| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Department of Physiology, University of Arizona College of Medicine, Tucson, AZ, USA
2 Chiron Corporation, Emeryville, CA, USA
* To whom correspondence should be addressed. E-mail: ejhenrik{at}u.arizona.edu.
A role for elevated glycogen synthase kinase-3 (GSK-3) activity in the multifactorial etiology of insulin resistance is now emerging. However, the utility of specific GSK-3 inhibition in modulating insulin resistance of skeletal muscle glucose transport is not yet fully understood. Therefore, we assessed the effects of novel, selective organic inhibitors of GSK-3 (CT98014 and CT98023) on glucose transport in insulin-resistant muscles of Zucker diabetic fatty (ZDF) rats. Incubation of type IIb epitrochlearis and type I soleus muscles from ZDF rats with CT98014 increased glycogen synthase (GSI) activity (49% and 50%, respectively, p<0.05), but did not alter basal glucose transport (2-deoxyglucose uptake). In contrast, CT98014 significantly increased the stimulatory effects of both submaximal and maximal insulin concentrations in epitrochlearis (37% and 24%) and soleus (43% and 26%), and these effects were associated with increased cell-surface GLUT-4 protein. Lithium enhanced GS activity and both basal and insulin-stimulated glucose transport in muscles from ZDF rats. Acute oral administration (2 X 30 mg/kg) of CT98024 to ZDF rats caused elevations in GSK-3 inhibitor concentrations in plasma and muscle. The glucose and insulin responses during a subsequent oral glucose tolerance test were reduced by 26% and 34%, respectively, in the GSK-3 inhibitor-treated animals. Thirty minutes after the final GSK-3 inhibitor treatment, insulin-stimulated glucose transport was significantly enhanced in epitrochlearis (57%) and soleus (43%). Two hours after the final treatment, insulin-mediated glucose transport was still significantly elevated (26%) only in the soleus. These results indicate that specific inhibition of GSK-3 enhances insulin action on glucose transport in skeletal muscle of insulin-resistant ZDF rat. This unique approach may hold promise as a pharmacological treatment against insulin resistance of skeletal muscle glucose disposal.
This article has been cited by other articles:
|
|
 |
|
  S. Patel, B. W. Doble, K. MacAulay, E. M. Sinclair, D. J. Drucker, and J. R. Woodgett Tissue-Specific Role of Glycogen Synthase Kinase 3{beta} in Glucose Homeostasis and Insulin Action Mol. Cell. Biol., October 15, 2008; 28(20): 6314 - 6328. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. L. Buller, R. D. Loberg, M.-H. Fan, Q. Zhu, J. L. Park, E. Vesely, K. Inoki, K.-L. Guan, and F. C. Brosius III A GSK-3/TSC2/mTOR pathway regulates glucose uptake and GLUT1 glucose transporter expression Am J Physiol Cell Physiol, September 1, 2008; 295(3): C836 - C843. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. J. Henriksen, M. K. Teachey, K. A. Lindborg, C. J. Diehl, and A. N. Beneze The high-fat-fed lean Zucker rat: a spontaneous isocaloric model of fat-induced insulin resistance associated with muscle GSK-3 overactivity Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2008; 294(6): R1813 - R1821. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Liberman, B. Plotkin, T. Tennenbaum, and H. Eldar-Finkelman Coordinated phosphorylation of insulin receptor substrate-1 by glycogen synthase kinase-3 and protein kinase C{beta}II in the diabetic fat tissue Am J Physiol Endocrinol Metab, June 1, 2008; 294(6): E1169 - E1177. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. B. Dokken, V. Saengsirisuwan, J. S. Kim, M. K. Teachey, and E. J. Henriksen Oxidative stress-induced insulin resistance in rat skeletal muscle: role of glycogen synthase kinase-3 Am J Physiol Endocrinol Metab, March 1, 2008; 294(3): E615 - E621. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. F. Anhe, S. M. Hirabara, T. C. Turrer, L. C. Caperuto, F. F. Anhe, L. M. Ribeiro, A. C. Marcal, C. R. O. Carvalho, R. Curi, U. F. Machado, et al. Postpartum glycemic homeostasis in early lactating rats is accompanied by transient and specific increase of soleus insulin response through IRS2/AKT pathway Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2007; 292(6): R2225 - R2233. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
A. Chabowski, J. C. Chatham, N. N. Tandon, J. Calles-Escandon, J. F. C. Glatz, J. J. F. P. Luiken, and A. Bonen Fatty acid transport and FAT/CD36 are increased in red but not in white skeletal muscle of ZDF rats Am J Physiol Endocrinol Metab, September 1, 2006; 291(3): E675 - E682. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 K. MacAulay, A. S. Blair, E. Hajduch, T. Terashima, O. Baba, C. Sutherland, and H. S. Hundal Constitutive Activation of GSK3 Down-regulates Glycogen Synthase Abundance and Glycogen Deposition in Rat Skeletal Muscle Cells J. Biol. Chem., March 11, 2005; 280(10): 9509 - 9518. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. S. Fernandez-Twinn, A. Wayman, S. Ekizoglou, M. S. Martin, C. N. Hales, and S. E. Ozanne Maternal protein restriction leads to hyperinsulinemia and reduced insulin-signaling protein expression in 21-mo-old female rat offspring Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2005; 288(2): R368 - R373. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Visit Other APS Journals Online |
