Endogenous Glucose-Dependent Insulinotropic Polypeptide Contributes to Sitagliptin-Mediated Improvement in Beta Cell Function in Patients with Type 2 Diabetes
Dipeptidyl peptidase 4 (DPP-4) degrades the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). DPP-4 inhibitors improve glycemic control in type 2 diabetes, but the importance of protecting GIP from degradation for their clinical effects is unknown. We included 12 patients with type 2 diabetes (mean±SD; BMI 27±2.6 kg/m2, HbA1c 7.1±1.4% (54±15 mmol/mol) in this double-blind, placebo-controlled, crossover study to investigate the contribution of endogenous GIP to the effects of the DPP-4 inhibitor sitagliptin. Participants underwent two randomized 13-day treatment courses of sitagliptin (100 mg/day) and placebo, respectively. At the end of each treatment period, we performed two mixed meal tests with infusion of the GIP receptor antagonist GIP(3-30)NH2 (1,200 pmol/kg/min) or saline placebo. Sitagliptin lowered mean fasting plasma glucose by 1.1 mmol/L compared to placebo treatment. During placebo treatment, postprandial glucose excursions were increased during GIP(3-30)NH2 compared to saline (ΔAUC%±SEM; +7.3±2.8%) but were unchanged during sitagliptin treatment. Endogenous GIP improved beta cell function by 37±12% during DPP-4 inhibition by sitagliptin. This was determined by the insulin secretion rate / plasma glucose ratio. We calculated an estimate of the ‘absolute sitagliptin-mediated impact of GIP on beta cell function’ as the insulinogenic index during sitagliptin treatment plus saline infusion minus the insulinogenic index during sitagliptin plus GIP(3-30)NH2. This estimate was expressed relative to the maximal potential contribution of GIP to the effect of sitagliptin (= 100%), defined as the difference between the full sitagliptin treatment effect, including actions mediated by GIP (sitagliptin plus saline) and the physiological response minus any contribution by GIP (placebo treatment plus GIP(3-30)NH2). We demonstrate insulinotropic and glucose-lowering effects of endogenous GIP in patients with type 2 diabetes, and that endogenous GIP contributes to the improved beta cell function observed during DPP-4 inhibition.