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

Z. J. Franklin, B. McDonnell, I. A. Montgomery, Peter Flatt, Nigel Irwin

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5 Citations (Scopus)

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.
LanguageEnglish
Pages742-749
JournalDIABETES OBESITY &amp; METABOLISM
Volume13
Issue number8
DOIs
Publication statusPublished - Aug 2011

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Gastric Inhibitory Polypeptide
Glucagon
Molecular Weight
Insulin
Blood Glucose
4-hydroxybenzoic acid 2-bromobenzylidene hydrazide
Obesity
Glucose
Injections
Glucagon-Like Peptide 1
Adipocytes
Type 2 Diabetes Mellitus
Oral Administration
Insulin Resistance

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title = "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.",
author = "Franklin, {Z. J.} and B. McDonnell and Montgomery, {I. A.} and Peter Flatt and Nigel Irwin",
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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; Irwin, Nigel.

In: DIABETES OBESITY &amp; METABOLISM, Vol. 13, No. 8, 08.2011, p. 742-749.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Dual modulation of GIP and glucagon action by the low molecular weight compound 4-hydroxybenzoic acid 2-bromobenzylidene hydrazide

AU - Franklin, Z. J.

AU - McDonnell, B.

AU - Montgomery, I. A.

AU - Flatt, Peter

AU - Irwin, Nigel

PY - 2011/8

Y1 - 2011/8

N2 - 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.

AB - 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.

U2 - 10.1111/j.1463-1326.2011.01401.x

DO - 10.1111/j.1463-1326.2011.01401.x

M3 - Article

VL - 13

SP - 742

EP - 749

JO - Diabetes, Obesity and Metabolism

T2 - Diabetes, Obesity and Metabolism

JF - Diabetes, Obesity and Metabolism

SN - 1463-1326

IS - 8

ER -