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J Cyst Fibros. 2019 Jul;18(4):557-565. doi: 10.1016/j.jcf.2019.01.010. Epub 2019 Feb 7.

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

Author information

1
Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA.
2
Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA 52242, USA; Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA.
3
Department of Biostatistics, University of Iowa, Iowa City, IA 52242, USA.
4
Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA 52242, USA; Department of Pathology, University of Iowa, Iowa City, IA 52242, USA.
5
Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA 52242, USA. Electronic address: john-engelhardt@uiowa.edu.
6
Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA 52242, USA; Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA; Department of Biochemistry, University of Iowa, Iowa City, IA 52242, USA. Electronic address: andrew-norris@uiowa.edu.

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.

KEYWORDS:

Cystic fibrosis related diabetes; Glucagon-like peptide-1; Glucose-dependent insulinotropic peptide; Growth hormone secretagogue receptor; [D-Lys3]-GHRP-6

PMID:
30738804
PMCID:
PMC6591024
[Available on 2020-07-01]
DOI:
10.1016/j.jcf.2019.01.010

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