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INSULIN RESISTANCE AND INSULIN
RESISTANCE SYNDROME
Frontiers in Animal Diabetes Research
Each volume of this series will be topic oriented with timely and liberally referenced reviews and
provide in depth coverage of basic experimental diabetes research.

Edited by Professor Anders A.F. Sima, Wayne State University, Detroit, USA and Professor Eleazar
Shafrir, Hadassah University Hospital, Jerusalem, Israel.

Volume 1
Chronic Complications in Diabetes: Animal Models and Chronic Complications
edited by Anders A.F. Sima

Volume 2
Animal Models of Diabetes: A Primer
edited by Anders A.F. Sima and Eleazar Shafrir

Volume 3
Insulin Signaling: From Cultured Cells to Animal Models
edited by George Grunberger and Yehiel Zick

Volume 4
Muscle Metabolism
edited by Juleen R. Zierath and Harriet Wallberg-Henriksson

Volume 5
Insulin Resistance and Insulin Resistance Syndrome
edited by Barbara Hansen and Eleazar Shafrir

This book is part of a series. The publisher will accept continuation orders which may be cancelled at any time
and which provide for automatic billing and shipping of each title in the series upon publication. Please write
for details.
INSULIN RESISTANCE AND INSULIN
RESISTANCE SYNDROME

Edited by

Barbara Hansen
School of Medicine
University of Maryland
Baltimore, USA
and
Eleazar Shafrir
Department of Biochemistry
Hadassah University Hospital
Jerusalem, Israel

London and New York

 First published 2002
by Taylor & Francis
11 New Fetter Lane, London EC4P 4EE

Simultaneously published in the USA and Canada

by Taylor & Francis Inc
29 West 35th Street, New York, NY 10001

Taylor & Francis is an imprint of the Taylor & Francis Group

This edition published in the Taylor & Francis e-Library, 2004.

© 2002 Taylor & Francis

All rights reserved. No part of this book may be reprinted or reproduced or utilised
in any form or by any electronic, mechanical, or other means, now known or hereafter invented,
including photocopying and recording, or in any information storage or retrieval system, without
permission in writing from the publishers.

Every effort has been made to ensure that the advice and information in this book is
true and accurate at the time of going to press. However, neither the publisher nor
the authors can accept any legal responsibility or liability for any errors or omissions that may be
made. In the case of drug administration, any medical procedure or the use of technical equipment
mentioned within this book, you are strongly advised to consult the manufacturer’s guidelines.

British Library Cataloguing in Publication Data

A catalogue record for this book is available from the British Library

Library of Congress Cataloging in Publication Data

A catalog record for this book has been requested

ISBN 0-203-21741-1 Master e-book ISBN

ISBN 0-203-27318-4 (Adobe eReader Format)

ISBN 0-415-29197-6 (Print Edition)
 CONTENTS

Preface to the Series vii

Preface ix

Contributors xi

1 Metabolism and Hypertension

1 Insulin Resistance and Glycogen Synthesis: Roles in Liver, Muscle and Adipose Tissue 3
Hagit Eldar-Finkelman and Merav Yarkoni

2 Gestational Diabetes and Maternal Insulin Resistance in the C57BLKS/JLeprdb/

Mouse – A Unique Model for Understanding its Impact on the Fetus 21
Jianhua Shao and Jacob E. Friedman

3 Role of Protein-Tyrosine Phosphatases in Insulin Action and Insulin Resistance:

Recent Insights from Cellular and Animal Studies 35
Barry J. Goldstein

4 Hypertension and Insulin Resistance in the Wistar Fatty Rat 51

Masami Suzuki, Hiroyuki Odaka and Yasuo Sugiyama

5 Cardiovascular Disease in the Insulin-Resistant, Atherosclerosis-Prone JCR :LA-cp Rat 59

J.C. Russell and S.E. Kelly

6 The C57BL/6J Mouse as a Model of Insulin Resistance and Hypertension 73

Tonya Martin, Sheila Collins and Richard S. Surwit

2 Molecular and Genetic

7 Molecular Features of Insulin Resistance, Obesity and Type 2 Diabetes in
Non-Human Primates 89
Stephen V. Angeloni and Barbara Caleen Hansen

