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

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 > School of Biomedical Sciences
Faculty of Life and Health Sciences > School of Pharmacy and Pharmaceutical Science
Faculty of Life and Health Sciences
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 10:35
Last Modified:19 Nov 2012 15:36

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