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

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.

• Authors: Z J Franklin, B McDonnell, I A Montgomery, P R Flatt, N Irwin
• Journal: Diabetes, obesity & metabolism (Diabetes Obes Metab) Vol. 13 Issue 8 Pg. 742-9 (Aug 2011) ISSN: 1463-1326 [Electronic] England
• PMID: 21418501 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 Blackwell Publishing Ltd.

Chemical References

• 4-hydroxybenzoic acid 2-bromobenzylidene hydrazide
• Adipokines
• Benzene Derivatives
• Hydrocarbons, Brominated
• Parabens
• Receptors, Gastrointestinal Hormone
• Gastric Inhibitory Polypeptide
• Glucagon
• gastric inhibitory polypeptide receptor
• 4-hydroxybenzoic acid

Topics

• Adipokines
• Animals
• Benzene Derivatives (pharmacology)
• Gastric Inhibitory Polypeptide (administration & dosage, pharmacology)
• Glucagon (administration & dosage, pharmacology)
• Hydrocarbons, Brominated (pharmacology)
• Insulin Resistance
• Male
• Mice
• Obesity (drug therapy)
• Parabens (metabolism, pharmacology)
• Receptors, Gastrointestinal Hormone (metabolism)