8 Effects of Genetic Alterations of Glut4 on Insulin Sensitivity 125

Naira Gorovits, J. Skye Laidlaw, Mollie Ranalletta, Gloria Tannenbaum,
Ellen B. Katz and Maureen J. Charron

9 Insulin Signaling Pathway and GLUT4-mediated Glucose Transport in

the Insulin Resistant Muscle 147
Daniel Konrad, Varinder K. Randhawa, Carol T.-L. Huang and Amira Klip

10 Which Genes are Important in the Development of Type 2 Diabetes? 175

G.R. Collier, K. Walder, A. de Silva, S. Morgan, D. Segal, L. Kantham and G. Augert

11 Leptin and Insulin Resistance in Rodent Models 187

Kevin L. Stark

v
vi CONTENTS

12 Fat Feeding and Muscle Fat Deposition Eliciting Insulin Resistance 195
E.W. Kraegen, G.J. Cooney, J.M. Ye and S.M. Furler

13 D-chiro-inositol and Insulin Resistance: An Allosteric Point of View 211

Joseph Larner

14 Glucagon-like Peptide-1, Exendin and Insulin Sensitivity 235

Andrew A. Young

15 Insulin Resistance and the Autonomic Nervous System 263

L. Penicaud, C. Leloup, A. Lorsignol and T. Alquier

16 Hypothalamic Role in the Insulin Resistance Syndrome 271

Anthony H. Cincotta

17 Insulin Resistance – Emerging Therapies for Affected Sites 313

Julie S. Moyers and José F. Caro

3 Aging
18 Effect of Age on the Emergence of Insulin Resistance 337
Nir Barzilai and Ilan Gabriely

19 Postnatal and Adult Insulin Sensitivity and Metabolism in Progeny of

Nutritionally Compromised Mothers 349
Clive J. Petry, Susan E. Ozanne and C. Nicholas Hales

Index 363
 PREFACE TO THE SERIES

Diabetes has been declared a major global health hazard by the WHO. Over the last few
decades there has been an alarming increase in the incidence of diabetes particularly in densely
populated areas such as India, China, southeast Asian countries and Arab nations. Even in
North America and Europe the incidence of diabetes increases by 5% a year. The direct and
indirect costs associated with diabetes are enormous. In the US they amounted to $137 billion
in 1997 or a seventh of the total health care costs in this country.
To avert this rapidly evolving global epidemic, it behoves the international biomedical
community and responsible federal agencies and interest groups to intensify research into the
causes of this disease and its complications, and to rapidly increase public awareness of the
disease through education.
Major advances have been made in diabetes research in animal models, contributing enor-
mously to the understanding of etiopathology of this disease and its dreaded chronic compli-
cations. In particular factors in the areas of immunology, insulin signal transduction and
insulin action as well as pathogenetic mechanisms involved in the development of the chronic
complication have become clearer. The new knowledge gained is only slowly being translated
to the benefit of the patients and to serve as a basis for the development of new therapeutic
modalities.
The accumulation of this scattered information and ongoing publication of data from the
interdisciplinary and critical reviews on diabetes in various animals is our fundamental motive.
It is our hope that this book series on Frontiers in Animal Diabetes Research will be an effi-
cient vehicle for communicating extensive up-to-date review articles by the leading world
experts in the field. Each volume will be topic oriented with timely and liberally referenced
reviews. It will fill a gap in the spectrum of diabetes related journals and publications in as far
as it will focus on all aspects of basic experimental diabetes research. As such we hope it will
provide a valuable reference source for graduate students, research fellows, basic academic and
pharmacological researchers as well as clinic investigators.

