwash@axelero.hu

Up-to-date therapy and patient care in diabetes started with reliable measuring of endogenous insulin in blood. In the past decades, extensive epidemiologic studies proved, that long lasting normoglycemia inhibits the development of chronic diabetic complications. It became also clear, that continous normotension, and normal lipid values have equal protective effect. These new findings were in strong correlation with the adoption of the concept of the Metabolic Syndrome. Holistic patient care and therapy must include all pathologic alterations of the Syndrome. This concept also fertilised the therapeutic possibilities of the prevention. Cleaning of up-to-date insulin preparations, with their better timing effect, contributed a lot to achieve and maintain normoglycemia. Besides rapid acting insulin analogues, long acting analogues are available on the market, with a significantly smoother effect. These new preparations provide a near ideal insulin effect. Modern oral antidiabetics try to restore physiologic circumstances. Their combined application in type 2 diabetes--in the majority of these patients--is able to maintain normoglycemia. In case when oral drugs seem to be ineffective in obtaining physiologic conditions, insulin therapy should introduced as early, as possible. Data gained from up-to-date clinical investigations, offer evidence about inflammatory origin of atherosclerosis, type 2 diabetes, and the Metabolic Syndrome as well. This new concept changes very likely therapeutic implications in the (very) next future. It seems, that widespread and radical transformation about our notion according to the diabetes syndrome, has priority in everyday practice. New insulin and oral preparations--together with frequent home checkings of blood pressure and blood sugar--just comply with our new concept.

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Clin Ther. 2004 Nov;26(11):1714-27.
Practical considerations and guidelines for dosing sulfonylureas as monotherapy or combination therapy.
Bell DS.

BACKGROUND:: Oral antidiabetic agents are the initial and most commonly used therapy for type 2 diabetes mellitus.To effectively utilize the oral antidiabetic agents, familiarity with the efficacy and side effects of each agent is essential so that strategies for effective therapy with 1 or more agents can be developed when transitioning is needed either with monotherapy or to combination therapy with another antidiabetic agent. OBJECTIVES:: The purposes of this article were to review the efficacy and adverse-event profile of sulfonylureas, the most widely used class of oral antidiabetic agents in the United States, and to provide a simple set of guidelines for use in transitioning patients between sulfonylureas or to combination therapy. METHODS:: A comprehensive search of the MEDLINE and PubMed databases for the years 1966 to present anda thorough review of abstracts of recently presented clinical trials were used to identify relevant literature on dosing conversion and equivalence between sulfonylureas. Search terms used were as follows: sulfonylureas, dosing conversion, equivalence, glyburide, glipizide, glimepiride, and combination therapy. Strategies are provided for switching patients between sulfonylureas so that switching within the sulfonylurea class or to a combination tablet can be accomplished efficaciously and safely. Recommendations for dosing conversion were based on the results of the literature and abstract search, manufacturer recommendations for each available agent, and the author's clinical experience. RESULTS:: When switching between agents or starting combination therapy, it is important to monitor for hypoglycemia. Fasting serum glucose levels and glycosylated hemoglobin should also be monitored to determine the optimal dose of sulfonylurea for each patient Patients not achieving adequate control on a single agent should be transferred to combination therapy. CONCLUSION:: When transferring a diabetic patient to a combination tablet, improved compliance, cost savings, and better glycemic control may be achieved.

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Best Pract Res Clin Anaesthesiol. 2004 Dec;18(4):631-43.
Strategies for managing the diabetic patient.
Robertshaw HJ, McAnulty GR, Hall GH.
St George's Hospital Medical School, Cranmer Terrace, London SWI7 0RE, UK.

Diabetes mellitus is now classified as either 'type 1' (failure of endogenous insulin production) or 'type 2' ('insulin resistance') and can be diagnosed if fasting blood glucose is >6.1 mmol/l (110mg/dl) on two separate occasions or there is unequivocal hyperglycaemia with acute metabolic decompensation or obvious symptoms. The prevalence of the disease is rising and may be as great as 12-14% in western populations aged over 40 years. Diabetes is complicated by micro- and macrovascular consequences of chronically elevated blood glucose concentrations, and diabetic patients are over-represented in hospital populations, particularly among patients requiring surgical interventions. It is associated with increased perioperative mortality and morbidity. Evidence is now accumulating that intensive glycaemic monitoring and the administration of insulin infusions to achieve tight glycaemic control are associated with an improvement of both perioperative mortality and morbidity.

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J Clin Invest. 2004 Oct;114(7):892-4.
Gene therapy for type 1 diabetes: a novel approach for targeted treatment of autoimmunity.
Creusot RE, Fathman CG.
Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California, USA.

It has been difficult to develop therapies that target those T cells initiating and mediating the pathogenesis of autoimmune disease. Indeed, most current treatments indiscriminately affect both the autoreactive T cells and the "good" T cells, putting the patient at risk of compromised immune function. A new approach raises the possibility of targeted therapy for autoimmunity. Transplantation of hematopoietic stem cells modified to express a protective form of MHC class II corrects a defect in central tolerance. This method contrasts with other targeted therapies that attempt to modify peripheral tolerance, which is also defective in type 1 diabetes mellitus.

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J Clin Invest. 2004 Oct;114(7):877-83.
Challenges facing islet transplantation for the treatment of type 1 diabetes mellitus.
Rother KI, Harlan DM.
Islet and Autoimmunity Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA.

Islet transplantation represents a most impressive recent advance in the search for a type 1 diabetes mellitus cure. While several hundred patients have achieved at least temporary insulin independence after receiving the islet "mini-organs" (containing insulin-producing beta cells), very few patients remain insulin independent beyond 4 years after transplantation. In this review, we describe historic as well as technical details about the procedure and provide insight into clinical and basic research efforts to overcome existing hurdles for this promising therapy.

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Am Heart J. 2004 Oct;148(4):551-8.
Approach to the management of diabetic patients with heart failure: role of thiazolidinediones.
Fonarow GC.
Ahmanson-UCLA Cardiomyopathy Center, UCLA Division of Cardiology, Los Angeles, Calif 90095-1679, USA. gfonarow@mednet.ucla.edu

Diabetes mellitus is a chronic, progressive disease that results in microvascular and macrovascular complications. Patients with diabetes are at high risk for developing heart failure, and the prevalence of diabetes in patients with heart failure ranges from 24% to 44%, with an estimated 1 to 2 million individuals in the United States having both diabetes and heart failure. Patients with diabetes and heart failure are at increased risk for mortality. Primary treatment goals in diabetes include restoration and maintenance of normoglycemia, avoidance of diabetic complications, and prevention of cardiovascular events. The range of therapeutic options for glycemic control has been extended with the introduction of thiazolidinediones (TZDs) used as monotherapy or in combination with other oral antidiabetic medications or insulin. TZDs decrease plasma insulin levels, improve endothelial function, decrease vascular inflammation, and decrease C-reactive protein levels, effects that are potentially beneficial in patients with heart failure. Weight gain and peripheral edema are recognized side effects of these drugs, particularly when used in combination with insulin. Although health care providers should be aware of the potential risk of worsened heart failure when TZDs are used in patients with diabetes and heart failure, these agents may be considered for use in patients with New York Heart Association class I and II heart failure when appropriate monitoring can be provided. Prospective clinical trials are currently under way to further define the cardiovascular safety and efficacy of TZDs in diabetic patients with heart failure.

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J Am Coll Nutr. 2004 Oct;23(5):506S-9S.
Clinical efficacy of magnesium supplementation in patients with type 2 diabetes.
Yokota K, Kato M, Lister F, Ii H, Hayakawa T, Kikuta T, Kageyama S, Tajima N.
3-15-8 Nishi-shinbashi Minato-ku 105-0003, JAPAN. yokota@jikei.ac.jp.

Effects of magnesium (Mg) supplementation on nine mild type 2 diabetic patients with stable glycemic control were investigated. Water from a salt lake with a high natural Mg content (7.1%) (MAG21) was used for supplementation after dilution with distilled water to 100mg/100mL; 300mL/day was given for 30 days. Fasting serum immunoreactive insulin level decreased significantly, as did HOMA squareR (both p < 0.05). There was also a marked decrease of the mean triglyceride level after supplementation. The patients with hypertension showed significant reduction of systolic (p < 0.01), diastolic (p = 0.0038), and mean (p < 0.01) blood pressure. The salt lake water supplement, MAG21, exerted clinical benefit as a Mg supplement in patients with mild type 2 diabetes mellitus.

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Ter Arkh. 2004;76(8):28-32.
[Thiaside diuretics in combination with inhibitors of angiotensin-converting enzyme in patients with diabetes mellitus type 2 comorbid with arterial hypertension]
[Article in Russian]
[No authors listed]

AIM: To study the effect of co-renitek monotherapy for 16 weeks on parameters of 24-h monitoring of arterial pressure, carbohydrate, lipid, purin metabolism in patients with mild and moderate arterial hypertension (AH) and diabetes mellitus (DM) type 2. MATERIAL AND METHODS: 20 patients with DM type 2, mild or moderate AH received co-renitek (1-2 tablets a day) for 16 weeks. Before the treatment and 16 weeks later the patients were examined (24-h AH monitoring, carbohydrate, lipid, purin, electrolyte metabolism). RESULTS: Co-renitek treatment of DM type 2 patients with hypertension led to a significant lowering of mean systolic and diastolic pressure, improvement of 24-h AP profile and reduction of fasting glucose level. Co-renitek proved to be metabolically neutral in relation to lipid, purin and electrolyte metabolism. CONCLUSION: Co-renitek is effective and safe antihypertensive drug for treatment of arterial hypertension in patients with diabetes mellitus type 2.

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Curr Control Trials Cardiovasc Med. 2004 Oct 1;5(1):9 [Epub ahead of print]
A novel approach to treatment of hypertension in diabetic patients—A multicenter, double-blind, randomized study comparing the efficacy of combination therapy of Eprosartan versus Ramipril with low-dose Hydrochlorothiazide and Moxonidine on blood pressure levels in patients with hypertension and associated diabetes mellitus type 2 - rationale and design. (ASTRID - Antihypertensive treatment of Systolic/diastolic hypertension comparing Teveten and Ramipril and type 2 Diabetics).
Pater C, Bhatnagar D, Berrou JP, Luszick J, Beckmann K.

Hypertension and diabetes mellitus are closely interrelated and coexist in as many as two-thirds of patients with type 2 diabetes. The consequent risk of such an association is an accelerated development of atherosclerotic cardiovascular disease and nephropathy complications. In choosing an antihypertensive agent effectiveness needs to be accompanied by favourable metabolic, cardioprotective, and nephroprotective properties. Given the multifactorial nature of hypertension, the approach that has gained widespread agreement is treatment with more than one agent. Agents with different mechanisms of action increase antihypertensive efficacy because of synergistic impacts on the cardiovascular system. Combination therapy allows the use of lower doses of each antihypertensive agent which accounts for the excellent tolerability of combination products. The aim of the present study is to quantify the efficacy of combination therapy of Eprosartan 600 mg respectively Ramipril 5mg with low-dose Hydrochlorothiazide and Moxonidine on blood pressure levels in patients with essential hypertension and associated diabetes mellitus type 2. The use of monotherapy (Eprosartan or Ramipril) followed by addition of low-dose Hydrochlorothiazide as second agent and of Moxonidine as a third agent will be individualized to the severity of hypertension in the particular patient and to his/her degree of response to current treatment.

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Semin Dial. 2004 Sep-Oct;17(5):365-70.
Use of insulin and oral hypoglycemic medications in patients with diabetes mellitus and advanced kidney disease.
Snyder RW, Berns JS.
Department of Medicine, Renal, Electrolyte, and Hypertension Division, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.

ABSTRACT Diabetes mellitus is recognized as a leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in the United States. There is a vast array of medications used to treat diabetes, including insulin and the sulfonylureas, as well as newer classes of drugs such as the thiazolidinediones and biguanides. In patients with reduced glomerular filtration rate (GFR), it is necessary to decrease the dosage of some of these drugs, while others are best avoided altogether. Accumulation of either the parent compound or its metabolites can result in symptomatic hypoglycemia, or in the case of metformin, significant lactic acidosis. In this article we will review the use of insulin and the various classes of oral medications used to treat type 2 diabetes mellitus, focusing on their pharmacokinetic properties and dosing in patients with advanced kidney disease.

