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.

The hyperglycemic activity of pancreatic extracts was encountered some 80 yr ago during efforts to optimize methods for the purification of insulin. The hyperglycemic substance was named "glucagon," and it was subsequently determined that glucagon is a 29-amino acid peptide synthesized and released from pancreatic alpha-cells. This article begins with a brief overview of the discovery of glucagon and the contributions that somatostatin and a sensitive and selective assay for pancreatic (vs. gut) glucagon made to understanding the physiological and pathophysiological roles of glucagon. Studies utilizing these tools to establish the function of glucagon in normal nutrient homeostasis and to document a relative glucagon excess in type 2 diabetes mellitus (T2DM) and precursors thereof are then discussed. The evidence that glucagon excess contributes to the development and maintenance of fasting hyperglycemia and that failure to suppress glucagon secretion contributes to postprandial hyperglycemia is then reviewed. Although key human studies are emphasized, salient animal studies highlighting the importance of glucagon in normal and defective glucoregulation are also described. The past eight decades of research in this area have led to development of new therapeutic approaches to treating T2DM that have been shown to, or are expected to, improve glycemic control in patients with T2DM in part by improving alpha-cell function or by blocking glucagon action. Accordingly, this review ends with a discussion of the status and therapeutic potential of glucagon receptor antagonists, alpha-cell selective somatostatin agonists, glucagon-like peptide-1 agonists, and dipeptidyl peptidase-IV inhibitors. Our overall conclusions are that there is considerable evidence that relative hyperglucagonemia contributes to fasting and postprandial hyperglycemia in patients with T2DM, and there are several new and emerging pharmacotherapies that may improve glycemic control in part by ameliorating the hyperglycemic effects of this relative glucagon excess.

Vildagliptin is an incretin degradation inhibitor that improves beta-cell function in diabetic patients by increasing the insulin secretory tone.

Aims/hypothesis We assessed the effects of vildagliptin, a novel dipeptidyl peptidase IV inhibitor, on postprandial lipid and lipoprotein metabolism in patients with type 2 diabetes. Subjects, materials and methods This was a single-centre, randomised, double-blind study in drug-naive patients with type 2 diabetes. Patients received vildagliptin (50 mg twice daily, n=15) or placebo (n=16) for 4 weeks. Triglyceride, cholesterol, lipoprotein, glucose, insulin, glucagon and glucagon-like peptide-1 (GLP-1) responses to a fat-rich mixed meal were determined for 8 h postprandially before and after 4 weeks of treatment. Results Relative to placebo, 4 weeks of treatment with vildagliptin decreased the AUC 0-8h for total trigyceride by 22±11% (p=0.037), the incremental AUC 0-8h for total triglyceride by 85±47% (p=0.065), the AUC 0-8h for chylomicron triglyceride by 65±19% (p=0.001) and the IAUC 0-8h for chylomicron triglyceride by 91±28% (p=0.002). This was associated with a decrease in chylomicron apolipoprotein B-48 (AUC 0-8h , −1.0±0.5 mg l −1 h, p=0.037) and chylomicron cholesterol (AUC 0-8h , −0.14± 0.07 mmol l −1 h, p=0.046). Consistent with previous studies, 4 weeks of treatment with vildagliptin also increased intact GLP-1, suppressed inappropriate glucagon secretion, decreased fasting and postprandial glucose, and decreased HbA 1c from a baseline of 6.7% (change, −0.4±0.1%, p<0.001), all relative to placebo. Conclusions/interpretation Treatment with vildagliptin for 4 weeks improves postprandial plasma triglyceride and apolipoprotein B-48-containing triglyceride-rich lipoprotein particle metabolism after a fat-rich meal. The mechanisms underlying the effects of this dipeptidyl peptidase IV inhibitor on postprandial lipid metabolism remain to be explored.

