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Dual modulation of GIP and glucagon action by the low molecular weight compound 4‐hydroxybenzoic acid 2‐bromobenzylidene hydrazide
Author(s) -
Franklin Z. J.,
McDonnell B.,
Montgomery I. A.,
Flatt P. R.,
Irwin N.
Publication year - 2011
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/j.1463-1326.2011.01401.x
Subject(s) - medicine , endocrinology , glucagon , insulin , gastric inhibitory polypeptide , in vivo , receptor , chemistry , insulin resistance , in vitro , biology , biochemistry , microbiology and biotechnology
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.