Acyl-ghrelin receptor antagonist [D-Lys3]-GHRP-6 improves glucose tolerance in cystic fibrosis ferrets
Background
Insufficient insulin secretion is a hallmark of cystic fibrosis (CF), often preceding overt diabetes. The precise mechanisms driving this hyperglycemia remain poorly understood, hindering effective therapeutic strategies for CF-related diabetes (CFRD). Acyl-ghrelin (AG), a hormone known to diminish insulin secretion, is notably elevated in humans with CF, suggesting it may play a critical role in this pancreatic dysfunction. Understanding AG's contribution could unlock novel targets for improving glucose homeostasis in CF patients.
Study Design
Researchers investigated the role of elevated acyl-ghrelin (AG) in CF-related hyperglycemia using a ferret model. They tested the hypothesis that AG contributes to insufficient insulin secretion. The study compared the effects of an acyl-ghrelin receptor antagonist, [D-Lys3]-GHRP-6, in both wild-type ferrets and CF ferrets. Glucose tolerance testing was performed, and subsequent insulin, GLP-1, and GIP responses were measured to assess the impact of ghrelin receptor blockade on glucose homeostasis and incretin function.
Results
The study revealed contrasting effects of acyl-ghrelin receptor antagonism in wild-type versus CF ferrets. In wild-type ferrets, administration of the acyl-ghrelin receptor antagonist [D-Lys3]-GHRP-6 impaired glucose tolerance, and notably abolished both insulin and incretin (GLP-1 and GIP) responses during glucose tolerance testing. This suggests a physiological role for acyl-ghrelin signaling in maintaining normal glucose regulation in healthy individuals.
By stark contrast, in CF ferrets, [D-Lys3]-GHRP-6 significantly improved glucose tolerance, enhanced the insulin-to-glucose ratio, and increased both
GLP-1andGIPresponses. This indicates that elevated acyl-ghrelin signaling actively contributes to glucose dysregulation and impaired incretin function in the context of cystic fibrosis.
Key Findings
- Acyl-ghrelin (AG) is elevated in humans with cystic fibrosis (CF) and can diminish insulin secretion.
- In wild-type ferrets, the AG receptor antagonist [D-Lys3]-GHRP-6 impaired glucose tolerance.
- [D-Lys3]-GHRP-6 abolished insulin, GLP-1, and GIP responses in wild-type ferrets during glucose tolerance testing.
- In CF ferrets, [D-Lys3]-GHRP-6 improved glucose tolerance.
- The antagonist enhanced the insulin-to-glucose ratio and increased GLP-1 and GIP responses in CF ferrets.
Why It Matters
This research highlights acyl-ghrelin receptor antagonism as a promising therapeutic strategy for managing hyperglycemia and incretin dysfunction in cystic fibrosis (CF). For individuals with CF-related diabetes (CFRD), targeting the ghrelin receptor could offer a novel approach beyond traditional insulin therapy, potentially improving endogenous insulin secretion and incretin responses. This suggests that blocking acyl-ghrelin's action could restore critical aspects of glucose homeostasis in CF patients. While currently preclinical, these findings pave the way for developing new pharmacological interventions that address a core mechanism of CF-related metabolic complications, potentially leading to more effective protocols for glucose control.
cystic-fibrosis
hyperglycemia
acyl-ghrelin
incretin
ghrelin-receptor-antagonist
preclinical-animal