The effect of DPP-4 inhibition with sitagliptin on incretin secretion and on fasting and postprandial glucose turnover in subjects with impaired fasting glucose

P>Objective Low glucagon-like peptide-1 (GLP-1) concentrations have been observed in impaired fasting glucose (IFG). It is uncertain whether 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-blinded, placebo-controlled, parallel-group design. At the time of enrolment, subjects ate a standardized meal labelled with [1-13C]-glucose. Infused [6-3H] glucose enabled measurement of systemic meal appearance (MRa). Infused [6,6-2H(2)] glucose enabled measurement of endogenous glucose production (EGP) and glucose disappearance (Rd). Subsequently, subjects were randomized to 100 mg 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 center dot 1 +/- 0 center dot 7 vs 17 center dot 6 +/- 0 center dot 8 mu mol/kg per min, P = 0 center dot 53), Rd (55 center dot 6 +/- 4 center dot 3 vs 58 center dot 9 +/- 3 center dot 3 mu mol/kg per min, P = 0 center dot 47) and MRa (6639 +/- 377 vs 6581 +/- 316 mu mol/kg per 6 h, P = 0 center dot 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.