OBJECTIVEGlucocorticoids (GCs) are regarded as diabetogenic because they impair insulin sensitivity and islet-cell function. This study assessed whether treatment with the glucagon-like peptide receptor agonist (GLP-1 RA) exenatide (EXE) could prevent GC-induced glucose intolerance.RESEARCH DESIGN AND METHODSA randomized, placebo-controlled, double-blind, crossover study in eight healthy men (age: 23.5 [20.0–28.3] years; BMI: 26.4 [24.3–28.0] kg/m2) was conducted. Participants received three therapeutic regimens for 2 consecutive days: 1) 80 mg of oral prednisolone (PRED) every day (q.d.) and intravenous (IV) EXE infusion (PRED+EXE); 2) 80 mg of oral PRED q.d. and IV saline infusion (PRED+SAL); and 3) oral placebo-PRED q.d. and intravenous saline infusion (PLB+SAL). On day 1, glucose tolerance was assessed during a meal challenge test. On day 2, participants underwent a clamp procedure to measure insulin secretion and insulin sensitivity.RESULTSPRED+SAL treatment increased postprandial glucose levels (vs. PLB+SAL, P = 0.012), which was prevented by concomitant EXE (vs. PLB+SAL, P = NS). EXE reduced PRED-induced hyperglucagonemia during the meal challenge (P = 0.018) and decreased gastric emptying (vs. PRED+SAL, P = 0.028; vs. PLB+SAL, P = 0.046). PRED+SAL decreased first-phase glucose- and arginine-stimulated C-peptide secretion (vs. PLB+SAL, P = 0.017 and P = 0.05, respectively), whereas PRED+EXE improved first- and second-phase glucose- and arginine-stimulated C-peptide secretion (vs. PLB+SAL; P = 0.017, 0.012, and 0.093, respectively).CONCLUSIONSThe GLP-1 RA EXE prevented PRED-induced glucose intolerance and islet-cell dysfunction in healthy humans. Incretin-based therapies should be explored as a potential strategy to prevent steroid diabetes.

Type 2 diabetes mellitus (T2DM) develops as a consequence of progressive β-cell dysfunction in the presence of insulin resistance. None of the currently-available T2DM therapies is able to change the course of the disease by halting the relentless decline in pancreatic islet cell function. Recently, dipeptidyl peptidase (DPP)-4 inhibitors, or incretin enhancers, have been introduced in the treatment of T2DM. This class of glucose-lowering agents enhances endogenous glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) levels by blocking the incretin-degrading enzyme DPP-4. DPP-4 inhibitors may restore the deranged islet-cell balance in T2DM, by stimulating meal-related insulin secretion and by decreasing postprandial glucagon levels. Moreover, in rodent studies, DPP-4 inhibitors demonstrated beneficial effects on (functional) β-cell mass and pancreatic insulin content. Studies in humans with T2DM have indicated improvement of islet-cell function, both in the fasted state and under postprandial conditions and these beneficial effects were sustained in studies with a duration up to 2 years. However, there is at present no evidence in humans to suggest that DPP-4 inhibitors have durable effects on β-cell function after cessation of therapy. Long-term, large-sized trials using an active blood glucose lowering comparator followed by a sufficiently long washout period after discontinuation of the study drug are needed to assess whether DPP-4 inhibitors may durably preserve pancreatic islet-cell function in patients with T2DM.

Objective: Type 2 diabetes mellitus (T2DM) management requires continuous treatment intensification due to progressive decline in b-cell function in insulin resistant individuals. Initial combination therapy of a dipeptidyl peptidase (DPP)-4 inhibitor with a thiazolidinedione (TZD) may be rational. We assessed the effects of the DPP4 inhibitor alogliptin (ALO) combined with the TZD pioglitazone (PIO), vs ALO monotherapy or placebo (PBO), on b-cell function and glycemic control in T2DM. Material and methods: A 16-week, two-center, randomized, double-blind, PBO-controlled, parallel-arm intervention study in 71 patients with well-controlled T2DM (age 59.1G6.3 years; A1C 6.7G0.1%) treated with metformin, sulfonylurea, or glinide monotherapy was conducted. Patients were treated with combined ALO 25 mg and PIO 30 mg daily or ALO 25 mg daily monotherapy or PBO. Main outcome measures included change in A1C and fasting plasma glucose (FPG) from baseline to week 16. In addition, change in b-cell function parameters obtained from standardized meal tests at baseline and at week 16 was measured. Results: ALO/PIO and ALO decreased A1C from baseline by 0.9G0.1 and 0.4G0.2% respectively (both P!0.001 vs PBO). FPG was decreased to a greater extent by ALO/PIO compared with ALO monotherapy (P!0.01). ALO/PIO treatment improved b-cell glucose sensitivity (vs PBO; P!0.001) and fasting secretory tone (vs PBO; PZ0.001), while ALO monotherapy did not change b-cell function parameters. All treatments were well tolerated. Conclusion: Short-term treatment with ALO/PIO or ALO improved glycemic control in well-controlled T2DM patients, but only combined ALO/PIO improved b-cell function. These data support that initial combination therapy with a DPP4 inhibitor and TZD to address multiple core defects in T2DM may be a sensible approach.

