Xingshen Sun1, Yaling Yi1, Bo Liang1, Yu Yang1, Nan He1, Katie Larson Ode2, Aliye Uc2, Kai Wang3, Katherine N Gibson-Corley4, John F Engelhardt5, Andrew W Norris6. 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.
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-6impaired 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.
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