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

Abstract

BACKGROUND:

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.

METHODS:

We tested the hypothesis that elevated AG contributes to reduced insulin secretion and hyperglycemia in CF ferrets.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: 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
• Journal: Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society (J Cyst Fibros) Vol. 18 Issue 4 Pg. 557-565 (07 2019) ISSN: 1873-5010 [Electronic] Netherlands
• PMID: 30738804 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Chemical References

• Ghrelin
• Incretins

Topics

• Animals
• Cystic Fibrosis (complications, metabolism)
• Disease Models, Animal
• Female
• Ferrets
• Ghrelin (physiology)
• Hyperglycemia (etiology)
• Incretins (physiology)
• Insulin Secretion
• Male