Development of cardiovascular disease is one of the major complications of type 2 diabetes mellitus (T2DM). The chronic hyperglycaemic state is often accompanied by dyslipidaemia, hypertension, low-grade systemic inflammation and oxidative stress which collectively result in a high risk of micro- and macrovascular complications. Current glucose-lowering agents do not sufficiently address fore-mentioned macrovascular-risk factors. Recently, new therapeutic agents were introduced, based on the incretin hormone glucagon-like peptide-1 (GLP-1), that is, the GLP-1 receptor agonists (GLP-1RA) and dipeptidyl-peptidase 4 (DPP-4) inhibitors. Beside its effect on pancreatic insulin secretion, GLP-1 exerts several extra-pancreatic effects such as slowing down gastric emptying, promoting satiety and reducing food intake and weight loss. Also, GLP-1 and GLP-1RA were shown to improve cardiovascular-risk profiles, by reducing body fat content, blood pressure, circulating lipids and inflammatory markers in patients with T2DM. This review summarizes the presently known evidence with regard to extra-pancreatic effects of the incretin-based agents, focusing on the actions that improve the cardiovascular-risk profile. We present available data from clinical trials of at least 24 week duration, but also findings from small-sized clinical 'proof of principle' studies. We conclude that GLP-1 RA and to a lesser extent DPP-4 inhibitors are promising agents with regard to their effects on body weight, blood pressure and lipids, which collectively ameliorate the cardiovascular-risk profile and as such may have added value in the treatment of T2DM. However, large-sized long-term outcome studies are warranted to show the true added value of these agents in the treatment of patients with T2DM.

Impaired fasting glucose (IFG) is more prevalent in men and impaired glucose tolerance (IGT) more prevalent in women. To explore whether this sex difference is related to female sex hormones, we performed a cross-sectional analysis of data from 2,164 (1,329 women and 835 men) firstdegree relatives of individuals with type 2 diabetes. Subjects were categorized based on a 75-g oral glucose tolerance test. Sex and hormone replacement therapy (HRT) effects on the distribution of glucose tolerance were assessed using multinomial logistic regression corrected for familial clustering. T he reclassification of glucose tolerance in 1997 included the subdivision of impaired glucose regulation into both impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) (1). When first defined, these both were expected to represent states of increased risk for developing type 2 diabetes and thus frequently have been referred to as pre-diabetes. Since that time, it has become clear that these two states do not always occur in the same individuals and that their pathogenesis may be different (2-6).In line with the fact that IFG and IGT may independently occur and may differ in their etiology, it has been reported that the prevalence of IFG and IGT differs by sex, with IFG being more prevalent in men and IGT more prevalent in women (6 -12). The reason(s) for this sex difference in glucose metabolism has not been explored, but some studies suggest that female sex hormones may contribute. In the Women's Health Initiative, when compared with placebo, the combination of estrogen and progesterone was associated with a decreased incidence of diabetes (13) and there was a trend for a decreased incidence of diabetes in the estrogen-only arm (P ϭ 0.07) (14). After the 1st year of treatment, both the combination of estrogen plus progesterone and the estrogen-alone groups demonstrated decreased fasting plasma glucose (FPG) and decreased insulin resistance, as measured by the homeostasis model assessment of insulin resistance (13,14). Similarly, the Heart and Estrogen/Progestin Replacement Study showed a lower incidence of diabetes in women using combination hormone replacement therapy (HRT) (15). However, neither the Women's Health Initiative nor the Heart and Estrogen/Progestin Replacement Study performed oral glucose tolerance tests (OGTTs) to determine the effect of treatment on postchallenge plasma glucose. Studies that have measured both fasting and 2-h plasma glucose levels have shown that the beneficial effects of HRT on the fasting glucose were accompanied by adverse effects on the 2-h glucose (16 -18), while others failed to see an effect on glucose metabolism (19 -21).While IFG and IGT both are known to increase the risk of developing diabetes, there are a number of other factors that also influence progression to hyperglycemia, including a family history of type 2 diabetes (22,23). As the