Diabetes
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cline, G. W.
Right arrow Articles by Shulman, G. I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cline, G. W.
Right arrow Articles by Shulman, G. I.
Social Bookmarking
Add to CiteULike   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Diabetes 51:2903-2910, 2002
© 2002 by the American Diabetes Association, Inc.

Effects of a Novel Glycogen Synthase Kinase-3 Inhibitor on Insulin-Stimulated Glucose Metabolism in Zucker Diabetic Fatty (fa/fa) Rats

Gary W. Cline1, Kirk Johnson2, Werner Regittnig1, Pascale Perret1, Effie Tozzo2, Linda Xiao2, Christine Damico2, and Gerald I. Shulman1,3,4

1 Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
2 Pharmacology and Preclinical Research, Chiron, Emeryville, California
3 Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut
4 Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut

Defects in liver and muscle glycogen synthesis are major factors contributing to postprandrial hyperglycemia in patients with type 2 diabetes. Therefore, activation of glycogen synthase through inhibition of glycogen synthase kinase (GSK)-3 represents a potential new therapeutic target. To examine this possibility, we performed oral glucose tolerance tests (OGTTs) and euglycemic-insulinemic clamp studies in Zucker diabetic fatty (fa/fa) rats before and after treatment with novel GSK-3 inhibitors. GSK-3 inhibition caused a 41 ± 2% (P < 0.001) and 26 ± 4% (P < 0.05) reduction in the area under the glucose and insulin concentration curves, respectively, during the OGTT. This improvement in glucose disposal could mostly be attributed to an approximate twofold increase in liver glycogen synthesis. In contrast, there was no significant increase in muscle glycogen synthesis despite an approximate threefold activation of muscle glycogen synthase activity. GSK-3 inhibitor treatment increased liver glycogen synthesis about threefold independent of insulin concentration during the clamp studies. In contrast, muscle glucose uptake and muscle glycogen synthesis were independent of drug treatment. GSK-3 inhibitor treatment lowered fasting hyperglycemia in diabetic rats by 6.0 ± 1.3 mmol/l but had no significant effect on glucose disposal during the clamp. In conclusion, GSK-3 inhibition significantly improved oral glucose disposal, mostly by increasing liver glycogen synthesis. These studies suggest that GSK-3 inhibition may represent an important new therapeutic target for treatment of patients with type 2 diabetes.


Add to CiteULike CiteULike   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 EndocrinologyHome page
T. P. Ciaraldi, S. E. Nikoulina, R. A. Bandukwala, L. Carter, and R. R. Henry
Role of Glycogen Synthase Kinase-3{alpha} in Insulin Action in Cultured Human Skeletal Muscle Cells
Endocrinology, September 1, 2007; 148(9): 4393 - 4399.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
R. Mussmann, M. Geese, F. Harder, S. Kegel, U. Andag, A. Lomow, U. Burk, D. Onichtchouk, C. Dohrmann, and M. Austen
Inhibition of GSK3 Promotes Replication and Survival of Pancreatic Beta Cells
J. Biol. Chem., April 20, 2007; 282(16): 12030 - 12037.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
E. R. Gross, A. K. Hsu, and G. J. Gross
Diabetes Abolishes Morphine-Induced Cardioprotection via Multiple Pathways Upstream of Glycogen Synthase Kinase-3{beta}
Diabetes, January 1, 2007; 56(1): 127 - 136.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
K. Morino, K. F. Petersen, and G. I. Shulman
Molecular Mechanisms of Insulin Resistance in Humans and Their Potential Links With Mitochondrial Dysfunction
Diabetes, December 1, 2006; 55(Supplement_2): S9 - S15.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
T. P. Ciaraldi, D. K. Oh, L. Christiansen, S. E. Nikoulina, A. P. S. Kong, S. Baxi, S. Mudaliar, and R. R. Henry
Tissue-specific expression and regulation of GSK-3 in human skeletal muscle and adipose tissue
Am J Physiol Endocrinol Metab, November 1, 2006; 291(5): E891 - E898.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
B. B. Dokken and E. J. Henriksen
Chronic selective glycogen synthase kinase-3 inhibition enhances glucose disposal and muscle insulin action in prediabetic obese Zucker rats
Am J Physiol Endocrinol Metab, August 1, 2006; 291(2): E207 - E213.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
B. Clodfelder-Miller, P. De Sarno, A. A. Zmijewska, L. Song, and R. S. Jope
Physiological and Pathological Changes in Glucose Regulate Brain Akt and Glycogen Synthase Kinase-3
J. Biol. Chem., December 2, 2005; 280(48): 39723 - 39731.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J. Diao, Z. Asghar, C. B. Chan, and M. B. Wheeler
Glucose-regulated Glucagon Secretion Requires Insulin Receptor Expression in Pancreatic {alpha}-Cells
J. Biol. Chem., September 30, 2005; 280(39): 33487 - 33496.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
B. B. Dokken, J. A. Sloniger, and E. J. Henriksen
Acute selective glycogen synthase kinase-3 inhibition enhances insulin signaling in prediabetic insulin-resistant rat skeletal muscle
Am J Physiol Endocrinol Metab, June 1, 2005; 288(6): E1188 - E1194.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Z. Liberman and H. Eldar-Finkelman
Serine 332 Phosphorylation of Insulin Receptor Substrate-1 by Glycogen Synthase Kinase-3 Attenuates Insulin Signaling
J. Biol. Chem., February 11, 2005; 280(6): 4422 - 4428.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
K. H. Kim, M. J. Song, E. J. Yoo, S. S. Choe, S. D. Park, and J. B. Kim
Regulatory Role of Glycogen Synthase Kinase 3 for Transcriptional Activity of ADD1/SREBP1c
J. Biol. Chem., December 10, 2004; 279(50): 51999 - 52006.
[Abstract] [Full Text] [PDF]