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Arch Intern Med. 2004 Sep 27;164(17):1850-7.
Treatment of hypertension in patients with diabetes.
Sowers JR.
Department of Internal Medicine, University of Missouri School of Medicine, Columbia 65212, USA. sowersj@health.missouri.edu

At least 17 million people in the United States have diabetes mellitus, and another 50 million have hypertension. These chronic diseases increasingly coexist in our aging population. Both diseases are important predisposing factors for the development of cardiovascular disease (CVD) and renal disease, and the coexistence of these risk factors is a very powerful promoter of CVD and renal disease. There is accumulating evidence that the rigorous treatment of hypertension and other risk factors such as dyslipidemia and hyperglycemia considerably lessens the burden of CVD and renal disease in patients with diabetes mellitus. There is considerable evidence that strategies addressing diet and exercise reduce the development of diabetes and are an important component of treatment in persons who have established diabetes. There are also considerable data suggesting that the treatment strategies that interrupt the renin-angiotensin system have special benefits in patients with diabetes and may prevent the development of clinical diabetes in hypertensive patients with impaired glucose tolerance. Data from a recent study indicate that the control of systolic blood pressure, using a diuretic agent as part of antihypertensive therapy, reduces the risk of stroke and other CVD end points. Recent reports indicate that angiotensin receptor-blocking agents decrease the rate of development of proteinuria and diabetic renal disease. These observations will likely have a significant impact on treatment of hypertension in patients with type 2 diabetes mellitus.

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Arch Intern Med. 2004 Jul 12;164(13):1395-404.
Efficacy of Pharmacotherapy for Weight Loss in Adults With Type 2 Diabetes Mellitus:
A Meta-analysis.
Norris SL, Zhang X, Avenell A, Gregg E, Schmid CH, Kim C, Lau J.
Division of Diabetes Translation.

BACKGROUND: Obesity is closely related to type 2 diabetes mellitus, and weight reduction is an important part of the care delivered to obese persons with diabetes. The objective of this review was to assess the efficacy of pharmacotherapy for weight loss in adults with type 2 diabetes. METHODS: A systematic review of the literature was performed, and studies were included if pharmacotherapy was used as the primary strategy for weight loss among adults with type 2 diabetes. Published and unpublished studies with any design were included. A random effects model was used to combine outcomes from randomized controlled trials. RESULTS: Sufficient data for the meta-analysis were available for fluoxetine, orlistat, and sibutramine. Fourteen randomized, placebo-controlled trials were included in the review, with a total of 2231 patients. Pharmacotherapy produced modest reductions in weight for fluoxetine (3.4 kg [95% confidence interval (CI), 1.7-5.2 kg] at 8-16 weeks of follow-up; 5.1 kg [95% CI, 3.3-6.9 kg] at 24-30 weeks; and 5.8 kg [ 95% CI, 0.8-10.8 kg] at 52 weeks); orlistat (2.6 kg [95% CI, 2.1-3.2 kg] [2.6% loss] at 52 weeks); and sibutramine (4.5 kg [95% CI, 1.8-7.2 kg] [3.3% loss] at up to 26 weeks). Glycated hemoglobin was also modestly reduced: fluoxetine (1.0% [95% CI, 0.4%-1.5%] at 8-16 weeks; 1.0% [95% 0.6%-1.4%] at 24-30 weeks; and 1.8% [95% CI, -0.2%-3.8%] at 52 weeks); orlistat (0.4% [95% CI, 0.3%-0.5%]); and sibutramine (0.7% [95% CI, -0.5%-1.9%]). Gastrointestinal adverse effects were common with orlistat; tremor, somnolence, and sweating with fluoxetine; and palpitations with sibutramine. CONCLUSIONS: Fluoxetine, orlistat, and sibutramine can achieve statistically significant weight loss over 26 to 52 weeks. However, the magnitude of weight loss was modest, and the long-term health benefits and safety remain unclear. Interventions that combine pharmacologic therapy with intensive behavioral interventions may be more effective but need additional research.

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Lancet. 2004 Jul 10;364(9429):203-5.
Stem-cell therapy for diabetes mellitus.
Hussain MA, Theise ND.
Liver and Stem Cell Research Laboratory, Division of Digestive Diseases, Department of Internal Medicine, Beth Israel Medical Center, Albert Einstein College of Medicine, New York, NY 10003, USA.

Context Curative therapy for diabetes mellitus mainly implies replacement of functional insulin-producing pancreatic beta cells, with pancreas or islet-cell transplants. However, shortage of donor organs spurs research into alternative means of generating beta cells from islet expansion, encapsulated islet xenografts, human islet cell-lines, and stem cells. Stem-cell therapy here implies the replacement of diseased or lost cells from progeny of pluripotent or multipotent cells. Both embryonic stem cells (derived from the inner cell mass of a blastocyst) and adult stem cells (found in the postnatal organism) have been used to generate surrogate beta cells or otherwise restore beta-cell functioning. Starting point Recently, Andreas Lechner and colleagues failed to see transdifferentiation into pancreatic beta cells after transplantation of bone-marrow cells into mice (Diabetes 2004; 53: 616-23). Last year, Jayaraj Rajagopal and colleagues failed to derive beta cells from embryonic stem cells (Science 2003; 299: 363). However, others have seen such effects. Where next? As in every emerging field in biology, early reports seem confusing and conflicting. Embryonic and adult stem cells are potential sources for beta-cell replacement and merit further scientific investigation. Discrepancies between different results need to be reconciled. Fundamental processes in determining the differentiation pathways of stem cells remain to be elucidated, so that rigorous and reliable differentiation protocols can be established. Encouraging studies in rodent models may ultimately set the stage for large-animal studies and translational investigation.

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Internist (Berl). 2004 Jun;45 Suppl 1:S15-22.
[Primary prevention of diabetes mellitus type 2]
[Article in German]
Gallwitz B.
Medizinische Klinik IV, Eberhard-Karls-Universitat Tubingen, baptist.gallwitz@med.uni-tuebingen.de

The increasing incidence of type 2 diabetes constitutes a considerable individual and socio-economic risk, therefore preventive concepts are urgently needed. Three prospective studies show that a "life-style-intervention" as well as drugs can prevent the development of diabetes as well as cardiovascular complications:TheDiabetesPreventionStudy (DPS) evaluated the influence of a "life-style-intervention". TheDiabetesPreventionProgram (DPP) additionally examined the effect of metformin. In theSTOP-NIDDM-Study acarbose was used for diabetes prevention and cardiovascular endpoints were also evaluated. The incidence of type 2 diabetes can be significantly reduced by a "life-style-intervention" and also by the administration of metformin or acarbose. With acarbose cardiovascular events are reduced significantly and comparably to a therapy with statins in primary prevention.

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Arch Neurol. 2004 Jun;61(6):914-8.
Effectiveness, tolerability, and impact on quality of life of the 5% lidocaine patch in diabetic polyneuropathy.
Barbano RL, Herrmann DN, Hart-Gouleau S, Pennella-Vaughan J, Lodewick PA, Dworkin RH.
Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA. Richard_Barbano@URMC.Rochester.edu

BACKGROUND: The treatment of painful diabetic polyneuropathy (DPN) is often inadequate and frequently limited by the systemic adverse effects of medications, necessitating the evaluation of novel treatments. OBJECTIVE: To evaluate the effectiveness, tolerability, and impact on quality of life of the 5% lidocaine patch in painful diabetic polyneuropathy. DESIGN: Open-label, flexible-dosing, 3-week study with a 5-week extension. SETTING: Outpatient clinics and clinical research centers.Patients Volunteer sample of 56 patients with clinically defined painful diabetic polyneuropathy of longer than 3 months' duration.Intervention The 5% lidocaine patch, with a maximum of 4 patches daily for 18 hours. MAIN OUTCOME MEASURES: Change in mean daily pain diary ratings from baseline to week 3. Secondary end points included assessments of safety, tolerability, and quality of life. RESULTS: Patients with painful diabetic polyneuropathy showed significant improvements in pain and quality-of-life outcome measures during a 3-week treatment period. These benefits were maintained in a subgroup of patients treated for an additional 5 weeks, during which taper of concomitant analgesic therapy was permitted. Adverse events were minimal, and systemic accumulation of lidocaine did not occur. CONCLUSIONS: Up to four 5% lidocaine patches for up to 18 h/d are well tolerated in patients with painful diabetic polyneuropathy, significantly improve pain and quality-of-life ratings, and may allow tapering of concomitant analgesic therapy. Given the open-label design of this trial, a randomized controlled trial is necessary to confirm these results.

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Diabetes Educ. 2004;Suppl:2-14.
A scientific review: the role of chromium in insulin resistance.
[No authors listed]

Chromium is an essential mineral that appears to have a beneficial role in the regulation of insulin action and its effects on carbohydrate, protein and lipid metabolism. Chromium is an important factor for enhancing insulin activity. Studies show that people with type 2 diabetes have lower blood levels of chromium than those without the disease. Insulin resistance is the common denominator in a cluster of cardiovascular disease risk factors. One out of every five Americans has metabolic syndrome. It affects 40% of people in their 60s and 70s. Insulin resistance, with or without the presence of metabolic syndrome, significantly increases the risk of cardiovascular disease. Insulin resistance is present in two serious health problems in women; polycystic ovarian syndrome (PCOS) and gestational diabetes. Several studies have now demonstrated that chromium supplements enhance the metabolic action of insulin and lower some of the risk factors for cardiovascular disease, particularly in overweight individuals. Chromium picolinate, specifically, has been shown to reduce insulin resistance and to help reduce the risk of cardiovascular disease and type 2 diabetes. Dietary chromium is poorly absorbed. Chromium levels decrease with age. Supplements containing 200-1,000 mcg chromium as chromium picolinate a day have been found to improve blood glucose control. Chromium picolinate is the most efficacious form of chromium supplementation. Numerous animal studies and human clinical trials have demonstrated that chromium picolinate supplements are safe.

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Hosp Med. 2004 May;65(5):288-92.
Intensive insulin therapy in type 1 and type 2 diabetes.
Dean J, Sharp P.
Bolton Diabetes Centre, Bolton BL1 4AL.

Intensive insulin regimens can produce substantial clinical benefits for patients with type 1 and type 2 diabetes, but they are associated with an increased incidence of hypoglycaemia. This article discusses such regimens and whether the risk of hypoglycaemia can be reduced by using the new basal insulin analogue, insulin glargine.

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School Nurse News. 2004 May;21(3):12-6.
Diabetes and physical activity in school.
Kollipara S, Warren-Boulton E.
Kaiser Permanente Medical Center, Sacramento, CA, USA.

Physical activity and exercise are critical components of diabetes management. Everyone can benefit from regular exercise, but it is even more important for a student with diabetes. In addition to maintaining cardiovascular fitness and controlling weight, physical activity can help to lower blood glucose levels and increase insulin sensitivity. With the nearly epidemic incidence of childhood obesity and type 2 diabetes in youth, physical education should be part of the school day for all children. Students with diabetes should participate fully in physical education classes and team sports. To maintain blood glucose levels within their target ranges during exercise, students with type 1 diabetes will make adjustments in their insulin and food intake. To prevent hypoglycemia, they also will need to check their blood glucose levels more frequently while engaging in physical activity. Physical education instructors and sports coaches must be able to recognize and assist with the treatment of hypoglycemia. A quick-acting source of glucose and the student's glucose meter should always be available, along with water. The student's Diabetes Medical Management Plan, nursing care plan, 504 Plan, IEP, or other education plan should include specific instructions.

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Am J Obstet Gynecol. 2004 May;190(5):1438-9.
Glyburide for the treatment of gestational diabetes.
Kremer CJ, Duff P.
Department of Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville, Florida, USA.

OBJECTIVE: This study was undertaken to evaluate the effectiveness of glyburide in patients with gestational diabetes who failed diet therapy. METHODS: Patients who were beyond the first trimester and who failed to achieve satisfactory glucose control with diet therapy were treated with glyburide, at a starting dose of 2.5 mg daily. The dose was increased in increments to a maximum of 20 mg/day. The main treatment outcome was achievement of satisfactory glucose control, defined as a mean plasma fasting glucose 90 mg % or less and mean 1-hour postprandial plasma glucose determinations 135 mg % or less. Patients who failed to achieve satisfactory control were treated with twice-daily doses of insulin. RESULTS: During the period July 2001 through December 2002, we managed 197 patients with gestational diabetes. One-hundred twenty-four patients responded to diet alone; 73 were treated with glyburide. Of the 73 patients, 59 (81%, 95% CI 76.4-85.6) achieved satisfactory glucose control with glyburide; 44 women required 7.5 mg/day or less. Eleven of the 59 women (19%) had macrosomic infants. Eight patients (11%) experienced noticeable side effects related to glyburide; only 1 patient discontinued treatment. CONCLUSION: Approximately 80% of patients with gestational diabetes who fail to respond to diet therapy can be treated effectively with glyburide.