Anders A.F. Sima

Eleazar Shafrir

vii
 PREFACE

In 1936, Himsworth (Himsworth, 1936) observed that some diabetic patients require increas-
ing amounts of insulin, and appear to become gradually insensitive to insulin, or “resistant” to
the actions of insulin. Today, the term “insulin resistance” is applied to a broad range of bio-
logical observations, with an equally wide variety of potential underlying mechanisms. Animal
models are being extensively used to examine both the causes of loss of insulin sensitivity, and
the potential for reversal of this loss.
Consensus has not yet developed around a specific and quantifiable definition of insulin
resistance. Most commonly, the presence of insulin resistance has been inferred when a given
amount of endogenous or exogenous insulin has shown less than its expected biological action.
In truth, insulin resistance is substantially related to the methods used to seek it, and the meth-
ods today differ widely from in vitro cellular methods to whole body euglycemic or hyper-
glycemic clamps. Over the past twenty years the so-called “gold standard” for measuring
in vivo (whole body) insulin resistance has been this “clamp”, as developed initially by
DeFronzo, Tobin, and Andres (DeFronzo et al., 1979). During the earliest phases in the devel-
opment of type 2 diabetes, insulin resistance gradually develops, accompanied by increasing
fasting hyperinsulinemia and increasing beta cell responsiveness to a glucose stimulus.
Animal models of obesity and diabetes have contributed to understanding the natural his-
tory of the development of insulin resistance and to identifying some of the factors underlying
this insulin resistance. In the present volume, we have drawn together some of the leaders in
the field who provide their perspectives on the mechanisms of insulin resistance, as discerned
from various animal models. While the exact mechanism underlying the appearance of resist-
ance to insulin remains unknown, the authors here have examined many of the important fac-
tors. The contribution of age, from early perinatal to aged adulthood, has been considered.
Insulin resistance is a major feature of the middle-aged onset, obesity-associated Metabolic
Syndrome, sometimes referred to as Diabesity (Shafrir, 1993), diabetogenic obesity (Vague,
1956), or syndrome X (Reaven, 1988). This syndrome, described by many clinicians and
investigators beginning nearly fifty years ago (Vague, 1956), derives from observation of the
frequent interactions of insulin resistance with obesity, dyslipidemia, glucose intolerance, car-
diovascular disease, hypertension, and abnormalities in whole body metabolism, as previously
reviewed (Hansen, 1999). These clinical features and their possible insulin resistance-
associated pathophysiology, as elucidated by a variety of animal models, are discussed in a
series of chapters included here. Finally, many pieces of the complex signaling pathways
involved in causing insulin resistance, or emerging as a consequence of insulin resistance have
been identified at the molecular level. The human genome revolution has been paralleled by
extensive study of the genetics of animal models. New targets for pharmaceutical and other
therapeutic interventions, based in part on key observations made in animal models, are being
identified, and these genetic and molecular studies are leading to growth in our understanding
of insulin sensitivity and insulin resistance.

REFERENCES

DeFronzo, R.A., Tobin, J.D. and Andres, R. (1979) Glucose clamp technique: A method for quantifying
insulin secretion and resistance. Am. J. Physiol., 237, E214–E223.

ix
x PREFACE

Hansen, B.C. (1999) The metabolic syndrome X. In Hansen, B.C., Saye, J., Wennogle, L.P. (eds) The
Metabolic Syndrome X. Convergence of Insulin Resistance, Glucose Intolerance Hypertension, Obesity and
Dyslipidemias – Searching for the Underlying Defects. New York: Annals of New York Academy of
Sciences, pp. 1–24.
Himsworth, H.P. (1936) Diabetes mellitus: Its differentiation into insulin sensitive and insulin insensi-
tive types. Lancet, i, 127–130.
Reavean, G. (1988) Banting lecture 1988: Role of insulin resistance in human disease. Diabetologia, 30,
1595–1607.
Shafrir, E. (1993) Animal models of syndrome X. Curr. Topics in Diab. Res., 12, 165–181.
Shafrir, E. (1996) Development and consequences of insulin resistance: lessons from animals with
hyperinsulinemia. Diabetes & Metabolism (Paris), 22, 122–151.
Vague, J. (1956) The degree of masculine differentiation of obesities: A factor determining predisposi-
tion to diabetes, atherosclerosis, gout, and uric calculous disease. Am. J. Clin. Nutr., 4, 20–34.
 CONTRIBUTORS

