@article{3d0dd47c45884b4b8927fc590cb7a889,
title = "Effects of GLP-1 and GIP on Islet Function in Glucose-Intolerant, Pancreatic-Insufficient Cystic Fibrosis",
abstract = "Impaired insulin and incretin secretion underlie abnormal glucose tolerance (AGT) in pancreatic insufficient cystic fibrosis (PI-CF). Whether the incretin hormones glucagonlike peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) can enhance pancreatic islet function in cystic fibrosis (CF) is not known. We studied 32 adults with PI-CF and AGT randomized to receive either GLP-1 (n = 16) or GIP (n = 16) during glucose-potentiated arginine (GPA) testing of islet function on two occasions, with either incretin or placebo infused, in a randomized, double-blind, cross-over fashion. Another four adults with PI-CF and normal glucose tolerance (NGT) and four matched control participants without CF 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 control participants without 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 benefitinthis population. Understanding loss of GIP{\textquoteright}s insulinotropic action in PI-CF may lead to novel insights into diabetes pathogenesis.",
author = "Nyirjesy, {Sarah C.} and Peleckis, {Amy J.} and Eiel, {Jack N.} and Kathryn Gallagher and Andriana Doliba and Abigail Tami and Flatt, {Anneliese J.} and {De Leon}, {Diva D.} and Denis Hadjiliadis and Saba Sheikh and Darko Stefanovski and Robert Gallop and D{\textquoteright}alessio, {David A.} and Rubenstein, {Ronald C.} and Andrea Kelly and Rickels, {Michael R.}",
note = "Funding Information: Acknowledgments. The authors thank members of the Data and Safety Monitoring Board: Dr. Marion Vetter, (chair) at Janssen Pharmaceuticals; Drs. Serena Cardillo and Daniel Dorgan, both members of the Cystic Fibrosis Program at the Hospital of the University of Pennsylvania; and the study monitor, Theresa Scattergood, at the University of Pennsylvania Perelman School of Medicine, for providing oversight of the study conduct and adverse events. We are indebted to the patients with CF for their participation; to Christina Kubrak of the Children{\textquoteright}s Hospital of Philadelphia (CHOP) Cystic Fibrosis Center for assistance with patient recruitment; to the nursing and dietary staff of the University of Pennsylvania Center for Human Phenomic Science for their patient care and technical assistance; to the pharmacy staff of the University of Pennsylvania Investigation Drug Service for preparation of GLP-1 and GIP for infusion; to Dr. Steven Seeholzer of the CHOP Research Institute Protein and Proteomics Core for providing analyses of the GLP-1 and GIP peptides; to Dr. Heather Collins of the University of Pennsylvania Diabetes Research Center for performance of the radioimmunoassays; to Dr. Xiangdong Ren of the CHOP{\textquoteright}s Translational Core Laboratory for performance of the ELISAs; to Huong-Lan Nguyen and Paola Alvarado of the Human Metabolism Resource of the University of Pennsylvania Institute for Diabetes, Obesity and Metabolism for laboratory and regulatory assistance; and to Philip Cross of Philip J. Cross & Associates for providing regulatory support. Funding. This study was supported by Public Health Service research grants R01 DK97830 (to A.K. and M.R.R.), K23 DK107937 (to S.S.), UL1 TR001878 (to University of Pennsylvania Center for Human Phenomic Science), P30 DK19525 (to University of Pennsylvania Diabetes Research Center), and T32 DK007314 (to University of Pennsylvania Training Grant in Diabetes, Endocrine and Metabolic Diseases) from the National Institutes of Health, Cystic Fibrosis Foundation grant RICKEL19A0-I (to M.R.R. and A.K.), and the Human Metabolism Resource of the University of Pennsylvania Institute for Diabetes, Obesity & Metabolism. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. S.C.N. conducted experiments, acquired and analyzed data, and wrote the manuscript; A.J.P., J.N.E., and K.G. conducted experiments, acquired data, and reviewed and edited the manuscript; A.D., A.T., and A.J.F. acquired and analyzed data, and reviewed and edited the manuscript; D.D.D. and D.H. contributed to the study design and study oversight, and reviewed and edited the manuscript; S.S., D.S., and R.G. analyzed data, and reviewed and edited the manuscript; D.A.D. contributed to the study design, provided reagents, and reviewed and edited the manuscript; R.C.R. contributed to the study design and study oversight, analyzed data, and reviewed and edited the manuscript; A.K. designed the study, provided study oversight, analyzed data, and reviewed and edited the manuscript; M.R.R. designed the study, conducted experiments, acquired and analyzed data, and wrote the manuscript. A.K. and M.R.R. are the guarantors of this work, and as such, had full access to all the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis. Publisher Copyright: {\textcopyright} 2022 by the American Diabetes Association.",
year = "2022",
month = oct,
doi = "10.2337/db22-0399",
language = "English",
volume = "71",
pages = "2153--2165",
journal = "Diabetes",
issn = "0012-1797",
number = "10",
}