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Isr Med Assoc J. 2004 May;6(5):284-6.
Insulin pump therapy for 1-6 year old children with type 1 diabetes.
Shehadeh N, Battelino T, Galatzer A, Naveh T, Hadash A, de Vries L, Phillip M.
Pediatric Diabetes Unit, Meyer Children's Hospital of Haifa, Haifa, Israel. n_shehadeh@rambam.health.gov.il

BACKGROUND: The management of diabetes in preschool children poses unique difficulties for both the families and the medical team. OBJECTIVE: To test the feasibility and safety of insulin pump therapy in the 1-6 year age group in order to improve quality of life and metabolic control. METHODS: The study group comprised 15 type 1 diabetic children aged 1-6 years old (mean +/- SD, 3.8 +/- 1.2 years) from three diabetes centers. Insulin pump therapy was applied for 12 months. Data, including insulin dose, hemoglobin A1c, hypoglycemic events, as well as scores on the Diabetes Quality of Life Measure Questionnaire and the Diabetes Treatment Satisfaction Questionnaire, were collected and compared with the multiple daily injection treatment prior to entry into the study, RESULTS: HbA1c was measured at the beginning of the study and at 2, 4, 8 and 12 months later; the respective levels (mean +/- SD) were 8.82 +/- 0.98, 8.45 +/- 1.05, 8.37 +/- 0.85, 8.32 +/- 0.71, 8.18 +/- 0.90%. HbA1c measurements after 12 months were significantly lower than at the beginning of the study (P < 0.05). There were no significant differences in insulin dose and the total number of hypoglycemic events. In both the DQOL and DTSQ scales there were significant differences in scores in favor of the insulin pump period (43.7 +/- 8.0 versus 33.7 +/- 7.9, P < 0.001; and 10.9 +/- 2.3 versus 14.5 +/- 2.3, P < 0.001), respectively. CONCLUSIONS: For very young diabetic children, insulin pump therapy improves quality of life and is feasible and safe. It should be considered as an optional mode of therapy for this age group.

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Isr Med Assoc J. 2004 May;6(5):271-5.
Why pumps? Continuous subcutaneous insulin infusion for children and adolescents with type 1 diabetes.
Weintrob N, Shalitin S, Phillip M.
Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel, Petah Tiqva, Israel. nweintrob@clalit.org.il

CSII is a feasible, safe and well-accepted mode of therapy for many children with type 1 diabetes. For a significant number of patients and parents, it serves as a much easier means of coping with the huge daily burden of diabetes. Therefore, we believe that both CSII and MDI should be made available to the diabetic team and the patients to better tailor therapy, improve satisfaction and decrease the fear of hypoglycemia.

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Ann Intern Med. 2004 May 18;140(10):778-85.
The effects of low-carbohydrate versus conventional weight loss diets in severely obese adults: one-year follow-up of a randomized trial.
Stern L, Iqbal N, Seshadri P, Chicano KL, Daily DA, McGrory J, Williams M, Gracely EJ, Samaha FF.
Philadelphia Veterans Affairs Medical Center, University of Pennsylvania Medical Center, and Drexel University College of Medicine, Philadelphia, Pennsylvania 19104, USA.

BACKGROUND: A previous paper reported the 6-month comparison of weight loss and metabolic changes in obese adults randomly assigned to either a low-carbohydrate diet or a conventional weight loss diet. OBJECTIVE: To review the 1-year outcomes between these diets. DESIGN: Randomized trial. SETTING: Philadelphia Veterans Affairs Medical Center. PARTICIPANTS: 132 obese adults with a body mass index of 35 kg/m2 or greater; 83% had diabetes or the metabolic syndrome. INTERVENTION: Participants received counseling to either restrict carbohydrate intake to <30 g per day (low-carbohydrate diet) or to restrict caloric intake by 500 calories per day with <30% of calories from fat (conventional diet). MEASUREMENTS: Changes in weight, lipid levels, glycemic control, and insulin sensitivity. RESULTS: By 1 year, mean (+/-SD) weight change for persons on the low-carbohydrate diet was -5.1 +/- 8.7 kg compared with -3.1 +/- 8.4 kg for persons on the conventional diet. Differences between groups were not significant (-1.9 kg [95% CI, -4.9 to 1.0 kg]; P = 0.20). For persons on the low-carbohydrate diet, triglyceride levels decreased more (P = 0.044) and high-density lipoprotein cholesterol levels decreased less (P = 0.025). As seen in the small group of persons with diabetes (n = 54) and after adjustment for covariates, hemoglobin A1c levels improved more for persons on the low-carbohydrate diet. These more favorable metabolic responses to a low-carbohydrate diet remained significant after adjustment for weight loss differences. Changes in other lipids or insulin sensitivity did not differ between groups. LIMITATIONS: These findings are limited by a high dropout rate (34%) and by suboptimal dietary adherence of the enrolled persons. CONCLUSION: Participants on a low-carbohydrate diet had more favorable overall outcomes at 1 year than did those on a conventional diet. Weight loss was similar between groups, but effects on atherogenic dyslipidemia and glycemic control were still more favorable with a low-carbohydrate diet after adjustment for differences in weight loss.

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Am J Surg. 2004 May;187(5A):25S-28S.
The use of antibiotics in the diabetic foot.
Edmonds M, Foster A.
Diabetic Foot Clinic, King's College Hospital, Denmark Hill, Camberwell, London SE5 9RS, United Kingdom UK. me@edmonds45.freesreve.co.uk

Lower limb infections are the most common indication for hospital admission in patients with diabetes. However, diagnosis of infection can be delayed because the normal clinical signs are often absent in patients with diabetes. The proper use of antibiotics in the treatment of the diabetic foot remains contested: one view is to administer antibiotics only in the presence of clinical infection; the other one is to give antibiotics freely to all patients with ulcers. This review of literature includes 2 controlled studies of antibiotics in diabetic foot ulcers. The first study showed no advantage from amoxicillin plus clavulanate as a supplement to standard therapy in uncomplicated ulcers. Patients (N = 44) with neuropathic ulcers (some of whom had cellulitis) were randomized to oral amoxicillin plus clavulanate or matched placebo. At 20 days' follow-up, there was no significant difference in outcome between the 2 groups. A further investigation (N = 64) compared ulcer patients who received oral antibiotics with those who did not. In the group with no antibiotics, 15 patients developed clinical infection, whereas none did in the antibiotic group (P <0.001). Seven patients in the nonantibiotic group needed hospital admission and 3 patients came to amputation. In the nonantibiotic group, 11 of 15 with infection had a positive swab compared with 1 of 17 without infection (P <0.01). In the nonantibiotic group, 17 patients healed, compared with 27 in the antibiotic group (P <0.02), with significantly more ischemic patients healing in the antibiotic group (P <0.01). Patients with diabetes who have clean ulcers associated with peripheral vascular disease and positive ulcer swabs should be considered for early antibiotic treatment. The diabetic foot is highly susceptible to repeat ulceration, and diabetic ulcers are more prone to infection than other ulcers. Furthermore, untreated infection can lead to amputation. This cycle can be broken only with aggressive treatment.

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J Chir (Paris). 2004 May;141(3):142-9.
[Pancreatic transplantation: 1. Indications and results]
[Article in French]
Duffas JP.
Service de Chirurgie Generale et Digestive, Hopital Rangueil - Toulouse.

In the face of a rising incidence of diabetes, pancreatic transplantation seems to be the only treatment capable of normalizing glycosylated hemoglobin and stabilizing or improving the complications of diabetes. To date, more than 19,000 pancreatic transplantations have been done worldwide. Surgical indications must take into account the constraints and risks specific to the diabetic illness, the risks of a complex surgical procedure, and the absolute necessity for long term immunosuppression. Combined kidney/pancreas transplantation is the most common procedure (90% of cases) and is the most effective treatment for renal insufficiency due to diabetes. Results have improved significantly over the last ten Years due to improvements in the surgical technique and to improvement of immunosuppressive regimens. Results are at least as good and perhaps better than those achieved in the transplantation of other solid organs; patient survival, renal graft survival, and pancreatic graft survival are respectively 95%, 92%, and 85% at one Year. Results of pancreatic transplantation alone have improved and now seem equal to those of combined organ transplantation. Transplantation seems to be cost-effective in the overall care of advanced diabetes, particularly in those patients on chronic dialysis or having degenerative complications.

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Int J Clin Pract. 2004 Apr;58(4):394-401.
Exubera inhaled insulin: a review.
Barnett AH.
University of Birmingham and Birmingham Heartlands Hospital, Department of Medicine-Undergraduate Centre, Birmingham, UK. anthony.barnett@heartsol.wmids.nhs.uk

The focus of this review is inhaled insulin, specifically Exubera, which represents a novel prandial insulin delivery method. Fear of hypoglycaemia and the reluctance of patients to use multiple daily injection regimens is a major barrier to achieving good glycaemic control in patients with type 1 and type 2 diabetes. Inhaled insulin has been developed to provide more physiological prandial insulin replacement than regular human insulin in patients with diabetes, with the advantage of non-invasive delivery. Good glycaemic control, comparable to modern subcutaneously administered insulin preparations, has already been demonstrated, and no unexpected safety concerns have been reported with inhaled insulin. The development of such insulin delivery technologies that are better tailored to patients' needs may improve patient compliance, thereby facilitating the attainment of treatment targets. This review summarises the studies available and discusses the potential implications to patients of needle-free insulin administration.

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Clin Ther. 2004 Apr;26(4):531-40.
Randomized, multinational, open-label, 2-period, crossover comparison of biphasic insulin aspart 30 and biphasic insulin lispro 25 and pen devices in adult patients with type 2 diabetes mellitus.
Niskanen L, Jensen LE, Rastam J, Nygaard-Pedersen L, Erichsen K, Vora JP.
Department of Medicine, Kuopio University Hospital, Building No. 5, PO Box 1777, 70211 Kuopio, Finland. leo.niskanen@kuh.fi

OBJECTIVE: The goal of this study was to compare the efficacy and safety profiles of biphasic insulin aspart 30 (30% soluble insulin aspart and 70% protaminated insulin aspart [BIAsp 30]) and biphasic insulin lispro 25 (25% soluble insulin lispro and 75% neutral protamine lispro [Mix25]) used in a BID injection regimen in patients with type 2 diabetes mellitus (DM). Also assessed was patients' preference for pen device--the NovoMix 30 FlexPen /NovoLog Mix 70/30 FlexPen (FlexPen) versus the Humalog Mix25 Pen/Humalog Mix75/25 Pen (Humalog Pen). METHODS: Patients with type 2 DM receiving current insulin treatment were randomized to a multinational, multicenter, open-label, 2-period, crossover comparison of BIAsp 30 and Mix25. Efficacy (by analyses of variance) and safety profiles were assessed after 12 weeks of treatment. Patients' preference for pen device was assessed by questionnaires. RESULTS: A total of 137 patients were randomized to treatment; 4 were withdrawn during the 2-week run-in treatment with biphasic human insulin 30. The mean (SD) characteristics of the remaining 133 patients (79 men, 54 women) were as follows: age, 62.3 (9.2) years; body mass index, 28.1 (3.9) kg/m(2); and glycosylated hemoglobin (HbA(1c)), 8.5% (1.1). Glycemic control was assessed by the measurement of HbA(1c) after 12 weeks of treatment. Treatment with BIAsp 30 was noninferior to treatment with Mix25 (upper limit of 90% CI for estimated difference [BIAsp 30 - Mix25] was <0.4%). Self-monitored blood glucose levels were comparable (P = NS). Adverse-event profiles were similar between treatments, as was the incidence of hypoglycemic episodes (0.69 episode/mo with BIAsp 30 and 0.62 episode/mo with Mix25, P = 0.292). For all device features assessed, the FlexPen consistently received higher scores (all P < 0.005). A total of 9.0% of patients experienced problems with the FlexPen, compared with 32.4% with the Humalog Pen (P < 0.001). Furthermore, 74.6% preferred to continue using the FlexPen, whereas 14.3% preferred the Humalog Pen (P < 0.001). CONCLUSIONS: In this study, glycemic control with BIAsp 30 and Mix25 was found to be comparable in these patients with type 2 DM. Safety profiles were similar for both regimens. Patients preferred and experienced fewer problems with the FlexPen than the Humalog Pen.

