Abstract
Compromise of gastric inhibitory polypeptide (GIP) receptor signalling represents a possible therapeutic strategy for the treatment of obesity-related diabetes. This study has characterised and evaluated the C-terminally fatty acid derivatised GIP analogues, GIP(3-30)Cex-K40[Pal] and Pro3GIP(3-30)Cex-K40[Pal], as potential GIP inhibitors. Both GIP analogues lack the two N-terminal amino acids cleaved by DPP-4 and have addition of nine amino acids from the C-terminal of exendin(1-39), Cex. GIP(3-30)Cex-K40[Pal] and Pro3GIP(3-30)Cex-K40[Pal] effectively (p <0.01 to p <0.001) inhibited GIP-induced cAMP production and insulin secretion in vitro. In normal mice, GIP(3-30)Cex-K40[Pal] and Pro3GIP(3-30)Cex-K40[Pal] displayed a significant (p <0.05 to p <0.001) and prolonged inhibitory effect on GIP-induced glucose-lowering and insulin-releasing actions. When injected once daily for 21 days in obese-diabetic high fat fed mice, both GIP(3-30)Cex-K40[Pal] and Pro3GIP(3-30)Cex-K40[Pal] significantly reduced body weight (p <0.01 to p <0.001) and lowered circulating glucose (p <0.001) and insulin (p <0.01 to p <0.001) concentrations. The observed beneficial changes were independent of effects on energy intake, locomotor activity or metabolic rate. Oral and intraperitoneal glucose tolerance were significantly (p <0.05 to p <0.001) improved in both treatment groups at the end of the study, despite reduced glucose-induced plasma insulin concentrations. This improvement of metabolic control was accompanied by enhanced (p <0.05 to p <0.01) insulin sensitivity compared with high fat controls. These data demonstrate the potential offered by GIP(3-30)Cex-K40[Pal] and Pro3GIP(3-30)Cex-K40[Pal] for the treatment of obesity-related diabetes.
Original language | English |
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Pages (from-to) | 120-129 |
Number of pages | 10 |
Journal | Molecular and Cellular Endocrinology |
Volume | 401 |
Early online date | 6 Nov 2014 |
DOIs | |
Publication status | Published (in print/issue) - 5 Feb 2015 |
Keywords
- Body weight
- Diabetes
- GIP
- Glucose homeostasis
- Insulin secretion
- Obesity
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Victor Gault
- Faculty Of Life & Health Sciences - Associate Dean (Research and Innovation)
Person: Academic