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

Abstract

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 enrollment, subjects ate a standardized meal labelled with [1-(13)C]-glucose. Infused [6-(3)H] glucose enabled measurement of systemic meal appearance (MRa). Infused [6,6-(2)H(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 (18.1 +/- 0.7 vs 17.6 +/- 0.8 micromol/kg per min, P = 0.53), Rd (55.6 +/- 4.3 vs 58.9 +/- 3.3 micromol/kg per min, P = 0.47) and MRa (6639 +/- 377 vs 6581 +/- 316 micromol/kg per 6 h, 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.

Figure 1

Intact GIP, Total GIP, Intact GLP-1 and Total GLP-1 in the presence (black squares = solid bars) and absence (white squares = open bars) of sitagliptin (left panels) and placebo (right panels).

Figure 2

Glucose, Insulin, C-Peptide and Glucagon concentrations in the presence (black squares = solid bars) and absence (white squares = open bars) of sitagliptin (left panels) and placebo (right panels).

Figure 3

Endogenous glucose production, glucose disappearance and meal appearance in the presence (black squares = solid bars) and absence (white squares = open bars) of sitagliptin (left panels) and placebo (right panels).