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Clin Ther. 2004 Apr;26(4):502-10.
Effects of multiple daily injection therapy with Humalog mixtures versus separately injected insulin lispro and NPH insulin in adults with type I diabetes mellitus.
Roach P, Bai S, Charbonnel B, Consoli A, Taboga C, Tiengo A, Bolli G; High Mix Study Group.
Department of Medicine, Indiana University School of Medicine, 545 Barnhill Drive, EH 421, Indianapolis, IN 46202, USA. paroach@iupui.edu

BACKGROUND: Injection of insulin lispro (LP) before meals provides a more physiologic insulin activity profile than regular human insulin, but the relatively short duration of action of LP may allow the blood glucose (BG) level to increase during the late postprandial period (4-7 hours after meals) unless basal insulin is optimally replaced. One approach to basal insulin optimization has been to combine small doses of NPH with LP before meals. When used in a similar fashion, premixed, fixed-ratio insulin preparations containing LP and NPL (an LP-based intermediate-acting insulin) may provide the basis for an optimized basal-bolus insulin regimen. OBJECTIVE: This study assessed mean late postprandial glycemic control during treatment with a premixed formulation consisting of a high proportion of LP (75% LP/25% NPL; H) and a premixed formulation consisting of a medium proportion of LP (50% LP/50% NPL; M). The H/M formulation was given before meals and was compared with treatment with preprandial LP + NPH (LP + N) in patients with type 1 diabetes mellitus (DM). METHODS: This multicenter, randomized, open-label, 2-period crossover study was conducted at 4 centers in Italy and 1 center in France. Patients eligible for the study had type 1 DM, were > or = 18 years of age, and had a glycosylated hemoglobin (HbA(1c)) <150% of the upper limit of normal. Patients were randomly assigned to 1 of 2 treatment sequences: LP self-mixed with NPH before meals plus NPH alone at bedtime for 8 weeks (LP + N) followed by preprandial H or M, plus NPH alone at bedtime for 8 weeks (H/M), or the opposite sequence. Assessments included 8-point self-monitored BG profiles, HbA(1c), and hypoglycemia (any sign or symptom of hypoglycemia or BG < 3.0 mmol/L [<54.0 mg/dL]). The primary outcome measure was the late postprandial BG value, calculated as the mean of the combined prelunch (late postbreakfast), predinner (late postlunch), and bedtime (late postdinner) values. RESULTS: A total of 89 patients with type 1 DM were enrolled (44 men, 45 women; mean [SD] age, 38.3 [12.8] years; mean [SD] body weight, 70.8 [11.6] kg; mean [SD] body mass index, 24.6 [3.0] kg/m(2); mean [SD] duration of diabetes, 17.8 [10.5] years; mean HbA(1c), 7.9% [0.88%]). The mean (SD) late postprandial BG values were similar between treatments (8.9 [2.1] mmol/L [160.3 (37.8) mg/dL] for H/M vs 9.0 [1.8] mmol/L [162.1 (32.4) mg/dL] for LP + N), as were the end point HbA(1c) values (7.8% [0.9%] for H/M vs 7.9% [0.8%] for LP + N). The rate of hypoglycemia was significantly higher during treatment with H/M, primarily because of episodes occurring between 12 PM and 6 PM, but was relatively low in both groups (mean/median rate per patient per 30 days: 2.87/2.14 for H/M and 2.11/1.07 for LP + N; P < 0.05). CONCLUSIONS: In this population of patients with type 1 DM, preprandial H/M provided an effective alternative regimen for prandial and basal insulin replacement. Late postprandial BG control, an indicator of basal insulin sufficiency, was similar to that achieved with an intensified regimen of LP + N injected separately before meals, and the end point HbA(1c) was similar between the 2 treatments.

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Nippon Ronen Igakkai Zasshi. 2004 Mar;41(2):157-60.
[Insulin therapy in elderly patients with diabetes mellitus]
[Article in Japanese]
Araki A.
Department of Endocrinology, Tokyo Metropolitan Geriatric Medical Center.

Insulin therapy is an effective measure of improving glucose control even in elderly patients with type 2 diabetes. However, it is controversial whether insulin therapy does disturb the quality of life (QOL) as well as cognitive function in the elderly. In our previous study of 455 diabetic patients, the well-being as assessed by the morale scale was similar in three treatment groups. In contrast, the symptom-burden, social burden, and worry about diabetes as assessed by the Elderly Diabetes Burden Scales was more increased in insulin-treated group as compared to the diet-treated group after adjustment for age, gender, HbAlc, frequency of hypoglycemia, microangiopathy, macroangiopathy, and social support. In another study of 213 patients, MMSE scores were similar among treatment groups, while attention and learning were most impaired in insulin-treated groups after adjustment for age, gender, HbAlc, and duration of diabetes. Although the mechanism for the association between insulin treatment and cognitive impairment is unknown, hyperglycemia, hypoglycemia, and cerebral complications in insulin-treated patients may be possible explanations. Whatever mechanism may be involved, hypoglycemia should be considered especially if unexpectedly low HbAlc (< 6.5%) is observed or atypical neuropsychological symptoms appear. It is unknown how insulin withdrawal is successful in elderly diabetic patients. Using rapid or ultrarapid insulin injections three times daily, good glucose control achieved the goal of plasma glucose level of < 140 mg/dl before meals and at bedtime. Then, insulin therapy was converted to oral treatment of glimepiride (2 to 6 mg/day) and/or voglibose (0.6 mg/day) in 30 patients with poorly controlled Type 2 diabetes. About 83% of the patients were successful in the insulin withdrawal according to the criteria of HbAlc levels after two months < 8.0%. After removal of glucose toxicity, insulin withdrawal should be attempted to improve QOL in elderly patients with diabetes mellitus.

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Diabetologia. 2004 Mar 12 [Epub ahead of print]
Insulin analogues (insulin detemir and insulin aspart) versus traditional human insulins (NPH insulin and regular human insulin) in basal-bolus therapy for patients with Type 1 diabetes.
Hermansen K, Fontaine P, Kukolja KK, Peterkova V, Leth G, Gall MA.
Department of Endocrinology and Metabolism, Aarhus University Hospital, 8000, Aarhus C, Denmark.

AIMS/HYPOTHESIS. The aim of the trial was to compare the efficacy and tolerability of two types of basal-bolus therapy, using either the soluble long-acting basal insulin analogue, insulin detemir, in combination with the rapid-acting analogue, insulin aspart, or NPH insulin in combination with mealtime regular human insulin. METHODS. In this 18-week, 1:1 randomised, open-labelled, parallel trial, 595 patients with Type 1 diabetes mellitus received insulin detemir or NPH insulin in the morning and at bedtime in combination with mealtime insulin aspart or regular human insulin respectively. RESULTS. Glycaemic control with insulin detemir/insulin aspart was improved in comparison with NPH insulin/regular human insulin (HbA(1)c: 7.88% vs 8.11%; mean difference: -0.22% point [95% CI: -0.34 to -0.10]; p<0.001). Self-measured 8-point plasma glucose profiles differed between the groups ( p<0.001), with lower postprandial plasma glucose levels in the insulin detemir/insulin aspart group. Within-person day-to-day variation in plasma glucose was lower with insulin detemir/insulin aspart than with NPH insulin/regular human insulin (SD: 2.88 vs 3.12 mmol/l; p<0.001). Risk of overall and nocturnal hypoglycaemia (23.00-06.00 hours) was, respectively, 21% ( p=0.036) and 55% ( p<0.001) lower in the insulin detemir/insulin aspart group than in the NPH insulin/regular human insulin group. Body weight (adjusted for baseline and change in HbA(1)c) was 1 kg lower with insulin detemir/insulin aspart than with NPH insulin/regular human insulin ( p<0.001). CONCLUSIONS/INTERPRETATION. Basal-bolus therapy using insulin detemir/insulin aspart offers a better balance of control and tolerability than with NPH insulin/regular human insulin. The low variability and more physiological action profiles generated with these insulin analogues resulted in improved glycaemic control with lower risk of hypoglycaemia and no concomitant body weight increase.

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Am J Med. 2004 Mar 8;116 Suppl 5A:23S-29S
Type 2 diabetes mellitus: what is the optimal treatment regimen?
Bell DS.
Department of Medicine, University of Alabama at Birmingham Medical School, Birmingham, Alabama 35294, USA.

Treatment options for type 2 diabetes mellitus currently consist of insulin sensitizers, alpha-glucosidase inhibitors, secretagogues, and insulin. However, the emphasis on initial therapy has been shifting from secretagogues and alpha-glucosidase inhibitors to insulin sensitizers such as metformin and the thiazolidinediones (TZDs). This article outlines the benefits of treatment with sensitizers vis a vis alpha-glucosidase inhibitors and secretagogues as part of a comprehensive treatment algorithm for type 2 diabetes. Secretagogues and alpha-glucosidase inhibitors effectively lower plasma glucose levels only, whereas insulin sensitizers reduce several important cardiac risk factors in addition to reducing plasma glucose levels. TZDs, in particular, are also beneficial for their ability to preserve or even rejuvenate pancreatic beta-cell function. The treatment algorithm has a layered approach, beginning with a combination of insulin-sensitizer therapy and incrementally progressing to triple oral therapy with the addition of secretagogues and, if necessary, the addition of subcutaneous insulin to maintain glycemic control.

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Acta Biomed Ateneo Parmense. 2003;74 Suppl 1:18-20.
New insulins and quality of life.
Iafusco D.
Department of Paediatrics, Second University of Naples, Naples, Italy. dario.iafusco@unina2.it

Extreme customization of treatment is even more necessary when dealing with young diabetic patients as compared with adult patients. From diagnosis the pediatrician must introduce treatment in the less traumatic way possible so that the child does not perceive a derangement of his/her life. In order to preserve the quality of life the diabetic child must be able to attend birthday parties, participate in sports, and generally lead a full social life just like his/her friends. In the present paper we evaluate the characteristics of the new insulin analogues and their advantages and disadvantages with respect to the needs of patients. The wide spectrum of available insulin formulations including also the new short- and long- acting insulin analogues are of great help in conceiving a therapeutic plan closely adherent to the patient's needs. As an example, in children aged less than 5-6 years a short acting insulin may be injected immediatly after the meal. The same insulin may be useful in older patients with an incostant style of life due to social activities. On the other hand the "old" insulins may still be used for the therapeutic plan in patients with a more constant life style as to the physical exercise and intervals between the meals. In conclusion, the quality of life in the children and adolescents with diabetes may be accomplished with a flexible and personalized therapeutic plan and a great attention to the education. The latter is a very important tool for the compliance and the reduction of anxiety in patients and their parents.

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Acta Biomed Ateneo Parmense. 2003;74 Suppl 1:21-5.
Quality of life and new devices in the management of type 1 diabetes in children and adolescents.
Piscopo MA, Chiesa G, Bonfanti R, Viscardi M, Meschi F, Chiumello G.
Department of Paediatrics, Endocrine Unit, Scientific Institute H San Raffaele, Universita Vita-Salute, Milan, Italy.

Insulin therapy is the cornerstone in treatment of type 1 diabetes in children and adolescents. In order to prevent long-term complication multiple daily injections (MDI) are required. Quality of life is dearly affected by the administrations of 3-4 daily injections with syringe. Insulin pens are new devices realized with the aim of simplifying insulin administration. More recently continuous blood sugar monitoring has become available for clinical studies and its role for better metabolic control and quality of life is now under investigation. The aim of this paper is to review published data on the significance of insulin pen and continuous blood sugar monitoring on quality of life in diabetic children and adolescents.

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Ann Intern Med. 2003 Jun 17;138(12):952-9.
Glimepiride combined with morning insulin glargine, bedtime neutral protamine hagedorn insulin, or bedtime insulin glargine in patients with type 2 diabetes. A randomized, controlled trial.
Fritsche A, Schweitzer MA, Haring HU; 4001 Study Group.
Medizinische Klinik, Abteilung fur Endokrinologie, Stoffwechsel und Pathobiochemie, Eberhard-Karls-Universitat, Tubingen, Germany.

BACKGROUND: Patients with type 2 diabetes are often treated with oral antidiabetic agents plus a basal insulin. OBJECTIVE: To investigate the efficacy and safety of glimepiride combined with either morning or bedtime insulin glargine or bedtime neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes. DESIGN: Open-label, randomized, controlled trial. SETTING: 111 centers in 13 European countries. PATIENTS: 695 patients with type 2 diabetes who were previously treated with oral antidiabetic agents. INTERVENTION: Randomization to treatment with morning insulin glargine, bedtime NPH insulin, or bedtime insulin glargine for 24 weeks in addition to 3 mg of glimepiride. The insulin dose was titrated by using a predefined regimen to achieve fasting blood glucose levels of 5.56 mmol/L or lower (< or =100 mg/dL). MEASUREMENTS: Hemoglobin A(1c) values, blood glucose levels, insulin dose, and body weight. RESULTS: Hemoglobin A(1c) levels improved by -1.24% (two-sided 90% CI, -1.10% to -1.38%) with morning insulin glargine, by -0.96% (CI, -0.81% to -1.10%) with bedtime insulin glargine, and by -0.84% (CI, -0.69% to -0.98%) with bedtime NPH insulin. Hemoglobin A(1c) improvement was more pronounced with morning insulin glargine than with NPH insulin (0.40% [CI, 0.23% to 0.58%]; P = 0.001) or bedtime insulin glargine (0.28% [CI, 0.11% to 0.46%]; P = 0.008). Baseline to end-point fasting blood glucose levels improved similarly in all three groups. Nocturnal hypoglycemia was less frequent with morning (39 of 236 patients [17%]) and bedtime insulin glargine (52 of 227 patients [23%]) than with bedtime NPH insulin (89 of 232 patients [38%]) (P < 0.001). CONCLUSION: The risk for nocturnal hypoglycemia was lower with glimepiride in combination with morning and bedtime insulin glargine than with glimepiride in combination with bedtime NPH insulin in patients with type 2 diabetes. Morning insulin glargine provided better glycemic control than did bedtime insulin glargine or bedtime NPH insulin.