Home page
 J. Nutr.Home page
Y. Wei, M. E. Bizeau, and M. J. Pagliassotti
An Acute Increase in Fructose Concentration Increases Hepatic Glucose-6-Phosphatase mRNA via Mechanisms That Are Independent of Glycogen Synthase Kinase-3 in Rats
J. Nutr., March 1, 2004; 134(3): 545 - 551.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
J. R. A. Schafer, D. A. Fell, D. Rothman, and R. G. Shulman
Protein phosphorylation can regulate metabolite concentrations rather than control flux: The example of glycogen synthase
PNAS, February 10, 2004; 101(6): 1485 - 1490.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
A. V. Skurat and A. D. Dietrich
Phosphorylation of Ser640 in Muscle Glycogen Synthase by DYRK Family Protein Kinases
J. Biol. Chem., January 23, 2004; 279(4): 2490 - 2498.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
A. Barthel and D. Schmoll
Novel concepts in insulin regulation of hepatic gluconeogenesis
Am J Physiol Endocrinol Metab, October 1, 2003; 285(4): E685 - E692.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
A. M. Valverde, D. J. Burks, I. Fabregat, T. L. Fisher, J. Carretero, M. F. White, and M. Benito
Molecular Mechanisms of Insulin Resistance in IRS-2-Deficient Hepatocytes
Diabetes, September 1, 2003; 52(9): 2239 - 2248.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
B. Plotkin, O. Kaidanovich, I. Talior, and H. Eldar-Finkelman
Insulin Mimetic Action of Synthetic Phosphorylated Peptide Inhibitors of Glycogen Synthase Kinase-3
J. Pharmacol. Exp. Ther., June 1, 2003; 305(3): 974 - 980.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
E. J. Henriksen, T. R. Kinnick, M. K. Teachey, M. P. O'Keefe, D. Ring, K. W. Johnson, and S. D. Harrison
Modulation of muscle insulin resistance by selective inhibition of GSK-3 in Zucker diabetic fatty rats
Am J Physiol Endocrinol Metab, May 1, 2003; 284(5): E892 - E900.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
D. B. Ring, K. W. Johnson, E. J. Henriksen, J. M. Nuss, D. Goff, T. R. Kinnick, S. T. Ma, J. W. Reeder, I. Samuels, T. Slabiak, et al.
Selective Glycogen Synthase Kinase 3 Inhibitors Potentiate Insulin Activation of Glucose Transport and Utilization In Vitro and In Vivo
Diabetes, March 1, 2003; 52(3): 588 - 595.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum
Copyright © 2002 by the American Diabetes Association.