T. Alquier G.R. Collier

UMR 5018 UPS-CNRS Metabolic Research Unit
IFR 31 School of Health Sciences
CHU Rangueil Deakin University
1 Avenue Jean Poulhés Geelong, Victoria 3217
31403 Toulouse Australia
France

Stephen V. Angeloni Sheila Collins

Obesity and Diabetes Research Center Duke University Medical Center
University of Maryland School of Medicine Durham
Baltimore, MD 21201 NC 27710
USA USA

G. Augert
Merck-Lipha G.J. Cooney
Lyon Garvan Institute of Medical Research
France St Vincent’s Hospital
Sydney, NSW 2010
Nir Barzilai Australia
Department of Medicine
Divisions of Geriatrics, Endocrinology, and
the Diabetes Research and the Training Hagit Eldar-Finkelman
Center Department of Human Genetics and
Albert Einstein College of Medicine Molecular Medicine
Bronx, NY 10461 Sackler School of Medicine
USA Tel Aviv University
Israel
José F. Caro
Endocrine Research
Eli Lilly and Company Jacob E. Friedman
Lilly Corporate Center Departments of Pediatrics, Biochemistry
Indianapolis, IN 46285 and Molecular Genetics
USA University of Colorado Health Sciences
Center
Maureen J. Charron 4200 East Ninth Avenue
Department of Biochemistry Denver, CO 80262
Albert Einstein College of Medicine USA
Bronx, NY 10461
USA
S.M. Furler
Anthony H. Cincotta Garvan Institute of Medical Research
158 Lake Road St Vincent’s Hospital
Tiverton, RI 02878 Sydney, NSW 2010
USA Australia

xi
xii CONTRIBUTORS

Ilan Gabriely Ellen B. Katz

Divisions of Geriatrics, Endocrinology, and Department of Biochemistry
the Diabetes Research and the Training Albert Einstein College of Medicine
Center Bronx, NY 10461
Department of Medicine USA
Albert Einstein College of Medicine
Bronx, NY 10461
USA S.E. Kelly
Department of Surgery
Barry J. Goldstein University of Alberta
Division of Endocrinology, Diabetes and Edmonton, Alberta
Metabolic Diseases Canada
Jefferson Medical College
Room 349 Alumni Hall
Philadelphia, PA 19107 Amira Klip
USA Programme in Cell Biology
The Hospital for Sick Children
Naira Gorovits Toronto, Ontario, M5G 1X8
Department of Chemistry Canada
Albert Einstein College of Medicine
Bronx, NY 10461
USA
E.W. Kraegen
Garvan Institute of Medical Research
C. Nicholas Hales
St Vincent’s Hospital
Clinical Biochemistry Department
Sydney, NSW 2010
University of Cambridge
Australia
Addenbrooke’s Hospital
Hills Road, Cambridge
UK
Daniel Konrad
Barbara Caleen Hansen Programme in Cell Biology
Obesity and Diabetes Research Center The Hospital for Sick Children
University of Maryland School of Medicine Toronto, Ontario, M5G 1X8
Baltimore, MD 21201 Canada
USA

Carol T.-L. Huang J. Skye Laidlaw

Programme in Cell Biology Department of Biochemistry
The Hospital for Sick Children Albert Einstein College of Medicine
Toronto, Ontario, M5G 1X8 Bronx, NY 10461
Canada USA

