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OBJECTIVE -Insulin resistance, associated with increased lipolysis, results in a high exposure of nonadipose tissue to lipids. Experimental data indicate that fatty infiltration of pancreatic islets may also contribute to ␤-cell dysfunction, but whether this occurs in humans in vivo is unknown.RESEARCH DESIGN AND METHODS -Using proton magnetic resonance spectroscopy and oral glucose tolerance tests, we studied the association of pancreatic lipid accumulation in vivo and various aspects of ␤-cell function in 12 insulin-naive type 2 diabetic and 24 age-and BMI-matched nondiabetic men.RESULTS -Patients versus control subjects had higher A1C, fasting plasma glucose, and insulin and triglyceride levels and lower HDL cholesterol, but similar waist circumference. Median (interquartile range) pancreatic fat content in patients and control subjects was 20.4% (13.4 -43.6) and 9.7% (7.0 -20.2), respectively (P ϭ 0.032). Pancreatic fat correlated negatively with ␤-cell function parameters, including the insulinogenic index adjusted for insulin resistance, early glucose-stimulated insulin secretion, ␤-cell glucose sensitivity, and rate sensitivity (all P Ͻ 0.05), but not potentiation. However, these associations were significantly affected by the diabetic state, such that a significant association of pancreatic fat with ␤-cell dysfunction was only present in the nondiabetic group (all P Ͻ 0.01), suggesting that once diabetes occurs, factors additional to pancreatic fat account for further ␤-cell function decline. In control subjects, the association of pancreatic fat and ␤-cell function remained significant after correction for BMI, fasting plasma glucose, and triglycerides (P ϭ 0.006).CONCLUSIONS -These findings indicate that pancreatic lipid content may contribute to ␤-cell dysfunction and possibly to the subsequent development of type 2 diabetes in susceptible humans. Diabetes Care 30:2916-2921, 2007P rogressive ␤-cell dysfunction, in the context of insulin resistance, is a hallmark of type 2 diabetes (1). Glucose toxicity, ensuing from diabetesrelated hyperglycemia, has been regarded as a contributor to ␤-cell damage (2). In contrast, chronic exposure of the pancreatic islets to nonesterified fatty acids (NEFAs) is considered as a potential primary cause of ␤-cell dysfunction (3). In obese individuals, increased lipolysis contributes to high levels of circulating NEFAs, whereas liver insulin resistance leads to elevated hepatic output of triglyceriderich particles (4). When NEFA supply exceeds utilization, nonadipose tissues, including the pancreatic islets, start accumulating triglycerides (3), which is aggravated by the simultaneous presence of hyperglycemia (2,5,6). Subsequently, various mechanisms including the formation of reactive long-chain fatty acyl-CoAs and toxic metabolites, such as ceramide, the activation of protein kinase C-␦, and increased oxidative stress, may all contribute to apoptosis and the decline of ␤-cell mass (2,3,5-7). Finally, experimental and autopsy data indicate that fatty infiltration of th...

OBJECTIVE Traditional blood glucose–lowering agents do not sustain adequate glycemic control in most type 2 diabetic patients. Preclinical studies with exenatide have suggested sustained improvements in β-cell function. We investigated the effects of 52 weeks of treatment with exenatide or insulin glargine followed by an off-drug period on hyperglycemic clamp–derived measures of β-cell function, glycemic control, and body weight. RESEARCH DESIGN AND METHODS Sixty-nine metformin-treated patients with type 2 diabetes were randomly assigned to exenatide (n = 36) or insulin glargine (n = 33). β-Cell function was measured during an arginine-stimulated hyperglycemic clamp at week 0, at week 52, and after a 4-week off-drug period. Additional end points included effects on glycemic control, body weight, and safety. RESULTS Treatment-induced change in combined glucose- and arginine-stimulated C-peptide secretion was 2.46-fold (95% CI 2.09–2.90, P < 0.0001) greater after a 52-week exenatide treatment compared with insulin glargine treatment. Both exenatide and insulin glargine reduced A1C similarly: −0.8 ± 0.1 and −0.7 ± 0.2%, respectively (P = 0.55). Exenatide reduced body weight compared with insulin glargine (difference −4.6 kg, P < 0.0001). β-Cell function measures returned to pretreatment values in both groups after a 4-week off-drug period. A1C and body weight rose to pretreatment values 12 weeks after discontinuation of either exenatide or insulin glargine therapy. CONCLUSIONS Exenatide significantly improves β-cell function during 1 year of treatment compared with titrated insulin glargine. After cessation of both exenatide and insulin glargine therapy, β-cell function and glycemic control returned to pretreatment values, suggesting that ongoing treatment is necessary to maintain the beneficial effects of either therapy.