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Curr Opin Investig Drugs. 2003 Apr;4(4):406-11.
Thiazolidinediones in diabetes: current status and future outlook.
Camp HS.
Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. heidi.camp@Pfizer.com

Thiazolidinediones have recently emerged as promising antidiabetic drugs. Unlike other oral antidiabetic drugs, thiazolidinediones function to ameliorate insulin resistance, a primary factor for the development of type 2 diabetes. Thiazolidinediones are ligands of the nuclear receptor, peroxisome proliferator-activated receptor-gamma, and their antidiabetic effects appear to be mediated by activation of this receptor. The two currently marketed thiazolidinediones, rosiglitazone and pioglitazone, display similar efficacies in their glucose lowering activities, but interestingly display slightly different clinical and side effect profiles. Understanding the molecular basis for these differences will help in the development of next generation thiazolidinediones that are more efficacious and safer for the treatment of type 2 diabetes.

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J Med Chem. 2003 Jun 19;46(13):2774-89.
1-[[(3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine: a potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties.
Villhauer EB, Brinkman JA, Naderi GB, Burkey BF, Dunning BE, Prasad K, Mangold BL, Russell ME, Hughes TE.
Novartis Institute for Biomedical Research, One Health Plaza, East Hanover, New Jersey 07936, USA. edwin.villhauer@pharma.novartis.com

Dipeptidyl peptidase IV (DPP-IV) inhibition has the potential to become a valuable therapy for type 2 diabetes. The synthesis and structure-activity relationship of a new DPP-IV inhibitor class, N-substituted-glycyl-2-cyanopyrrolidines, are described as well as the path that led from clinical development compound 1-[2-[5-cyanopyridin-2-yl)amino]ethylamino]acetyl-2-cyano-(S)-pyrrolidine (NVP-DPP728, 8c) to its follow-up, 1-[[(3-hydroxy-1-adamantyl) amino]acetyl]-2-cyano-(S)-pyrrolidine (NVP-LAF237, 12j). The pharmacological profile of 12j in obese Zucker fa/fa rats along with pharmacokinetic profile comparison of 8c and 12j in normal cynomolgus monkeys is discussed. The results suggest that 12j is a potent, stable, selective DPP-IV inhibitor possessing excellent oral bioavailability and potent antihyperglycemic activity with potential for once-a-day administration.

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Metabolism. 2003 Jun;52(6):753-9.
Effect of thiazolidinediones on glucose and fatty acid metabolism in patients with type 2 diabetes.
Boden G, Cheung P, Mozzoli M, Fried SK.
Division of Endocrinology/Diabetes/Metabolism and the General Clinical Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.

The current study aimed to compare the effects of treatment (2 months) with thiazolidinediones (TZDs) and placebo on glucose and fat metabolism in patients with type 2 diabetes (T2DM) in a crossover design. Eight patients received placebo (2 months) followed by TZD (2 months). Two-stage (1.5 and 6.0 pmol/kg min) hyperinsulinemic-euglycemic clamps were performed in all 8 patients pre- and post-placebo and post-TZD (post-placebo = pre-TZD). We determined rates of glucose disappearance (G(Rd)), glycolysis (GLS), glycogen synthesis (GS) (all with 3-(3)H glucose), carbohydrate (CHO) oxidation (indirect calorimetry), endogenous glucose production (EGP), free fatty acid (FFA) release ((2)H(5) glycerol), and oxidation (indirect calorimetry) and re-esterification, as well as plasma adiponectin and leptin concentrations, and fat cell size and number (determined in upper thigh biopsy samples). Placebo treatment had no effects on any of the measured parameters. TZD treatment improved insulin-stimulated glucose uptake (ISGU) from 17.1 to 26.4 micromol/kg min (P <.01) and insulin-stimulated GS from 4.8 to 13.4 micromol/kg min (P < 0.03), potentiated insulin-induced suppression of lipolysis from 4.3 to 2.3 micromol/kg min (P <.03) and FFA re-esterification from 1.9 to 1.0 micromol/kg min (P <.02), increased plasma adiponectin levels from 2.7 to 7.2 microg/mL (P <.05), and decreased plasma leptin levels from 30.8 to 23.4 ng/mL (P <.02). In addition, TZD tended to increase the number of small adipocytes (<50 microm) in subcutaneous adipose tissue. We conclude that TZDs have multiple actions and that many, but perhaps not all, can be accounted for by their action on adipose tissue.

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J Clin Endocrinol Metab. 2003 Jun;88(6):2719-25.
Normalization of glucose concentrations and deceleration of gastric emptying after solid meals during intravenous glucagon-like peptide 1 in patients with type 2 diabetes.
Meier JJ, Gallwitz B, Salmen S, Goetze O, Holst JJ, Schmidt WE, Nauck MA.
Department of Medicine I, St. Josef Hospital, Ruhr University, 44791 Bochum, Germany. Juris.Meier@ruhr-uni-bochum.de

The effects of different i.v. doses of glucagon-like peptide 1 (GLP-1) on glucose homeostasis and gastric emptying were compared in patients with type 2 diabetes. Twelve patients with type 2 diabetes received three different infusion rates of GLP-1 (0.4, 0.8, and 1.2 pmol/kg x min) or placebo in the fasting state and after a solid test meal (containing [(13)C]octanoic acid). Blood was drawn for glucose, insulin, C-peptide, glucagon, and GLP-1 determinations. The gastric emptying rate was calculated from the (13)CO(2) excretion rates in breath samples. Statistics were determined using repeated measures ANOVA and Duncan's post hoc test. Plasma glucose concentrations were equally normalized with all GLP-1 doses (P < 0.001). Insulin and C-peptide concentrations dose-dependently rose during GLP-1 infusion in the fasting state (P < 0.05), but were dose-dependently reduced by GLP-1 after meal ingestion (P = 0.0031 and 0.0074, respectively). Glucagon secretion was suppressed with GLP-1. Gastric emptying was decelerated by GLP-1 in a dose-dependent fashion (P < 0.001). Despite a dose-dependent stimulation of insulin secretion, glucose normalization can be achieved even with 0.4 pmol GLP-1/kg x min. Due to the dose-dependent inhibition of gastric emptying, lower GLP-1 doses than previously used may be as suitable for glucose control in patients with type 2 diabetes.

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Eur J Vasc Endovasc Surg. 2003 Jun;25(6):513-8.
The role of hyperbaric oxygen therapy in ischaemic diabetic lower extremity ulcers: a double-blind randomised-controlled trial.
Abidia A, Laden G, Kuhan G, Johnson BF, Wilkinson AR, Renwick PM, Masson EA, McCollum PT.
Academic Surgical Unit, University of Hull and Hull Royal Infirmary, Hull, U.K.

OBJECTIVE: ischaemic lower-extremity ulcers in the diabetic population are a source of major concern because of the associated high risk of limb-threatening complications. The aim of this study was to evaluate the role of hyperbaric oxygen in the management of these ulcers. METHOD: eighteen diabetic patients with ischaemic, non-healing lower-extremity ulcers were recruited in a double-blind study. Patients were randomly assigned either to receive 100% oxygen (treatment group) or air (control group), at 2.4 atmospheres of absolute pressure for 90 min daily (total of 30 treatments). RESULTS: healing with complete epithelialisation was achieved in five out of eight ulcers in the treatment group compared to one out of eight ulcers in the control group. The median decrease of the wound areas in the treatment group was 100% and in the control group was 52% (p=0.027). Cost-effectiveness analysis has shown that despite the extra cost involved in using hyperbaric oxygen, there was a potential saving in the total cost of treatment for each patient during the study. CONCLUSION: hyperbaric oxygen enhanced the healing of ischaemic, non-healing diabetic leg ulcers and may be used as a valuable adjunct to conventional therapy when reconstructive surgery is not possible.

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Postgrad Med. 2003 May;Spec No:63-72.
Constructing an algorithm for managing type 2 diabetes. Focus on role of the thiazolidinediones.
Wyne KL, Drexler AJ, Miller JL, Bell DS, Braunstein S, Nuckolls JG.
Division of Endocrinology and Metabolism, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75390-8857, USA. kathleen.wyne@utsouthwestern.edu

With the understanding of type 2 diabetes mellitus constantly evolving, and with the introduction of many new agents during the past few years, it is often difficult to keep up to date with the management of type 2 diabetes. This article reviews the pathophysiology of type 2 diabetes, oral pharmacologic treatment, and proposed diabetes treatment algorithms, which aim to guide clinicians in the use of thiazolidinediones (TZDs) earlier in the course of diabetes. This is important because studies indicate that sulfonylureas, biguanides, and insulin do not protect the beta cell and cannot provide sustainable glycemic control. The basis for TZD use earlier in diabetes is 2-fold: to preserve beta-cell function while maintaining appropriate glycemic control for a longer duration than is usually attained through monotherapy with a secretagogue or biguanide, and to prevent or reverse the insulin resistance phenomenon of reduced insulin utilization that appears even prior to the clinical diagnosis of diabetes. Notably, decreasing insulin resistance also may reduce the incidence of adverse atherosclerotic consequences.

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Postgrad Med. 2003 May;Spec No:35-44.
Beneficial effects resulting from thiazolidinediones for treatment of type 2 diabetes mellitus.
Bell DS.
University of Alabama at Birmingham, School of Medicine, Department of Medicine, Birmingham, USA. dbell@endo.dom.uab.edu

Because new drugs continue to be developed, physicians treating patients with type 2 diabetes have a wide range of agents from which to choose. The newest class, the thiazolidinediones (TZDs), should be a mainstay of treatment for most patients with type 2 diabetes, because these agents reduce insulin resistance as well as improve glycemic control. Patients with the insulin resistance syndrome are at increased risk for developing cardiovascular disease. However, decreasing insulin resistance with TZD use may reduce the incidence of adverse cardiovascular outcomes. TZDs also may reduce cardiovascular events by acting directly on vascular smooth muscle cells and by helping patients maintain normal hemoglobin levels, without the risk of hypoglycemia. Furthermore, prolonged glycemic control is expected with TZDs because of their effects on beta-cell rejuvenation, a function unique to this class. TZDs can be used safely in renally impaired patients with diabetes, and hepatotoxicity has not been a problem with second-generation TZDs, making these agents both safe and effective in the treatment of type 2 diabetes.

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Postgrad Med. 2003 May;Spec No:15-26.
Lessons learned from landmark trials of type 2 diabetes mellitus and potential applications to
clinical practice.
Drexler AJ.
Mount Sinai Diabetes Center, Mount Sinai Medical Center, 1200 5th Ave, Box 1616, New York, NY 10029, USA. andrew_drexler@smtplink.mssm.edu

Landmark studies have demonstrated that diabetes is a significant risk factor for cardiovascular disease and mortality. Strong relationships exist between insulin resistance/hyperglycemia and mortality, microvascular complications, and cardiovascular complications. Lipid abnormalities frequently associated with type 2 diabetes and insulin resistance include low high-density lipoprotein cholesterol (HDL-C) and elevated triglyceride levels. Lowering low-density lipoprotein cholesterol levels has been shown to improve the prognosis of patients with diabetes, and increasing HDL-C levels will significantly reduce the incidence of major coronary events. Higher levels of insulin sensitivity are associated with thinner intimal-medial thickness of the carotid artery, which indicates less atherosclerosis. Thiazolidinediones increase insulin sensitivity, decrease intimal-medial thickness, and appear to have inhibitory effects on the progression of atherosclerotic lesions. It is hoped that by preventing the onset of diabetes in high-risk individuals--and improving insulin sensitivity with lifestyle changes or pharmacologic treatment--the profound complications of type 2 diabetes will be prevented or delayed, as well.

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Postgrad Med. 2003 May;Spec No:5-14.
The need for reappraisal of type 2 diabetes mellitus management.
Wyne KL.
Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75390-8857, USA. kathleen.wyne@utsouthwestern.edu

Type 2 diabetes is a multiorgan disease that results from the combination of insulin resistance and a beta-cell secretory defect. Because the complications associated with this disease are so significant, the importance of lowering glycosylated hemoglobin levels to within the normal range cannot be overemphasized. Thiazolidinediones (TZDs) modulate lipid metabolism, improve insulin sensitivity, exert numerous nonglycemic effects on the vasculature and lipid metabolism, and may improve many risk factors associated with the metabolic syndrome. Data from the UK Prospective Diabetes Study showed that conventional methods of managing type 2 diabetes, including sulfonylureas and biguanides, do not provide long-term glycemic control. Consequently, new treatment paradigms stressing earlier use of TZDs may lead to more durable glycemic control, facilitating the reduction of complications in patients with type 2 diabetes.

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S Afr Med J. 2003 Mar;93(3):219-23.
Humalog Mix25 improves 24-hour plasma glucose profiles compared with the human insulin mixture 30/70 in patients with type 2 diabetes mellitus.
Herz M, Arora V, Campaigne BN, Scholtz HE, Potgieter MA, Mollentze W.
Eli Lilly, Indianapolis, Indiana, USA.