L. Kantham
Metabolic Research Unit Joseph Larner
School of Health Sciences Insmed Pharmaceuticals, Inc.
Deakin University 800 E. Leigh St
Geelong, Victoria 3217 Richmond, VA 23219
Australia USA
 CONTRIBUTORS xiii

C. Leloup L. Penicaud
UMR 5018 UPS-CNRS UMR 5018 UPS-CNRS
IFR 31 IFR 31
CHU Rangueil CHU Rangueil
1 Avenue Jean Poulhés 1 Avenue Jean Poulhes
31403 Toulouse 31403 Toulouse
France France
A. Lorsignol Clive J. Petry
UMR 5018 UPS-CNRS Clinical Biochemistry Department
IFR 31 University of Cambridge
CHU Rangueil Addenbrooke’s Hospital
1 Avenue Jean Poulhés Hills Road, Cambridge
31403 Toulouse UK
France
Tonya Martin Mollie Ranalletta
Duke University Medical Center Department of Biochemistry
Durham Albert Einstein College of Medicine
NC 27710 Bronx, NY 10461
USA USA

S. Morgan Varinder K. Randhawa

Metabolic Research Unit Programme in Cell Biology
School of Health Sciences The Hospital for Sick Children
Deakin University Toronto, Ontario, M5G 1X8
Geelong, Victoria 3217 Canada
Australia
J.C. Russell
Julie S. Moyers
Department of Surgery
Endocrine Research
University of Alberta
Eli Lilly and Company
Edmonton, Alberta
Lilly Corporate Center
Canada
Indianapolis, IN 46285
USA
D. Segal
Hiroyuki Odaka Metabolic Research Unit
Pharmacology Research Laboratories II School of Health Sciences
Takeda Chemical Industries Ltd Deakin University
2-17-85 Juso honmachi Geelong, Victoria 3217
Yodogawa-ku Australia
Osaka 532-8686
Japan Jianhua Shao
Departments of Pediatrics, Biochemistry
Susan E. Ozanne and Molecular Genetics
Clinical Biochemistry Department University of Colorado Health Sciences
University of Cambridge Center
Addenbrooke’s Hospital 4200 East Ninth Avenue
Hills Road, Cambridge Denver, CO 80262
UK USA
xiv CONTRIBUTORS

A. de Silva Gloria Tannenbaum

Metabolic Research Unit Department of Biochemistry
School of Health Sciences Albert Einstein College of Medicine
Deakin University Bronx, NY 10461
Geelong, Victoria 3217 USA
Australia

Kevin L. Stark K. Walder

Department of Metabolic Disorders Metabolic Research Unit
Amgen School of Health Sciences
One Amgen Center Drive Deakin University
Thousand Oaks, CA 91362 Geelong, Victoria 3217
USA Australia

Yasuo Sugiyama
Pharmacology Research Laboratories II Merav Yarkoni
Takeda Chemical Industries Ltd Department of Human Genetics and
2-17-85 Juso honmachi Molecular Medicine
Yodogawa-ku Sackler School of Medicine
Osaka 532-8686 Tel Aviv University
Japan Israel

Richard S. Surwit
Duke University Medical Center J.M. Ye
Durham Garvan Institute of Medical Research
NC 27710 St Vincent’s Hospital
USA Sydney, NSW 2010
Australia
Masami Suzuki
Pharmacology Research Laboratories II
Takeda Chemical Industries Ltd Andrew A. Young
2-17-85 Juso honmachi Amylin Pharmaceuticals Inc.
Yodogawa-ku 9373 Towne Center Drive
Osaka 532-8686 San Diego, CA 92121
Japan USA
Part 1

Metabolism and Hypertension

 1. INSULIN RESISTANCE AND GLYCOGEN
SYNTHESIS: ROLES IN LIVER, MUSCLE AND
ADIPOSE TISSUE

HAGIT ELDAR-FINKELMAN AND MERAV YARKONI

Department of Human Genetics and Molecular Medicine, Sackler School of
Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel

