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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.

OBJECTIVEGlucagon-like peptide (GLP)-1 receptor is encoded by GLP1R. The effect of genetic variation at this locus on the response to GLP-1 is unknown. This study assessed the effect of GLP1R polymorphisms on insulin secretion in response to hyperglycemia and to infused GLP-1 in nondiabetic subjects.RESEARCH DESIGN AND METHODSEighty-eight healthy individuals (aged 26.3 ± 0.6 years, fasting glucose 4.83 ± 0.04 mmol/l) were studied using a hyperglycemic clamp. GLP-1 was infused for the last 2 h of the study (0.75 pmol/kg/min over 121–180 min, 1.5 pmol/kg/min over 181–240 min). β-Cell responsivity (ΦTotal) was measured using a C-peptide minimal model. The effect of 21 tag single nucleotide polymorphisms (SNPs) in GLP1R on ΦTotal was examined.RESULTSTwo SNPs (rs6923761 and rs3765467) were nominally associated with altered β-cell responsivity in response to GLP-1 infusion.CONCLUSIONSVariation in GLP1R may alter insulin secretion in response to exogenous GLP-1. Future studies will determine whether such variation accounts for interindividual differences in response to GLP-1–based therapy.

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.

Objective Low Glucagon-like Peptide-1 (GLP-1) concentrations have been observed in impaired fasting glucose (IFG). It is uncertain if these abnormalities contribute directly to the pathogenesis of IFG and impaired glucose tolerance. Dipeptidyl peptidase-4 (DPP-4) inhibitors raise incretin hormone concentrations enabling an examination of their effects on glucose turnover in IFG. Research Design and Methods We studied 22 subjects with IFG using a double blind, placebo-controlled parallel group design. At the time of enrollment, subjects ate a standardized meal labeled with [1-13C]-glucose. Infused [6-3H] glucose enabled measurement of systemic meal appearance (MRa). Infused [6,6-2H2] glucose enabled measurement of endogenous glucose production (EGP) and glucose disappearance (Rd). Subsequently, subjects were randomized to100mg of sitagliptin daily or placebo. After an 8-week treatment period, the mixed meal was repeated. Results As expected, subjects with IFG who received placebo did not experience any change in glucose concentrations. Despite raising intact GLP-1 concentrations, treatment with sitagliptin did not alter either fasting or postprandial glucose, insulin or C-peptide concentrations. Postprandial EGP (18.1±0.7 vs. 17.6±0.8 µmol/kg/min, p = 0.53), Rd (55.6±4.3 vs. 58.9±3.3 µmol/kg/min, p = 0.47) and MRa (6639±377 vs. 6581±316 µmol/kg per 6h, p = 0.85) were unchanged. Sitagliptin was associated with decreased total GLP-1 implying decreased incretin secretion. Conclusions DPP-4 inhibition did not alter fasting or postprandial glucose turnover in people with IFG. Low incretin concentrations are unlikely to be involved in the pathogenesis of IFG.