OBJECTIVE: To compare the effects of Humalog Mix25 (Humalog Mix75/25 in the USA) (Mix25) and human insulin 30/70 (30/70) on the 24-hour inpatient plasma glucose (PG) profile in patients with type 2 diabetes mellitus (T2DM). DESIGN: A randomised, open-label, 8-week crossover study. Study insulins were injected twice daily, 5 minutes before breakfast and dinner. SETTING: Four-week outpatient (dose-adjustment) treatment phase, and 3-day inpatient (test) phase. PATIENTS: Twenty-five insulin-treated patients with T2DM (ages 40-66 years), mean (+/- standard error of the mean) (SEM) HbA1c 7.7% +/- 0.23%, and body mass index (BMI) 29.3 +/- 0.83 kg/m2. OUTCOME MEASURES: 24-hour PG profiles, PG excursions after meals, PG area under the curve (AUC), and 30-day hypoglycaemia rate. RESULTS: The 2-hour PG excursions following breakfast (5.5 +/- 0.34 v. 7.2 +/- 0.34 mmol/l, p = 0.002) and dinner (2.4 +/- 0.27 v. 3.4 +/- 0.27 mmol/l, p = 0.018) were smaller with Mix25 than with 30/70. PG AUC between breakfast and lunch was smaller with Mix25 than with 30/70 (77.6 +/- 3.8 v. 89.5 +/- 4.3 mmol/h/ml, p = 0.001). PG AUC between lunch and dinner, dinner and bedtime, and bedtime and breakfast did not differ between treatments. Pre-meal and nocturnal PG were comparable. The postprandial insulin requirement for lunch meals was supplied equally by the two insulin treatments. The thirty-day hypoglycaemia rate was low (Mix25 0.049 +/- 0.018 v. 30/70 0.100 +/- 0.018 episodes/patient/30 days, p = 0.586) for both treatments. CONCLUSION: In patients with T2DM, Mix25 improved the 24-hour PG profile with lower postprandial PG excursions than with human insulin 30/70.

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Diabetes. 2003 Jun;52(6):1364-70.
Pioglitazone reduces hepatic fat content and augments splanchnic glucose uptake in patients
with type 2 diabetes.
Bajaj M, Suraamornkul S, Pratipanawatr T, Hardies LJ, Pratipanawatr W, Glass L, Cersosimo E, Miyazaki Y, DeFronzo RA.
Diabetes Division, Department of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78284-7886, USA. mandeepbajaj@hotmail.com

The effect of pioglitazone on splanchnic glucose uptake (SGU), endogenous glucose production (EGP), and hepatic fat content was studied in 14 type 2 diabetic patients (age 50 +/- 2 years, BMI 29.4 +/- 1.1 kg/m(2), HbA(1c) 7.8 +/- 0.4%). Hepatic fat content (magnetic resonance spectroscopy) and SGU (oral glucose load- insulin clamp technique) were quantitated before and after pioglitazone (45 mg/day) therapy for 16 weeks. Subjects received a 7-h euglycemic insulin (100 mU. m(-2). min(-1)) clamp, and a 75-g oral glucose load was ingested 3 h after starting the insulin clamp. Following glucose ingestion, the steady-state glucose infusion rate during the insulin clamp was decreased appropriately to maintain euglycemia. SGU was calculated by subtracting the integrated decrease in glucose infusion rate during the 4 h after glucose ingestion from the ingested glucose load. 3-[(3)H]glucose was infused during the initial 3 h of the insulin clamp to determine rates of EGP and glucose disappearance (R(d)). Pioglitazone reduced fasting plasma glucose (10.0 +/- 0.7 to 7.5 +/- 0.6 mmol/l, P < 0.001) and HbA(1c) (7.8 +/- 0.4 to 6.7 +/- 0.3%, P < 0.001) despite increased body weight (83 +/- 3 to 86 +/- 3 kg, P < 0.001). During the 3-h insulin clamp period before glucose ingestion, pioglitazone improved R(d) (6.9 +/- 0.5 vs. 5.2 +/- 0.5 mg. kg(-1). min(- 1), P < 0.001) and insulin-mediated suppression of EGP (0.21 +/- 0.04 to 0.06 +/- 0.02 mg. kg(-1). min(-1), P < 0.01). Following pioglitazone treatment, hepatic fat content decreased from 19.6 +/- 3.6 to 10.4 +/- 2.1%, (P < 0.005), and SGU increased from 33.0 +/- 2.8 to 46.2 +/- 5.1% (P < 0.005). Pioglitazone treatment in type 2 diabetes 1) decreases hepatic fat content and improves insulin-mediated suppression of EGP and 2) augments splanchnic and peripheral tissue glucose uptake. Improved splanchnic/peripheral glucose uptake and enhanced suppression of EGP contribute to the improvement in glycemic control in patients with type 2 diabetes.

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Med Health R I. 2003 Apr;86(4):107-11.
Achieving glycemic control in young children with type 1 diabetes: approaches, pitfalls and new technologies.
Gruppuso PA.
Brown Medical School, Hasbro Children's Hospital, Providence, RI, USA. PGrupposo@lifespan.org

Advances in technologies for insulin administrations, glucose monitoring, development of an artificial pancreas and cell-based therapy will ultimately have a profound effect on the lives of people with diabetes. There is both current success and substantial promise, indicating that these approches may offer, for the first time, real potential for achieving euglycemia without hypoglycemia. Given the physiological and psychosocial impact of type 1 diabetes in young children, this group of patients and their parents stand to gain especially great benefit from these developments. However, the potential for improvements in the mangement of diabetes in young children based on available technologies should not be overlooked and should be effectively utilized as the standard for patient care. Only twenty years ago blood glucose reagent strips were first coming into routine use. Current meters have greatly reduced the amount of blood required ( now less than 1 microliter for many meters) and greatly imporved precision. The advent modified, recombinant insulins, which became available only in the last several years, allows for an insulin regimen to better match the absorption of dietary carbohydrate. All technologies have improved our ability to attain glycemic control, thereby reducing the risk of long-term complication in even our youngest patients.

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Clin Ther. 2003 Feb;25(2):515-29.
Glycemic control in patients with type 2 diabetes mellitus switched from twice-daily immediate-release metformin to a once-daily extended-release formulation.
Fujioka K, Pans M, Joyal S.
Nutrition and Metabolic Research Center, Scripps Clinic Del Mar, San Diego, California 92310, USA. kfujioka@scrippsclinic.com

BACKGROUND: The extended-release formulation of metformin (MXR) prolongs drug absorption in the upper gastrointestinal tract and permits once-daily dosing in patients with type 2 diabetes mellitus. This newer formulation may enhance patient compliance with oral therapy and improve long-term control of diabetes compared with the conventional immediate-release formulation of metformin (MIR). OBJECTIVE: The goal of this study was to determine the effects on glycemic control of a switch to MXR therapy in patients with type 2 diabetes currently treated with MIR. METHODS: This was a multicenter, randomized, double-blind, parallel-group study in patients with established type 2 diabetes. Eligible patients were to have a glycated hemoglobin (HbA1c) value < or = 8.5% and mean fasting plasma glucose (FPG) concentrations < or = 200 mg/dL while receiving MIR 500 mg BID for at least 8 weeks. After a 2-week, single-blind lead-in period, patients were randomly assigned to receive MXR 1000 or 1500 mg QD for 24 weeks or to continue MIR 500 mg BID for 24 weeks. The primary efficacy variable was change in HbA1c from baseline to week 12. Other variables included change in FPG levels; change in HbA1c; distribution of HbA1c values; mean daily blood glucose concentrations (self-monitored); levels of fructosamine, serum insulin, and lipids; and body weight. RESULTS: Two hundred seventeen patients were randomized to treatment. The mean change from baseline in HbA1c values at weeks 12 and 24 were small and similar in the 3 treatment groups. At week 12, the mean change from baseline in HbA1c was 0.15% for MIR, 0.23% for MXR 1000 mg, and 0.04% for MXR 1500 mg. The corresponding mean changes at week 24 were 0.06%, 0.25%, and 0.14%. CONCLUSIONS: In this study, patients with type 2 diabetes who had been receiving twice-daily MIR achieved comparable glycemic control when therapy was switched to once-daily MXR at the same or a greater total daily dose.

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Clin Ther. 2003 Feb;25(2):472-84.
Comparison between repaglinide and glimepiride in patients with type 2 diabetes mellitus: a one-year, randomized, double-blind assessment of metabolic parameters and cardiovascular risk factors.
Derosa G, Mugellini A, Ciccarelli L, Crescenzi G, Fogari R.
Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy. giuderosa@tin.it

BACKGROUND: Repaglinide and glimepiride are relatively new oral hypoglycemic agents. Few data are available concerning their effects on metabolic parameters other than measures of glycemic control. OBJECTIVES: In addition to assessing the effects of repaglinide and glimepiride on glycemic control in patients with type 2 diabetes mellitus, this study also examined the effects of these agents on 3 metabolic parameters known to be cardiovascular risk factors--lipoprotein(a) (Lp[a]), plasminogen activator inhibitor-1 (PAI-1), and homocysteine (Hcy). METHODS: This randomized, placebo-controlled, double-blind trial was conducted at a single center in Italy. Eligible patients were nonsmokers; had no hypertension or coronary heart disease; were taking no hypolipidemic drugs, diuretics, beta-blockers, or thyroxin; and had normal renal function. After an initial 4-week placebo washout period, patients were randomized to receive repaglinide 1 mg/d or glimepiride 1 mg/d. The dose of study drug was optimized over an 8-week titration period, which was followed by a 12-month treatment period. Measures of glycemic control (glycated hemoglobin [HbA1c], fasting plasma glucose [FPG], postprandial plasma glucose [PPG], fasting plasma insulin [FPI], postprandial plasma insulin [PPI]) and the other metabolic parameters of interest were assessed after 6 and 12 months of treatment. RESULTS: One hundred twenty-four patients (63 women, 61 men) completed the study, 62 in each treatment group. There were no significant differences in demographic characteristics between groups. After 6 and 12 months of treatment, FPG levels and HbA1c values were significantly reduced from baseline in both groups (6 months, P < 0.05; 12 months, P < 0.01). After 6 months, PPG levels were significantly decreased only in the repaglinide group (P < 0.05 vs baseline); at 12 months, however, PPG levels were significantly reduced from baseline in both groups (P < 0.01 repaglinide, P < 0.05 glimepiride). No significant changes from baseline in FPI or PPI levels were seen in either group at 6 months, although FPI levels were significantly increased in the repaglinide group at 12 months (P < 0.05). Repaglinide significantly lowered levels of Lp(a), PAI-1, and Hcy after 12 months (all, P < 0.05 vs baseline). Glimepiride significantly lowered levels of Lp(a) and Hcy after 6 months (both, P < 0.05 vs baseline) and levels of Lp(a) (P < 0.01 vs baseline), Hcy (P < 0.01 vs baseline), and PAI-1 (P < 0.05 vs baseline) after 12 months. CONCLUSIONS: Repaglinide and glimepiride improved glycemic control and reduced levels of other metabolic parameters of interest in this population of patients with type 2 diabetes. It is possible that the reductions in Lp(a), PAI-1, and Hcy were the result of improved glucose metabolism; however, the possibility that repaglinide and glimepiride may have a direct effect on these parameters should not be excluded.

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Diabetes Metab. 2003 Apr;29(2 Pt 2):S54-62.
[Insulin therapy by insulin pump: continuous or conventional self-blood glucose monitoring? ]
[Article in French]
Renard E.
Service des Maladies Endocriniennes, Hopital Lapeyronie, 34295 Montpellier Cedex 5, France.

Use of portable pumps is increasing to achieve intensive insulin treatment. Beside unpredictable insulin absorption and insufficient reactivity to changes of insulin flow rate due to the subcutaneous route, this therapy is however limited by the lack of information on blood glucose level provided by self-blood glucose monitoring. Thus, patient interpretation only leads to speculative adaptation of pump flow rate. The lack of alert toward the risk of hypoglycemia or hyperglycemic ketogenic deviations can lead to the occurrence of deleterious metabolic distorsions, among which severe hypoglycemia stands in first rank. Starting experiences of continuous recording of interstitial glucose level by portable systems using glucose-oxidase allow on short time durations the identification of daily periods of poor metabolic control. Retrospective availability of information gives the possibility of more adequate treatment adaptations than conventional capillary blood glucose monitoring, but does not allow immediate prevention of metabolic events. Only devices providing real time or near-real time information to the patient can fulfill this function. However, the absence of tight parallelism between variations of interstitial and blood glucose levels may lead to erroneous decisions. A true continuous real time information on blood glucose level on long-term seems only expectable from implantable glucose sensors. Still under investigation, these systems should be able to insure vigilance toward the risk of hypo- and hyperglycemia on weekly or monthly periods. Initially used as complementary to capillary self-monitoring, their reliability should allow their use as substitutes for conventional monitoring, except for measurements aimed at signal calibration. Pump control by the sensor signal is conceivable if it corresponds to a direct, continuous, real time measurement of blood glucose, and subject to a simultaneous improvement of insulin infusion modes.

