Dipeptidyl Peptidase-4 Inhibition by Vildagliptin and the Effect on Insulin Secretion and Action in Response to Meal Ingestion in Type 2 Diabetes

Abstract

OBJECTIVE -The purpose of this study was to determine the mechanism by which dipeptidyl peptidase-4 inhibitors lower postprandial glucose concentrations.RESEARCH DESIGN AND METHODS -We measured insulin secretion and action as well as glucose effectiveness in 14 subjects with type 2 diabetes who received vildagliptin (50 mg b.i.d.) or placebo for 10 days in random order separated by a 3-week washout. On day 9 of each period, subjects ate a mixed meal. Insulin sensitivity (S I ), glucose effectiveness, and ␤-cell responsivity indexes were estimated using the oral glucose and C-peptide minimal models. At 300 min 0.02 unit/kg insulin was administered intravenously.RESULTS -Vildagliptin reduced postprandial glucose concentrations (905 Ϯ 94 vs. 1,008 Ϯ 104 mmol/6 h, P ϭ 0.02). Vildagliptin did not alter net S I (7.71 Ϯ 1.28 vs. 6.41 Ϯ 0.84, P ϭ 0.13) or glucose effectiveness (0.019 Ϯ 0.002 vs. 0.018 Ϯ 0.002 dl ⅐ kg Ϫ1 ⅐ min Ϫ1 , P ϭ 0.65). However, the net ␤-cell responsivity index was increased (35.7 Ϯ 5.2 vs. 28.9 Ϯ 5.2 10 Ϫ9 min Ϫ1 , P ϭ 0.03) as was total disposition index (381 Ϯ 48 vs. 261 Ϯ 35 10Vildagliptin lowered postprandial glucagon concentrations (27.0 Ϯ 1.1 vs. 29.7 Ϯ 1.5 g ⅐ l Ϫ1 ⅐ 6 h Ϫ1 , P ϭ 0.03), especially after administration of exogenous insulin (81.5 Ϯ 6.4 vs. 99.3 Ϯ 5.6 ng/l, P ϭ 0.02).CONCLUSIONS -Vildagliptin lowers postprandial glucose concentrations by stimulating insulin secretion and suppressing glucagon secretion but not by altered insulin action or glucose effectiveness. A novel observation is that vildagliptin alters ␣-cell responsiveness to insulin administration, but the significance of this action is as yet unclear.

A Protein Preload Enhances the Glucose-Lowering Efficacy of Vildagliptin in Type 2 Diabetes

“…Despite augmentation of intact GLP-1 after vildagliptin, particularly when combined with whey, there was minimal increase in insulin, probably because the insulinotropic activity of GLP-1 is glucose dependent (1). The glycemic effect of vildagliptin observed in the current study was also unlikely to be related to improvement in insulin sensitivity; administration of 50 mg vildagliptin twice daily for 9 days was previously reported not to alter insulin action in patients with type 2 diabetes (22). Nevertheless, during pancreatic clamp studies where insulin and glucagon secretion are inhibited, GLP-1 remains effective to suppress endogenous glucose production (23) and enhance peripheral glucose uptake (24), suggesting that GLP-1 has the capacity to lower blood glucose independent of changes in islet hormones.…”

Cholecalciferol Supplementation Does Not Influence β-Cell Function and Insulin Action in Obese Adolescents: A Prospective Double-Blind Randomized Trial,

“…In a similar experiment conducted in 14 adults with type 2 diabetes, we previously observed an overall mean change 6 SD [ΔDI] = 120 (6138) 10 214 dL Á kg 21 Á min 21 Á pmol 21 Á L 21 (32). Assuming similar variation in the changes from study 1 to study 2 (within-subject CV = 43% defined as the SD of the deltas divided by the overall mean DI), 20 subjects per group would provide ;80% power (at a 2-sided 0.05 a level), to detect a difference in mean ΔDI values of 128 10 214 dL Á kg 21 Á min 21 Á pmol 21 Á L 21 between groups (i.e., a 40% difference in mean ΔDI values relative to the overall mean of 321 10 214 dL Á kg 21 Á min 21 Á pmol 21 Á L 21 observed in the previous study) (32). Such a difference would be clinically important in light of our previous studies observing similar-size treatment effects for a pharmacologic intervention (dipeptidyl peptidase-4 inhibition) (32).…”

Efficacy of mitiglinide and sitagliptin, alone or in combination, on postprandial excursion and glycemic variability assessed by continuous glucose monitoring: apost hocanalysis with single-day treatment

“…In addition, there were no differences in glucagon levels between groups treated with either sitagliptin or mitiglinide [12]. Many studies have reported a decrease in post-meal glucagon concentration in patients treated with DPP-4 inhibitors [17][18][19][20], and a single dose of sitagliptin in T2DM patients increased insulin/C-peptide and decreased glucagon levels after oral glucose tolerance test [21]. The discrepancy between the results of the current study and the previous literatures may be explained by the difference between single-day and longerterm treatment settings.…”