Effects of GLP-1 and GIP on islet function in glucose intolerant, pancreatic insufficient cystic fibrosis

• DOI: 10.2337/figshare.20213744.v1
• Publication Date: 2022-07-07T13:43:55Z
• Authors: Sarah C. Nyirjesy; Amy J. Peleckis; Jack N. Eiel; Kathryn Gallagher; Andriana Doliba; Abigail Tami; Anneliese J. Flatt; Diva D. De Leon; Denis Hadjiliadis; Saba Sheikh; Darko Stefanovski; Robert Gallop; David A. D’Alessio; Ronald C. Rubenstein; Andrea Kelly; Michael R. Rickels
• Keywords: Adult; Blood Glucose; Cystic Fibrosis; Gastric Inhibitory Polypeptide; Arginine; Glucagon; Incretins; 03 medical and health sciences; Glucose; 0302 clinical medicine; Glucagon-Like Peptide 1; Humans; Insulin; Proinsulin

<p> </p> <p>Impaired insulin and incretin secretion underlie abnormal glucose tolerance (AGT) in pancreatic insufficient cystic fibrosis (PI-CF). Whether the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) can enhance pancreatic islet function in CF is not known. We studied 32 adults with PI-CF and AGT randomized to receive either GLP-1 (<em>n</em>=16) or GIP (<em>n</em>=16) during glucose-potentiated arginine (GPA) testing of islet function on two occasions with either incretin or placebo infused by randomized, double-blind, cross-over fashion. Another 4 adults with PI-CF and normal glucose tolerance (NGT) and 4 matched non-CF controls underwent similar assessment with GIP. In PI-CF with AGT, GLP-1 substantially augmented second-phase insulin secretion, but without effect on the acute insulin response to GPA or the proinsulin secretory ratio (PISR), while GIP infusion did not enhance second phase or GPA-induced insulin secretion but increased the PISR. GIP also did not enhance second-phase insulin in PI-CF with NGT but did so markedly in non-CF controls. These data indicate that GLP-1, but not GIP, augments glucose-dependent insulin secretion in PI-CF, supporting the likelihood that GLP-1 agonists could have therapeutic benefit in this population. Understanding loss of GIP’s insulinotropic action in PI-CF may lead to novel insights into diabetes pathogenesis. </p>