Effects of GLP-1 and GIP on Insulin Secretion in Glucose Intolerant, Pancreatic Insufficient Cystic Fibrosis

Abstract

Individuals with pancreatic insufficient cystic fibrosis (PI-CF) and glucose intolerance demonstrate impaired incretin and insulin secretion. The goal of this study was to assess β-cell responsiveness to the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) during glucose potentiated arginine (GPA) testing in adults with PI-CF and abnormal glucose tolerance. Participants were randomized to receive either GLP-1 (n=15) or GIP (n=15) and then underwent GPA testing during either incretin or placebo infusion in a randomized, cross-over fashion. OGTT was similar between groups (1hr: 214±8 vs. 208±7 mg/dL; 2hr: 141±18 vs. 150±18 mg/dL). During GPL-1 infusion, fasting glucose was lower after 30 min vs. placebo (p<0.001), and during the 230 mg/dL glucose clamp the glucose infusion rate (GIR) was higher (p<0.001). Second phase insulin levels were substantially increased prior to arginine administration under 230 mg/dL clamp conditions vs. placebo (p<0.001), but no difference in the acute insulin response (AIR) to GPA was present. At 230 mg/dL, proinsulin and C-peptide were increased under GLP-1 vs. placebo (both p<0.001), but the proinsulin secretory ratio (PISR) was unchanged. During GIP infusion, fasting glucose was slightly lower after 30 min vs. placebo (p<0.05), but no difference in the GIR required to achieve 230 mg/dL was found. Second phase insulin levels were not different during the 230 mg/dL glucose clamp. The AIR to GPA was lower during GIP vs. placebo (p<0.01). Second phase proinsulin and C-peptide levels were higher with GIP vs. placebo (both p<0.01) with an increased PISR (p<0.05). These results indicate that GLP-1 augments glucose-dependent insulin secretion while GIP may lead to disproportionate proinsulin secretion in glucose intolerant PI-CF. Further studies should determine whether GLP-1 may provide a therapeutic benefit in this population. Disclosure J.N. Eiel: None. S. Nyirjesy: None. A.J. Peleckis: None. D. De Leon: Employee; Spouse/Partner; Merck & Co., Inc.. Research Support; Self; Zealand Pharma A/S. Consultant; Self; XOMA Corporation, ProSciento. Research Support; Self; Biomarin Corporation. D. Hadjiliadis: None. C. Kubrak: None. A. Tami: None. S. Sheikh: None. R.C. Rubenstein: None. A. Kelly: None. M.R. Rickels: Consultant; Self; Hua Medicine, Xeris Pharmaceuticals, Inc..