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Diabetes Metab. 2003 Apr;29(2 Pt 2):S21-5.
[Insulin therapy and self-monitoring of blood glucose: therapeutic management and recommendations]
[Article in French]
Hanaire-Broutin H.
Service de Diabetologie, Maladies Metaboliques et Nutrition, Hopital Rangueil, 1, avenue Jean-Poulhes, 31403 Toulouse Cedex 4, France.

Self-monitoring of blood glucose (SMBG) has been widely spread during the last twenty years, and is at present considered as mandatory for the management of insulin therapy. The ALFEDIAM and the ADA recommend type 1 diabetic patients to perform more than 4 capillary glucose determinations per day, ideally 4 to 6. To be efficient in using these results, several parameters are required: glycemic targets have to be clearly defined, an intensified insulin regimen (3 or 4 injections per day or insulin pump therapy) should be proposed, and the patient should be teached how to modify his insulin doses. Short acting insulin analogs are available, and long acting insulin analog will be soon. This is a real progress in the choice of flexible insulin regimen. The practice of SMBG and its use for insulin adjustment requires continuing education, in order to translate SMBG in real diabetes self-management. This prerequisite is mandatory to obtain a sustained improvement in metabolic control.

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Arch Intern Med. 2003 May 12;163(9):1025-9.
Combination therapy with angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists in the treatment of patients with type 2 diabetes mellitus.
Rosner MH, Okusa MD.
Division of Nephrology, Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville, VA, USA. rosner@medscape.com

Aggressive therapy for patients with type 2 diabetes mellitus and renal disease is warranted given the natural history of this disease. Although antagonizing the renin-angiotensin system is clearly important, how this is accomplished is of considerable controversy. On the one hand, recent clinical trials of patients with type 2 diabetes mellitus with renal disease demonstrate unequivocally the renal protective effect of angiotensin receptor blockers (ARBs). Although the results of the recently published LIFE trial are encouraging, inconsistencies have been observed with ARBs in reducing cardiovascular end points. On the other hand, angiotensin-converting enzyme inhibitors have a dramatic effect in reducing cardiovascular events but have not been shown convincingly to reduce progression of renal disease in patients with type 2 diabetes mellitus. These studies leave us in a quandary as to the optimal initial treatment regimen for patients with type 2 diabetes mellitus and renal disease despite the recent recommendations from the American Diabetes Association (Alexandria, Va). Given the fact that many of these individuals will require administration of multiple antihypertensive agents, perhaps the initial treatment with a combination of an ARB and angiotensin-converting enzyme inhibitor affords optimal cardiovascular and renal protection for patients with type 2 diabetes mellitus and renal disease. Future clinical trials should be designed to address this issue.

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JAMA. 2003 May 7;289(17):2265-9.
Using new insulin strategies in the outpatient treatment of diabetes: clinical applications.
DeWitt DE, Dugdale DC.
Division of General Internal Medicine, Department of Medicine, University of Washington, Seattle, USA. ddewitt@unimelb.edu.au

Understanding when to use insulin and how to apply the principles of physiologic insulin replacement using existing and new insulins is a key step to improving diabetes care. Insulin analogues and premixed insulins increase physicians' and patients' ability to lower hemoglobin A1C levels with fewer episodes of hypoglycemia. Earlier use of insulin and more aggressive dose escalation are important steps in achieving treatment goals. This article discusses using bedtime insulin with oral agents, basal-prandial insulin strategies, and the new insulin analogues.

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JAMA. 2003 May 7;289(17):2254-64.
Outpatient insulin therapy in type 1 and type 2 diabetes mellitus: scientific review.
DeWitt DE, Hirsch IB.
Division of General Internal Medicine, Department of Medicine, University of Washington, Seattle, USA. ddewitt@unimelb.edu.au

CONTEXT: Newer insulin therapies, including the concept of physiologic basal-prandial insulin and the availability of insulin analogues, are changing clinical diabetes care. The key to effective insulin therapy is an understanding of principles that, when implemented, can result in improved diabetes control. OBJECTIVE: To systematically review the literature regarding insulin use in patients with type 1 and type 2 diabetes mellitus (DM). DATA SOURCES: A MEDLINE search was performed to identify all English-language articles of randomized controlled trials involving insulin use in adults with type 1 or type 2 DM from January 1, 1980, to January 8, 2003. Bibliographies and experts were used to identify additional studies. STUDY SELECTION AND DATA EXTRACTION: Studies were included (199 for type 1 DM and 144 for type 2 DM, and 38 from other sources) if they involved human insulins or insulin analogues, were at least 4 weeks long with at least 10 patients in each group, and glycemic control and hypoglycemia were reported. Studies of insulin-oral combination were similarly selected. DATA SYNTHESIS: Twenty-eight studies for type 1 DM, 18 for type 2 DM, and 48 for insulin-oral combination met the selection criteria. In patients with type 1 DM, physiologic replacement, with bedtime basal insulin and a mealtime rapid-acting insulin analogue, results in fewer episodes of hypoglycemia than conventional regimens. Rapid-acting insulin analogues are preferred over regular insulin in patients with type 1 DM since they improve HbA1C and reduce episodes of hypoglycemia. In patients with type 2 DM, adding bedtime neutral protamine Hagedorn (isophane) insulin to oral therapy significantly improves glycemic control, especially when started early in the course of disease. Bedtime use of insulin glargine results in fewer episodes of nighttime hypoglycemia than neutral protamine Hagedorn regimens. For patients with more severe insulin deficiency, a physiologic insulin regimen should allow lower glycemic targets in the majority of patients. Adverse events associated with insulin therapy include hypoglycemia, weight gain, and worsening diabetic retinopathy if hemoglobin A1C levels decrease rapidly. CONCLUSIONS: Many options for insulin therapy are now available. Physiologic insulin therapy with insulin analogues is now relatively simple to use and is associated with fewer episodes of hypoglycemia.

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Gene Ther. 2003 May;10(10):875-89.
Gene- and cell-based therapeutics for type I diabetes mellitus.
Bottino R, Lemarchand P, Trucco M, Giannoukakis N.
Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.

Type 1 diabetes mellitus, an autoimmune disorder is an attractive candidate for gene and cell-based therapy. From the use of gene-engineered immune cells to induce hyporesponsiveness to autoantigens to islet and beta cell surrogate transplants expressing immunoregulatory genes to provide a local pocket of immune privilege, these strategies have demonstrated proof of concept to the point where translational studies can be initiated. Nonetheless, along with the proof of concept, a number of important issues have been raised by the choice of vector and expression system as well as the point of intervention; prophylactic or therapeutic. An assessment of the current state of the science and potential leads to the conclusion that some strategies are ready for safety trials while others require varying degrees of technical and conceptual refinement.

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Nippon Rinsho. 2003 Mar;61(3):504-8.
Regenerative medicine of the pancreas]
[Article in Japanese]
Minami K, Okuno M, Miyawaki K, Seino S.
Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital.

Insulin has been used generally in treatment of diabetic patients with absolute insulin deficiency since its discovery. However, while normal pancreatic beta-cells continually adjust insulin secretion in response to varying blood glucose levels, insulin administration cannot maintain blood glucose levels within a physiological range that protects from the development of various diabetic complications. It is possible to achieve normoglycemia in absolute insulin insufficiency by transplantation of pancreas or pancreatic islets, but the approach is impractical especially because of the shortage of transplantable pancreases and islets. For this reason, the transplantation of pancreatic beta-cells or islets generated from stem cells has become the more promising therapeutic approach to normoglycemia. In this article, recent progress of regenerative medicine of the pancreas is reviewed.

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Diabetes Obes Metab. 2003 May;5(3):163-70.
Addition of rosiglitazone to metformin is most effective in obese, insulin-resistant patients with
type 2 diabetes.
Jones TA, Sautter M, Van Gaal LF, Jones NP.
GlaxoSmithKline, Harlow, UK.

AIM: These analyses were undertaken to evaluate the efficacy of the insulin sensitizer rosiglitazone (RSG) when added to the therapy of obese type 2 diabetes mellitus patients (T2DM) taking near-maximal doses (2.5 g/day) of metformin (MET). In obese, insulin-resistant patients with T2DM who are inadequately controlled on MET, the addition of an agent that reduces insulin resistance may be a more rational and innovative approach than the addition of an insulin secretagogue. METHODS: Data were pooled from two double-blind studies of RSG added to 2.5 g/day MET, involving a total of 550 T2DM patients. Patients were categorized as non-overweight, overweight and obese according to their baseline BMI using WHO criteria (<25 kgm(-2), 25-30 kgm(-2), >30 kgm(-2) respectively). RESULTS: RSG improved glycaemia (HbA1c) and fasting plasma glucose (FPG) to a clinically significant extent in all three subgroups but the effect was most pronounced in the obese patients. Improvements in HOMA estimates of insulin resistance and beta-cell function were also greatest in the obese patients (4 mg: -16% and +19%; 8 mg: -37% and + 33% respectively), as were reductions in fasting insulin. The profile of adverse events was not demonstrably different in obese patients from the non-obese. CONCLUSIONS: In obese type 2 diabetic patients inadequately controlled on MET alone, addition of rosiglitazone improves glycaemic control, insulin sensitivity and beta-cell function to a clinically important extent.

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Mayo Clin Proc. 2003 Apr;78(4):471-9.
Insulin sensitizers.
Zangeneh F, Kudva YC, Basu A.
Division of Endocrinology, Diabetes, Metabolism, Nutrition and Internal Medicine, Mayo Clinic, Rochester, Minn 55905, USA.

Type 2 diabetes mellitus is an increasingly prevalent disorder associated with multiple metabolic derangements. Insulin resistance is the most prominent feature common in both type 2 diabetes and its associated metabolic abnormalities. Until 1995, the only therapeutic interventions available in the United States were the insulin secretagogues sulfonylureas and insulin. With the introduction of metformin in the United States in the mid-1990s and the subsequent advent of thiazolidinediones, an opportunity exists to address and directly reverse, at least in part, the defects in insulin action seen in individuals with type 2 diabetes. Evidence shows that insulin sensitizers not only have beneficial effects on glycemic control but also have multiple effects on lipid metabolism and atherosclerotic vascular processes that could prove to be beneficial. We discuss safety issues of these agents, their potential use in preventing onset and progression of diabetes, and their use in other related metabolic conditions such as polycystic ovary syndrome.

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Mayo Clin Proc. 2003 Apr;78(4):459-67.
Pharmacological management of type 2 diabetes mellitus: rationale for rational use of insulin.
Chan JL, Abrahamson MJ.
Joslin Diabetes Center and Beth Israel Deaconess Medical Center, Boston, Mass 02215, USA.

Type 2 diabetes mellitus is a chronic metabolic disorder associated with high morbidity and mortality from long-term microvascular and macrovascular complications. Evidence from randomized controlled trials indicates that aggressive treatment directed at improving glycemic control reduces the incidence of diabetes-related microvascular complications. Traditionally, oral monotherapy for type 2 diabetes is initiated when diet and exercise do not control hyperglycemia, followed by the sequential, stepwise addition of oral agents as glycemic control deteriorates. Insulin is the last therapeutic option used, generally reserved for advanced stages of the disease when multiple oral combination treatment fails. Despite a better understanding of the pathophysiologic disease mechanisms in the past decade, the expanded armamentarium of targeted oral antidiabetic drugs, and the conclusive evidence of the benefits of stringent glycemic control, actual treatment outcomes in clinical practice remain suboptimal relative to established treatment goals (glycosylated hemoglobin A1c level <7%). Earlier detection and aggressive treatment are critical to address the natural progression of diabetes because multiple defects (insulin resistance, insulin insufficiency, glucotoxicity, and lipotoxicity) and vascular complications may be present at the time of diagnosis. Acknowledging the inadequacy of traditional strategies and underscoring the importance of insulin as an integral part of the therapeutic armamentarium, clinical trends are moving toward earlier use of insulin combined with 1 or more oral agents. Such strategies can address the multiple abnormalities present early in the disease course and may restore optimal control. A new treatment paradigm for patients with type 2 diabetes to achieve and maintain near-normal glycemic control is warranted.