Aims/Hypothesis: Vildagliptin is a selective dipeptidyl peptidase IV inhibitor that augments meal-stimulated levels of biologically active glucagon-like peptide-1. Chronic vildagliptin treatment decreases postprandial glucose levels and reduces hemoglobin A 1c in type 2 diabetic patients. However, little is known about the mechanism(s) by which vildagliptin promotes reduction in plasma glucose concentration.Methods: Sixteen patients with type 2 diabetes (age, 48 Ϯ 3 yr; body mass index, 34.4 Ϯ 1.7 kg/m 2 ; hemoglobin A 1c , 9.0 Ϯ 0.3%) participated in a randomized, double-blind, placebo-controlled trial. On separate days patients received 100 mg vildagliptin or placebo at 1730 h followed 30 min later by a meal tolerance test (MTT) performed with double tracer technique (3-3 H-glucose iv and 1-14 C-glucose orally).Results: After vildagliptin, suppression of endogenous glucose production (EGP) during 6-h MTT was greater than with placebo (1.02 Ϯ 0.06 vs. 0.74 Ϯ 0.06 mg⅐kg Ϫ1 ⅐min Ϫ1 ; P ϭ 0.004), and insulin secretion rate increased by 21% (P ϭ 0.003) despite significant reduction in mean plasma glucose (213 Ϯ 4 vs. 230 Ϯ 4 mg/dl; P ϭ 0.006). Consequently, insulin secretion rate (area under the curve) divided by plasma glucose (area under the curve) increased by 29% (P ϭ 0.01). Suppression of plasma glucagon during MTT was 5-fold greater with vildagliptin (P Ͻ 0.02). The decline in EGP was positively correlated (r ϭ 0.55; P Ͻ 0.03) with the decrease in fasting plasma glucose (change ϭ Ϫ14 mg/dl). Conclusions

Although there is abundant evidence that hyperglucagonaemia plays a key role in the development of hyperglycaemia in type 2 diabetes, efforts to understand and correct this abnormality have been overshadowed by the emphasis on insulin secretion and action. However, recognition that the incretin hormone glucagon-like peptide-1 (GLP-1) exerts opposing effects on glucagon and insulin secretion has revived interest in glucagon, the neglected partner of insulin, in the bihormonal hypothesis. In healthy subjects, glucagon secretion is regulated by a variety of nutrient, neural and hormonal factors, the most important of which is glucose. The defect in alpha cell function that occurs in type 2 diabetes reflects impaired glucose sensing. GLP-1 inhibits glucagon secretion in vitro and in vivo in experimental animals, and suppresses glucagon release in a glucose-dependent manner in healthy subjects. This effect is also evident in diabetic patients, but GLP-1 does not inhibit glucagon release in response to hypoglycaemia, and may even enhance it. Early clinical studies with agents acting through GLP-1 signalling mechanisms (e.g. exenatide, liraglutide and vildagliptin) suggest that GLP-1 can improve alpha cell glucose sensing in patients with type 2 diabetes. Therapeutic approaches based around GLP-1 have the potential to improve both alpha cell and beta cell function, and could be of benefit in patients with a broad range of metabolic disorders.

This trial (NCT00390520) is registered with ClinicalTrials.gov.Precis: We conclude that vildagliptin enhances α-cell responsiveness to both the suppressive effects of hyperglycemia and the stimulatory effects of hypoglycemia.Page 2 of 25 Conclusions:Vildagliptin enhances α-cell responsiveness to both the suppressive effects of hyperglycemia and the stimulatory effects of hypoglycemia. These effects likely contribute to the efficacy of vildagliptin to improve glycemic control as well as to its low hypoglycemic potential.

OBJECTIVE-We sought to determine whether alterations in meal absorption and gastric emptying contribute to the mechanism by which inhibitors of dipeptidyl peptidase-4 (DPP-4) lower postprandial glucose concentrations.RESEARCH DESIGN AND METHODS-We simultaneously measured gastric emptying, meal appearance, endogenous glucose production, and glucose disappearance in 14 subjects with type 2 diabetes treated with either vildaglipitin (50 mg b.i.d.) or placebo for 10 days using a double-blind, placebo-controlled, randomized, crossover design.RESULTS-Fasting (7.3 Ϯ 0.5 vs. 7.9 Ϯ 0.5 mmol/l) and peak postprandial (14.1 Ϯ 0.6 vs. 15.9 Ϯ 0.9 mmol/l) glucose concentrations were lower (P Ͻ 0.01) after vildagliptin treatment than placebo. Despite lower glucose concentrations, postprandial insulin and C-peptide concentrations did not differ during the two treatments. On the other hand, the integrated (area under the curve) postprandial glucagon concentrations were lower (20.9 Ϯ 1.6 vs. 23.7 Ϯ 1.3 mg/ml per 5 h, P Ͻ 0.05), and glucagon-like peptide 1 (GLP-1) concentrations were higher (1,878 Ϯ 270 vs. 1,277 Ϯ 312 pmol/l per 5 h, P ϭ 0.001) during vildagliptin administration compared with placebo. Gastric emptying and meal appearance did not differ between treatments.CONCLUSIONS-Vildagliptin does not alter gastric emptying or the rate of entry of ingested glucose into the systemic circulation in humans. DPP-4 inhibitors do not lower postprandial glucose concentrations by altering the rate of nutrient absorption or delivery to systemic circulation. Alterations in islet function, secondary to increased circulating concentrations of active GLP-1, are associated with the decreased postprandial glycemic excursion observed in the presence of vildagliptin.