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.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 <140], impaired glucose tolerance [2-hour ≥140 and <200 mg/dl], or diabetes [2-hour ≥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 (ISR), glucagon suppression, and glycemia and glucose-potentiated arginine (GPA) test-derived measures of β- and α-cell function.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.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.
Andrea Kelly, Saba Sheikh, Darko Stefanovski, Amy J Peleckis C R N P, Sarah C Nyirjesy, Jack N Eiel, Aniket Sidhaye, Russell Localio, Robert Gallop, Diva D De Leon, Denis Hadjiliadis, Ronald C Rubenstein, Michael R Rickels