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J Clin Endocrinol Metab. 2003 Apr;88(4):1637-45.
Effect of pioglitazone compared with metformin on glycemic control and indicators of insulin sensitivity in recently diagnosed patients with type 2 diabetes.
Pavo I, Jermendy G, Varkonyi TT, Kerenyi Z, Gyimesi A, Shoustov S, Shestakova M, Herz M, Johns D, Schluchter BJ, Festa A, Tan MH.
Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana 46201, USA. pavo_imre@lilly.com

Pioglitazone, a thiazolidinedione, improves glycemic control primarily by increasing peripheral insulin sensitivity in patients with type 2 diabetes, whereas metformin, a biguanide, exerts its effect primarily by decreasing hepatic glucose output. In the first head-to-head, double-blind clinical trial comparing these two oral antihyperglycemic medications (OAMs), we studied the effect of 32-wk monotherapy on glycemic control and insulin sensitivity in 205 patients with recently diagnosed type 2 diabetes who were naive to OAM therapy. Subjects were randomized to either 30 mg pioglitazone or 850 mg metformin daily with titrations upward to 45 mg (77% of pioglitazone patients) and 2550 mg (73% of metformin patients), as indicated, to achieve fasting plasma glucose levels of less than 7.0 mmol/liter (126 mg/dl). Pioglitazone was comparable to metformin in improving glycemic control as measured by hemoglobin A1C and fasting plasma glucose. At endpoint, pioglitazone was significantly more effective than metformin in improving indicators of insulin sensitivity, as determined by reduction of fasting serum insulin (P = 0.003) and by analysis of homeostasis model assessment for insulin sensitivity (HOMA-S; P = 0.002). Both OAM therapies were well tolerated. Therefore, pioglitazone and metformin are equally efficacious in regard to glycemic control, but they exert significantly different effects on insulin sensitivity due to differing mechanisms of action. The more pronounced improvement in indicators of insulin sensitivity by pioglitazone, as compared with metformin monotherapy in patients recently diagnosed with type 2 diabetes who are OAM-naive, may be of interest for further clinical evaluation.

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Expert Opin Investig Drugs. 2003 Apr;12(4):623-33.
Treatment of non-insulin-dependent diabetes mellitus.
Patel M, Rybczynski PJ.
Room PC110, Bldg: PCC, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 1000 Route 202, Raritan, NJ 08869, USA. mpatel5@prdus.jnj.com

Diabetes mellitus has been declared to be at an epidemic level by the World Health Organization. The syndrome is characterised as either Type I (insulin-dependent) or Type II (non-insulin-dependent) diabetes mellitus. Impaired glucose tolerance for extended periods of time results in serious complications such as kidney damage and impaired blood circulation and is the main cause for blindness and amputations in patients with diabetes. A combination of life-style change, dietary change and oral medications can treat Type II diabetes mellitus effectively and prevent long-term complications. Combination therapy appears to be the most effective approach in controlling blood glucose levels. This review updates the progress made in medicinal chemistry towards promising biological targets, with the development of a new generation of small molecules having improved efficacy and safety profiles.

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Acta Chir Belg. 2003 Feb;103(1):73-80.
Pancreatic transplantation.
Coosemans W, Pirenne J.
Abdominal Transplant Surgery Department, K.U. Leuven, U.Z. Gasthuisberg, Herestraat 49, B-3000 Leuven.

Pancreas transplantation is the only treatment of Type I diabetes that consistently establishes an insulin-independent, normoglycemic state. Currently long-term insulin-independence is achieved in > 80% of recipients of pancreas grafts placed simultaneous with the kidney and in > 70% of recipients of a pancreas after a kidney and non-uremic recipients of a pancreas alone. The penalty is immunosuppression, already obligatory for a kidney recipient, but the benefits are improved quality of life and the effect that perfect control of glycemia can have on secondary complications of diabetes.

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Diabet Med. 2003 Apr;20(4):312-8.
A randomized trial of insulin aspart with intensified basal NPH insulin supplementation in people with Type 1 diabetes.
DeVries JH, Lindholm A, Jacobsen JL, Heine RJ, Home PD; Tri-Continental Insulin Aspart Study Group.
Department of Endocrinology, VU University Medical Centre, Amsterdam, the Netherlands. j.h.devries@amc.uva.nl

AIMS: Insulin aspart has been shown to improve post-prandial and overall glycaemic control in people with Type 1 diabetes. We hypothesized that insulin aspart with intensified basal NPH insulin supplementation would result in better overall glycaemic control than human regular insulin with standard basal NPH insulin. METHODS: The trial was conducted in 43 centres in seven countries. People with Type 1 diabetes were randomized to mealtime insulin aspart with up to four daily NPH doses if meals were > 5 h apart and a 25% increase in bedtime NPH dose (n = 187), or to mealtime human unmodified insulin with once or twice daily basal NPH insulin (n = 181). Efficacy and safety were evaluated at 12 weeks (primary evaluation period) and 64 weeks. RESULTS: At 12 and 64 weeks there was no statistically significant difference in HbA1c between the insulin aspart and regular insulin groups: -0.09 (95% confidence interval (CI) -0.23, +0.05)% and -0.14 (-0.32, +0.04)%. Post-prandial glucose values were lower and the area under the 24-h self-monitored blood glucose curve above 7.0 mmol/l was 28% smaller with insulin aspart (35.2 +/- 3.2 vs. 48.9 +/- 3.1 mmol/l h, P = 0.0015). No significant differences were found in mild or severe hypoglycaemia, or adverse event rate. At 64 weeks treatment satisfaction was higher in the insulin aspart group (difference 1.57 (95% CI 0.49, 2.64) points, P = 0.004), while quality of life was not different. CONCLUSIONS: Improved post-prandial glycaemic control and treatment satisfaction with insulin aspart were confirmed. Intensifying basal insulin supplementation resulted in a similar HbA1c decrement as previously found with the use of insulin aspart and standard NPH insulin supplementation. This does not support routinely basal NPH insulin intensification when using rapid-acting insulin analogues in daily practice.

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Curr Diab Rep. 2002 Aug;2(4):365-70.
Islet transplantation: travels up the learning curve.
Robertson RP.
Pacific Northwest Research Institute, 720 Broadway, Seattle, WA 98122, USA. rpr@u.washington.edu

Great excitement was generated in 2000 by a report from the University of Alberta in Edmonton, Canada, that seven of seven type I diabetic patients transplanted with intrahepatic cadaveric islets were normal glycemic, 1-year post-transplantation without the use of exogenous insulin treatment. The follow-up information from the same researchers with a larger group of patients indicated that in a group of 12 alloislet recipients, five had impaired glucose tolerance and three had post-transplantation diabetes. Great attention is now being directed toward understanding why alloislet recipients who are initially successful may later develop partial failure. At the same time, the Immune Tolerance Network is sponsoring a multicenter trial using the Edmonton protocol to ascertain whether these results can be replicated by other transplant groups in the United States, Canada, and Europe. Detailed studies of islet beta-cell function have revealed intact insulin secretion in autoislet and alloislet transplant recipients. In contrast, glucagon responses to insulin-induced hypoglycemia are absent from islets transplanted intrahepatically; however, alpha cells within intrahepatic islets are capable of releasing glucagon in response to intravenous arginine. Although many technical refinements are underway to make this procedure even more efficacious, supply and demand issues are a major concern and must be dealt with before the procedure of islet transplantation can be considered generally available for patients with diabetes.

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J Indian Med Assoc. 2002 Jul;100(7):467-8.
Efficacy and safety of nateglinide in the treatment of type II diabetes mellitus.
Chandrasekharan S, Rao PP, Jayaram S, Jain SD, Ganesan R, Desai A.
Sri Ramachandra Medical College, Porur, Chennai 600 116.

Nateglinide a new short-acting D-phenylalanine derivative represents a new chemical class of drugs for treating type 2 diabetes that is pharmacologically and therapeutically distinct from currently existing agents. Studies in normal patients and those with type 2 diabetes have shown that nateglinide reduces mealtime blood glucose excursions by physiologic regulation of insulin secretion. Nateglinide binds to and inhibits the K+(ATP) channel of the beta-cell, causing membrane depolarisation, with a subsequent influx of extracellular calcium that results in insulin secretion. A total of 105 patients in 5 centres with type II diabetes mellitus were taken according to the inclusion criteria and given drug treatment and were evaluated on their improvement in fasting and postprandial plasma glucose and glycosylated haemoglobin values for efficacy, besides physician's assessment of the overall safety and efficacy. Nateglinide in a dose of 60 mg before three main meals was given and increased to a maximum of 120 mg thrice daily over the first 3-4 weeks. Nateglinide had to be taken 10 minutes before meals. Duration of treatment was 12 weeks. The patients showed decrease in fasting plasma glucose from 2nd week onwards and reduction in glycosylated haemoglobin by 6th week onwards. Postprandial glucose reduction was also significant at the end of 12th week. The frequency of adverse effects was low and no serious adverse effects were encountered.

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Curr Diab Rep. 2002 Aug;2(4):359-64.
Pancreas and kidney transplantation.
Larsen J, Lane J, Mack-Shipman L.
Department of Internal Medicine, 983020 Nebraska Medical Center, Omaha, NE 69198-3020, USA. jlarsen@unmc.edu

Kidney transplantation is preferred over dialysis for management of end-stage renal disease complicating type I or type 2 diabetes, for those who are eligible. Simultaneous pancreas-kidney (SPK) or pancreas after kidney transplantation (PAK) is an important alternative to kidney transplantation alone for type I diabetes patients if the patient is able to withstand the additional risks of these procedures, because of the benefits of glucose control on other diabetic complications. Pancreas transplantation alone (PTA) is most useful for the treatment of debilitating, frequent hypoglycemia complicating type I diabetes, if renal function is adequate. One-year pancreas graft survival is best after SPK (82%) but has significantly improved after both PAK (74%) and PTA (76%). The I-year kidney graft and patient survival rates after SPK are similar to kidney transplantation alone. Pancreas transplantation normalizes glucose beyond what can be achieved with insulin therapy and has been shown to decrease progression of or improve most, if not all, diabetic end-organ complications using current immunosuppression regimens. However, the diabetologist and endocrinologist should remain involved in the care of the pancreas or kidney transplant recipient for treatment of vascular disease risk factors such as dyslipidemia, surveillance of other diabetic complications including foot ulcers, surveillance and treatment of bone loss, and management of hyperglycemia if it recurs.

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Curr Diab Rep. 2002 Jun;2(3):289-94.
The effect of dietary intervention on serum lipid levels in type 2 diabetes mellitus.
Cater NB, Garg A.
Department of Internal Medicine, Center for Human Nutrition, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9052, USA.

Dietary therapy is the cornerstone of lipid management in patients with type 2 diabetes mellitus. The key strategies are the reduction of intake of saturated fat, trans unsaturated fat and cholesterol, and the reduction of energy intake to promote weight loss. This approach will produce significant improvements in the serum levels of low-density lipoprotein (LDL) cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol. According to both the American Diabetes Association and the National Cholesterol Education Program (NCEP), the primary target of therapy is the serum LDL cholesterol level, with the secondary targets being non-HDL cholesterol, triglycerides, and HDL cholesterol. The recently updated guidelines of the NCEP place new emphasis on increasing soluble fiber intake to 10 to 25 g/d and adding foods fortified with plant stanols/sterols (2 g/d) as options to enhance the LDL cholesterol-lowering effect of diet.

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Curr Diab Rep. 2002 Oct;2(5):448-56.
Antioxidant vitamins and their influence in diabetes mellitus.
Hasanain B, Mooradian AD.
Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Saint Louis University School of Medicine, 1402 South Grand Boulevard, Saint Louis, MO 63104, USA.

Diabetes mellitus is a chronic disease associated with serious complications. A number of studies have suggested that enhanced oxidation is the underlying abnormality responsible for some of the complications of diabetes. It is not known whether the ingestion of antioxidant vitamins could retard or perhaps reverse the oxidative damage. The information regarding the benefit of antioxidant vitamin supplementation is conflicting some trials have demonstrated adverse effects of excessive consumption of vitamin supplements. In this article, we review the available literature on the association of cardiovascular events and ingestion of vitamins with antioxidant properties. Given the lack of data to substantiate the benefit and safety of ingestion of antioxidant vitamins in excess of the recommended dietary allowance, physicians should avoid the recommendation of vitamin supplementation to their patients.

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Curr Diab Rep. 2002 Oct;2(5):403-8.
Insulin analogues: new therapies for type 2 diabetes mellitus.
Bethel MA, Feinglos MN.
Department of Medicine, Box 3921, Duke University Medical Center, Durham, NC 27710, USA. bethe002@mc.duke.edu

Insulin therapy is ultimately necessary for the control of blood glucose in a majority of patients with type 2 diabetes mellitus. Unfortunately, the pharmacokinetic characteristics of previously available rapid-, intermediate-, and long-acting preparations make sustained normoglycemia almost impossible. Advances in molecular genetic engineering have made possible the development of insulin analogues with pharmacokinetics that more closely mimic the needs of patients with type 2 diabetes. In the following article, we explore the insulin analogues currently available for clinical use, their pharmacokinetics, and the rationale for their use in the treatment of type 2 diabetes, and follow-up with a brief examination of future developments.

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