INTRODUCTION

Insulin resistance is a key factor in the pathogenesis of obesity and type 2 diabetes, the world’s
most prevalent metabolic disorder. Insulin resistance is also the cause of insulin resistance syn-
drome, syndrome X, in which physiological abnormalities such as renal failure, hypertension
and neuropathy cluster together. Insulin resistance is characterized by the failure of tissues to
respond to insulin, resulting in reduced glucose intake to peripheral tissue and increased
hepatic glucose output. Since the major portion of ‘whole body’ glucose is metabolized into
glycogen (Bogardus et al., 1984; Roden and Shulman, 1999), defects in its metabolism may
represent an important factor underlying the development of insulin resistance and type 2 dia-
betes. Glycogen synthase is the rate-limiting enzyme for glycogen synthesis, and its regulation
is one of the few examples of complex, hierarchical, multisite phosphorylation. Studies to date
have not fully uncovered the in vivo mechanisms regulating glycogen synthase; they have,
however, established important concepts in cellular regulation such as enzyme regulation by
reversible phosphorylation, the role of targeting molecules and function of signaling cascades.
In this chapter we describe the regulation of glycogen synthase in type 2 diabetes, focusing
on glycogen synthase in muscle, liver and fat. We discuss the concept that defects in glycogen
synthase are early manifestations of insulin resistance.

REGULATION OF GLYCOGEN SYNTHASE

Glycogen synthase catalyzes the incorporation of the glycosyl residue from UDP-glucose
into glycogen. Glycogen synthase is phosphorylated on multiple sites and is highly regulated
by phosphorylation–dephosphorylation mechanisms, also termed covalent modification.
Different protein kinases can phosphorylate the enzyme in vitro, including c-AMP-dependent
protein kinases (PKA), calmodulin dependent protein kinases, glycogen synthase kinase-3
(GSK-3), and casein kinase-2 (CK-2) (reviewed in Cohen, 1986; Roach, 1991). It is probable
that only a few kinases are physiological kinases of glycogen synthase.
Phosphorylation of glycogen synthase determines its activity. In general, increased phos-
phorylation of the enzyme inhibits its activity, while the extent of inactivation apparently
depends on the specific site phosphorylated. Early in vitro studies implicated GSK-3 and PKA
as the kinases that inhibit glycogen synthase (Cohen, 1986). Studies of rabbit muscle glycogen
synthase identified its in vivo phosphorylation sites and correlated them with the correspon-
ding kinase (Figure 1): at the N-terminus sites 2a and 2b phosphorylated by PKA and CK-1
3
4 HAGIT ELDAR-FINKELMAN AND MERAV YARKONI

PKA CK-1 GSK-3 CK-2 PKA

a b c

C
N 2a 2b 3 5 1a 1b

Figure 1 Schematic presentation of the phosphorylation sites of muscle glycogen synthase. Site 2a
is phosphorylated by PKA and promotes the phosphorylation of site 2b by CK-1, sites 1a and 1b are
phosphorylated by PKA, site 5 is phosphorylated by CK-2 and promotes the phosphorylation of sites
3a, 3b and 3c by GSK-3.

