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Dual modulation of GIP and glucagon action by the low molecular weight compound 4-hydroxybenzoic acid 2-bromobenzylidene hydrazide

Biomedical Sciences Research Institute Computer Science Research Institute Environmental Sciences Research Institute Nanotechnology & Advanced Materials Research Institute

Franklin, Z. J., McDonnell, B., Montgomery, I. A., Flatt, Peter and Irwin, Nigel (2011) Dual modulation of GIP and glucagon action by the low molecular weight compound 4-hydroxybenzoic acid 2-bromobenzylidene hydrazide. DIABETES OBESITY & METABOLISM, 13 (8). pp. 742-749. [Journal article]

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DOI: 10.1111/j.1463-1326.2011.01401.x

Abstract

Aim: The presence of functional gastric inhibitory polypeptide (GIP) receptors on adipocytes and knowledge that GIP plays a key role in fat deposition suggests a beneficial effect of GIP receptor antagonism in obesity and insulin resistance. GIP receptor antagonists studied to date are peptidic GIP analogues that must be administered by injection. Methods: The present study has examined in vitro and in vivo metabolic actions of a low molecular weight GIP receptor modulator 4-hydroxybenzoic acid 2-bromobenzylidene hydrazide (4H2BH), suitable for oral administration. Results: 4H2BH alone had no significant effect on cAMP production or insulin secretion from BRIN-BD11 cells. However, 4H2BH significantly inhibited GIP-mediated cAMP production and insulin secretion in vitro. 4H2BH also suppressed (p < 0.05 to p < 0.001) glucagon-induced elevations of cAMP generation and insulin secretion in BRIN-BD11 cells. However, 4H2BH had no effect on glucagon-like peptide-1 (GLP-1) mediated insulinotropic actions. Administration of 4H2BH to mice in combination with glucose and GIP significantly annulled the glucose-lowering actions of GIP. In agreement with this, 4H2BH completely annulled GIP-mediated insulin secretion. Combined injection of 4H2BH with glucagon also partially (p < 0.05 to p < 0.001) impaired glucagon-induced elevations in blood glucose and plasma insulin. 4H2BH had no effect on blood glucose or insulin levels when administered alone. Conclusion: These results indicate that 4H2BH has a dual effect of inhibiting GIP and glucagon-mediated biological actions. Given that hyperglucagonaemia is also a cardinal feature of type 2 diabetes, 4H2BH and related low molecular weight compounds appear worthy of further evaluation for therapeutic potential in obesity diabetes.

Item Type:Journal article
Faculties and Schools:Faculty of Life and Health Sciences
Faculty of Life and Health Sciences > School of Biomedical Sciences
Faculty of Life and Health Sciences > School of Pharmacy and Pharmaceutical Science
Research Institutes and Groups:Biomedical Sciences Research Institute
Biomedical Sciences Research Institute > Diabetes
ID Code:19683
Deposited By:Dr Nigel Irwin
Deposited On:18 Aug 2011 11:35
Last Modified:19 Nov 2012 15:36

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