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

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 postprandial glycemia in PI-CF with AGT. Methods: 26 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-h≥155 and 2-h<140), impaired glucose tolerance (2-h≥140 and <200 mg/dL), or diabetes (2-h≥200)] were randomized to a 6-month double-blind trial of DPP-4 inhibitor sitagliptin 100 mg daily or matched placebo; 24 completed the trial (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 (ISRs), 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 < 0.001), ISR dynamics improved (P < 0.05), and glucagon suppression was modestly enhanced (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 postprandial glycemia.