Effect of Sitagliptin on Islet Function in Pancreatic Insufficient Cystic Fibrosis With Abnormal Glucose Tolerance

Abstract

Purpose Impaired incretin secretion may contribute to the defective insulin secretion and abnormal glucose tolerance (AGT) that associate with worse clinical outcomes in pancreatic insufficient cystic fibrosis (PI-CF). The study objective was to test the hypothesis that dipeptidyl peptidase-4 (DPP-4) inhibitor-induced increases in intact incretin hormone (glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]) concentrations augment insulin secretion and glucagon suppression and lower post-prandial glycemia in PI-CF with AGT. Methods Twenty-six adults from Children’s Hospital of Philadelphia and University of Pennsylvania CF Center with PI-CF and AGT (defined by oral glucose tolerance test glucose [mg/dL]: early glucose intolerance [1-hour ≥155 & 2-hour n=12 sitagliptin; n=12 placebo). Main outcome measures were mixed-meal tolerance test (MMTT) responses for intact GLP-1 and GIP, insulin secretory rates (ISR), glucagon suppression, and glycemia and glucose-potentiated arginine (GPA) test-derived measures of β- and α-cell function. Results Following 6-months of sitagliptin vs. placebo, MMTT intact GLP-1 and GIP responses increased (P P P <0.05) while GPA test responses for glucagon were lower. No improvements in glucose tolerance or β-cell sensitivity to glucose, including for second-phase insulin response were found. Conclusions In glucose intolerant PI-CF, sitagliptin intervention augmented meal-related incretin responses with improved early insulin secretion and glucagon suppression without affecting post-prandial glycemia.