respectively (Flotow and Roach, 1989); at the C-terminus two sites 1a and 1b phosphorylated
by PKA (Parker et al., 1983); GSK-3 phosphorylates a cluster of 3 serine sites collectively
termed ‘site 3’ (Parker et al., 1983; Woodgett and Cohen, 1984); and ‘site 5’ located down-
stream to ‘site 3’ phosphorylated by CK-2 (Fiol et al., 1987; Woodgett and Cohen, 1984).
Administration of insulin to rabbit muscle led to a specific decrease in the phosphorylation of
‘site 3’ (Parker et al., 1983), indicating that dephosphorylation of this site is important for
activation of the enzyme by insulin. Recent work using tissue cultured cells and molecular
biology manipulations supported the notion that GSK-3 is a major physiological regulator of
glycogen synthase (Cross et al., 1994; Eldar-Finkelman et al., 1996; Skurat et al., 1994).
Insulin promotes dephosphorylation of glycogen synthase via inhibition of GSK-3 (Cross
et al., 1994) and activation of a serine/threonine protein phosphatase (Dent et al., 1990). The
phosphatase that is mainly responsible for dephosphorylation of glycogen synthase is the
glycogen-bound form of type 1 protein phosphatase, PP1G, that comprise catalytic subunit
and a targeting subunit (Dent et al., 1990). Activation of the phosphatase is controlled mainly
by the targeting subunit that directs the enzyme to glycogen particles (Dent et al., 1990;
Hubbard and Cohen, 1993). Tissue specific targeting subunits were identified in muscle and
liver (Hubbard and Cohen, 1993). Recently, a protein targeting to glycogen (PTG) molecule
was isolated from 3T3L1 adipocytes and was shown to assemble the enzymes involved in
glycogen metabolism such as PP1, phosphorylase and phosphorylase kinase (Printen et al.,
1997), and to promote glycogen synthesis when expressed in cells (Berman et al., 1998).
Glycogen synthase is controlled by several allosteric effectors, of which the intracellular
metabolite glucose 6 phosphate (G6P) is the most important (reviewed in Villar-Palasi and
Guinovart, 1997). G6P can activate glycogen synthase even at highly phosphorylated states,
and is therefore often used as an index of the enzyme activity. The enzyme activity assayed in
the presence of high concentrations of G6P (6–10 mM) represents the active
inactive
enzyme and is the total activity. The activity ratio is the ratio of activity assayed in the absence
or presence of G6P and represents the fraction of active enzyme. Some studies measure the
activity ratio in the presence of low or high concentrations of G6P in order to enhance the sen-
sitivity of the enzyme (Guinovart et al., 1979); this ratio is usually termed as fraction velocity.
The phosphorylation content of glycogen synthase determines its sensitivity to G6P; the more
phosphorylated the less sensitive. Nevertheless, certain sites are more effective in changing the
sensitivity of the enzyme to G6P (Embi and Cohen, 1980). As shown in Figure 2, phosphory-
lation of glycogen synthase by GSK-3 led to a shift to the right of the G6P dose response curve
leading to a 10-fold increase in its Ka (i.e. the concentration of G6P required for half maximal
activation of the enzyme). These results indicate that GSK-3 reduces glycogen synthase
sensitivity to G6P.
 INSULIN RESISTANCE AND GLYCOGEN SYNTHESIS 5

20

GS activity (nmol/min/mg)
15

10 +GSK-3

0 2 4 6 8 10
G6P (mM)

Figure 2 Effect of GSK-3 on allosteric activation of glycogen synthase by G6P. Glycogen

synthase was phosphorylated in vitro by GSK-3 and then assayed for glycogen synthase activity in the
presence of varied concentrations of G6P as indicated. Glycogen synthase activity is presented as UDPG
incorporated into glycogen (nmol/min/mg protein) and results are an average of duplicated sample of
one representative experiment.

Insulin

Insulin
Glut-4 ? receptor

Glucose IRS
HKII

G6P Pl3K

?
G1P PKB
–

UDPG GSK-3 PPIG

Glycogen synthase

– +

Glycogen synthase

Glycogen synthesis

Figure 3 Activation of glycogen synthase by insulin. Insulin stimulates the activation of IRS/PI
3-kinase downstream pathway resulting in inhibition of GSK-3, and activation of the phosphatase PP1G.
Insulin initiates the translocation of glucose transporters Glut4 from intracellular vesicles to the mem-
brane, which promotes glucose entering into cells. Glucose is phosphorylated by hexokinaseII to glucose-
6-phopsphate (G6P) that binds and activates glycogen synthase. G6P is also an intermediate metabolite
for utilization of UDP glucose (UDPG) required for glycogen synthesis.
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