Men with the metabolic syndrome (MetS) and type 2 diabetes (T2D) often have low testosterone levels. Elevating low testosterone levels may improve features of the MetS and glycemic control. In a single blind, 52-week randomized clinical trial, the effects of supervised diet and exercise (D&E) with or without transdermal testosterone administration on components of the MetS in hypogonadal men with the MetS and newly diagnosed T2D were assessed. A total of 32 hypogonadal men (total testosterone ,12.0 nmol/L) with newly diagnosed T2D and with the MetS as defined by the Adult Treatment Panel III and the International Diabetes Federation received supervised D&E, but 16 received it in combination with testosterone gel (50 mg) once daily (n 5 16). No glucose-lowering agents were administered prior to or during the study period. Outcome measures were components of the MetS as defined by the Adult Treatment Panel III and the International Diabetes Federation. Serum testosterone, glycosylated hemoglobin (HbA 1c ), fasting plasma glucose, high-density lipoprotein cholesterol, triglyceride concentrations, and the waist circumference improved in both treatment groups after 52 weeks of treatment. Addition of testosterone significantly further improved these measures compared with D&E alone. All D&E plus testosterone patients reached the HbA 1c goal of less than 7.0%; 87.5% of them reached an HbA 1c of less than 6.5%. Based on Adult Treatment Panel III guidelines, 81.3% of the patients randomized to D&E plus testosterone no longer matched the criteria of the MetS, whereas 31.3% of the D&E alone participants did. Additionally, testosterone treatment improved insulin sensitivity, adiponectin, and high-sensitivity C-reactive protein. Addition of testosterone to supervised D&E results in greater therapeutic improvements of glycemic control and reverses the MetS after 52 weeks of treatment in hypogonadal patients with the MetS and newly diagnosed T2D.

Cross-sex hormone treatment of transsexuals seems acceptably safe over the short and medium term, but solid clinical data are lacking.

OBJECTIVEWe previously showed that exenatide (EXE) enhanced insulin secretion after 1 year of treatment, relative to insulin glargine (GLAR), with a similar glucose-lowering action. These effects were not sustained after a 4-week off-drug period. This article reports the results after additional 2 years of exposure.RESEARCH DESIGN AND METHODSSixty-nine metformin-treated patients with type 2 diabetes were randomized to EXE or GLAR. Forty-six patients entered the 2-year extension study in which they continued their allocated therapy. Thirty-six completed (EXE: n = 16; GLAR: n = 20) the 3-year exposure period. Insulin sensitivity (M value) and β-cell function were measured by euglycemic hyperinsulinemic clamp followed by hyperglycemic clamp with arginine stimulation at pretreatment (week 52) and 4 weeks after discontinuation of study medication (week 56 and week 172). First-phase glucose stimulated C-peptide secretion was adjusted for M value and calculated as the disposition index (DI).RESULTSAt 3 years, EXE and GLAR resulted in similar levels of glycemic control: 6.6 ± 0.2% and 6.9 ± 0.2%, respectively (P = 0.186). EXE compared with GLAR significantly reduced body weight (−7.9 ± 1.8 kg; P < 0.001). After the 4-week off-drug period, EXE increased the M value by 39% (P = 0.006) while GLAR had no effect (P = 0.647). Following the 4-week off-drug period, the DI, compared with pretreatment, increased with EXE, but decreased with GLAR (1.43 ± 0.78 and −0.99 ± 0.65, respectively; P = 0.028).CONCLUSIONSEXE and GLAR sustained HbA1c over the 3-year treatment period, while EXE reduced body weight and GLAR increased body weight. Following the 3-year treatment with EXE, the DI was sustained after a 4-week off-drug period. These findings suggest a beneficial effect on β-cell health.

Objective: Glucocorticoids (GCs), such as prednisolone, are associated with adverse metabolic effects, including glucose intolerance and diabetes. In contrast to the well known GC-induced insulin resistance, the effects of GCs on b-cell function are less well established. We assessed the acute and short-term effects of prednisolone treatment on b-cell function in healthy men. Research design and methods: A randomised, double-blind, placebo-controlled trial consisting of two protocols was conducted. In protocol 1 (nZ6), placebo and a single dose of 75 mg of prednisolone were administered. In protocol 2 (nZ23), participants received 30 mg of prednisolone daily or placebo for 15 days. Both empirical and model-based parameters of b-cell function were calculated from glucose, insulin and C-peptide concentrations obtained during standardised meal tests before and during prednisolone treatment (protocols 1 and 2), and 1 day after cessation of treatment (protocol 2). Results: Seventy-five milligrams of prednisolone acutely increased the area under the postprandial glucose curve (AUC gluc ; PZ0.005), and inhibited several parameters of b-cell function, including AUC c-pep /AUC gluc ratio (PZ0.004), insulinogenic index (PZ0.007), glucose sensitivity (PZ0.02) and potentiation factor ratio (PFR; PZ0.04). A 15-day treatment with prednisolone increased AUC gluc (P!0.001), despite augmented C-peptide secretion (PZ0.05). b-cell function parameters were impaired, including the fasting insulin secretory tone (PZ0.02) and PFR (PZ0.007). Conclusions: Acute and short-term exposure to prednisolone impairs different aspects of b-cell function, which contribute to its diabetogenic effects.

OBJECTIVETo study the effect of exenatide on body composition and circulating cardiovascular risk biomarkers.RESEARCH DESIGN AND METHODSMetformin-treated patients with type 2 diabetes (N = 69) were randomized to exenatide or insulin glargine and treated for 1 year. Body composition was evaluated by dual-energy X-ray absorptiometry. Additionally, body weight, waist circumference, and cardiovascular biomarkers were measured.RESULTSTreatment with exenatide for 1 year significantly reduced body weight, waist circumference, and total body and trunkal fat mass by 6, 5, 11, and 13%, respectively. In addition, exenatide increased total adiponectin by 12% and reduced high-sensitivity C-reactive protein by 61%. Insulin glargine significantly reduced endothelin-1 by 7%. These changes were statistically independent of the change in total body fat mass and body weight.CONCLUSIONSExenatide treatment for 1 year reduced body fat mass and improved the profile of circulating biomarkers of cardiovascular risk. No significant changes were seen with insulin glargine except a trend for reduced endothelin-1 levels.