Incretin dysfunction and hyperglycemia in cystic fibrosis: Role of acyl-ghrelin

Xingshen Sun; Yaling Yi; Bo Liang; Yu Yang; Nan He; Katie Larson Ode; Aliye Uc; Kai Wang; Katherine N Gibson-Corley; John F Engelhardt; Andrew W Norris

doi:10.1016/j.jcf.2019.01.010

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Incretin dysfunction and hyperglycemia in cystic fibrosis: Role of acyl-ghrelin

Journal article

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Incretin dysfunction and hyperglycemia in cystic fibrosis: Role of acyl-ghrelin

Xingshen Sun, Yaling Yi, Bo Liang, Yu Yang, Nan He, Katie Larson Ode, Aliye Uc, Kai Wang, Katherine N Gibson-Corley, John F Engelhardt, …

Journal of cystic fibrosis, Vol.18(4), pp.557-565

07/2019

DOI: 10.1016/j.jcf.2019.01.010

PMID: 30738804

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Abstract

Insulin secretion is insufficient in cystic fibrosis (CF), even before diabetes is present, though the mechanisms involved remain unclear. Acyl-ghrelin (AG) can diminish insulin secretion and is elevated in humans with CF. We tested the hypothesis that elevated AG contributes to reduced insulin secretion and hyperglycemia in CF ferrets. Fasting AG was elevated in CF versus non-CF ferrets. Similar to its effects in other species, AG administration in non-CF ferrets acutely reduced insulin, increased growth hormone, and induced hyperglycemia. During oral glucose tolerance testing, non-CF ferrets had responsive insulin, glucagon like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) levels and maintained normal glucose levels, whereas CF ferrets had insufficient responses and became hyperglycemic. Interestingly in wild-type ferrets, the acyl-ghrelin receptor antagonist [D-Lys3]-GHRP-6 impaired glucose tolerance, and abolished insulin, GLP-1, and GIP responses during glucose tolerance testing. By contrast, in CF ferrets [D-Lys3]-GHRP-6 improved glucose tolerance, enhanced the insulin-to-glucose ratio, but did not impact the already low GLP-1 and GIP levels. These results suggest a mechanism by which elevated AG contributes to CF hyperglycemia through inhibition of insulin secretion, an effect magnified by low GLP-1 and GIP. Interventions that lower ghrelin, ghrelin action, and/or raise GLP-1 or GIP might improve glycemia in CF. [Display omitted] •Like in humans, serum acyl-ghrelin levels were elevated in CF ferrets.•Treatment of CF ferrets with ghrelin receptor antagonist (GRA) lowered blood sugar.•Treatment of CF ferrets with GRA raised the insulin-to-glucose ratio.•GRA had the opposite effects in normal ferrets.•Altered beta-cell supporting gut hormones may account for these differences.

Glucose-dependent insulinotropic peptide

[D-Lys3]-GHRP-6

Growth hormone secretagogue receptor

Glucagon-like peptide-1

Cystic fibrosis related diabetes

Details

Title: Subtitle: Incretin dysfunction and hyperglycemia in cystic fibrosis: Role of acyl-ghrelin
Creators: Xingshen Sun - Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA
Yaling Yi - Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA
Bo Liang - Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA
Yu Yang - Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA
Nan He - Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA
Katie Larson Ode - Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA 52242, USA
Aliye Uc - Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA 52242, USA
Kai Wang - Department of Biostatistics, University of Iowa, Iowa City, IA 52242, USA
Katherine N Gibson-Corley - Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA 52242, USA
John F Engelhardt - Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA
Andrew W Norris - Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA 52242, USA
Resource Type: Journal article
Publication Details: Journal of cystic fibrosis, Vol.18(4), pp.557-565
Publisher: Elsevier B.V
DOI: 10.1016/j.jcf.2019.01.010
PMID: 30738804
ISSN: 1569-1993
eISSN: 1873-5010
Grant note: DOI: 10.13039/100000002, name: NIH, award: R24 DK096518, R01 DK097820, R01 DK115791; DOI: 10.13039/100002069, name: Fraternal Order of Eagles Diabetes Research Center; DOI: 10.13039/100008893, name: University of Iowa, award: DK54759; name: National Ferret Resource and Research Center, award: R24 HL123482
Language: English
Date published: 07/2019
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Endocrinology and Diabetes; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Pathology; Biostatistics; Radiation Oncology; Gastroenterology, Hepatology, Pancreatology, and Nutrition; Biochemistry and Molecular Biology; Internal Medicine; Ophthalmology and Visual Sciences
Record Identifier: 9984024546402771

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