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Metformin treatment of lean and obese Zucker rats modulates the ability of glucagon and insulin to regulate hepatocyte adenylate cyclase activity

Metformin treatment of lean and obese Zucker rats modulates the ability of glucagon and insulin... ABSTRACTGlucagon stimulated adenylate cyclase activity some 21-fold in liver membranes from lean (Fa/Fa) and some 20-fold in membranes from obese (fa/fa) Zucker rats, with constants yielding half-maximal activation (Ka values) of 12·6 and 120·1 nmol/l respectively. Treatment of animals with the biguanide drug metformin (N′,N′-dimethylbiguanide) decreased the ability of glucagon to stimulate this enzyme to some 16-fold for both the lean and obese animals and reduced the Ka values for activation of this enzyme by glucagon to 6·3 and 60·9 nmol/l respectively. Insulin inhibited glucagon-stimulated adenylate cyclase activity by some 24% in liver membranes from lean animals and some 17% in liver membranes from obese animals, with constants yielding half-maximal inhibition (Ki values) of 110 and 160 nmol/l respectively. The ability of insulin to inhibit the adenylate cyclase activity, from obese but not lean animals, was attenuated when insulin concentrations over 5 nmol/l were employed. Treatment of animals with metformin profoundly altered the sensitivity of adenylate cyclase to inhibition by insulin, with inhibition being increased to some 32% using liver membranes from either lean or obese animals. Values of Ki for this inhibitory action of insulin were 520 and 500 nmol/l using membranes from the lean and obese animals respectively, and no reduction in the ability of insulin, at concentrations over 5 nmol/l, to inhibit adenylate cyclase activity was observed using membranes from obese animals. Metformin also changed the kinetics of inhibition of adenylate cyclase by insulin. These were apparently negatively co-operative, with Hill coefficients of 0·76 and 0·89 using membranes from the untreated lean and obese animals respectively, and positively co-operative, with Hill coefficients of 1·45 and 1·20 for the metformin-treated lean and obese animals respectively.Journal of Endocrinology (1989) 122, 207–212 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Endocrinology Bioscientifica

Metformin treatment of lean and obese Zucker rats modulates the ability of glucagon and insulin to regulate hepatocyte adenylate cyclase activity

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Publisher
Bioscientifica
Copyright
Copyright © 1989 The Authors. All Rights Reserved.
ISSN
0022-0795
eISSN
1479-6805
DOI
10.1677/joe.0.1220207
Publisher site
See Article on Publisher Site

Abstract

ABSTRACTGlucagon stimulated adenylate cyclase activity some 21-fold in liver membranes from lean (Fa/Fa) and some 20-fold in membranes from obese (fa/fa) Zucker rats, with constants yielding half-maximal activation (Ka values) of 12·6 and 120·1 nmol/l respectively. Treatment of animals with the biguanide drug metformin (N′,N′-dimethylbiguanide) decreased the ability of glucagon to stimulate this enzyme to some 16-fold for both the lean and obese animals and reduced the Ka values for activation of this enzyme by glucagon to 6·3 and 60·9 nmol/l respectively. Insulin inhibited glucagon-stimulated adenylate cyclase activity by some 24% in liver membranes from lean animals and some 17% in liver membranes from obese animals, with constants yielding half-maximal inhibition (Ki values) of 110 and 160 nmol/l respectively. The ability of insulin to inhibit the adenylate cyclase activity, from obese but not lean animals, was attenuated when insulin concentrations over 5 nmol/l were employed. Treatment of animals with metformin profoundly altered the sensitivity of adenylate cyclase to inhibition by insulin, with inhibition being increased to some 32% using liver membranes from either lean or obese animals. Values of Ki for this inhibitory action of insulin were 520 and 500 nmol/l using membranes from the lean and obese animals respectively, and no reduction in the ability of insulin, at concentrations over 5 nmol/l, to inhibit adenylate cyclase activity was observed using membranes from obese animals. Metformin also changed the kinetics of inhibition of adenylate cyclase by insulin. These were apparently negatively co-operative, with Hill coefficients of 0·76 and 0·89 using membranes from the untreated lean and obese animals respectively, and positively co-operative, with Hill coefficients of 1·45 and 1·20 for the metformin-treated lean and obese animals respectively.Journal of Endocrinology (1989) 122, 207–212

Journal

Journal of Endocrinology – Bioscientifica

Published: Jul 1, 1989

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