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

Andrea Kelly, Saba Sheikh, Darko Stefanovski, Amy J. Peleckis, Sarah C. Nyirjesy, Jack N. Eiel, Aniket Sidhaye, Russell Localio, Robert Gallop, Diva D. De Leon, Denis Hadjiliadis, Ronald C. Rubenstein, Michael R. Rickels

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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 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.

Original languageEnglish
Pages (from-to)2617-2634
Number of pages18
JournalJournal of Clinical Endocrinology and Metabolism
Volume106
Issue number9
DOIs
StatePublished - Sep 1 2021

Keywords

  • DPP-4
  • abnormal glucose tolerance
  • cystic fibrosis
  • dipeptidyl peptidase-4 inhibitor
  • glucagon
  • glucagon-like peptide-1
  • glucose dependent insulinotropic polypeptide
  • incretin
  • insulin

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