HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lochhead, P. A. Articles by Sutherland, C. Search for Related Content PubMed PubMed Citation Articles by Lochhead, P. A. Articles by Sutherland, C. Social Bookmarking                What's this?

Inhibition of GSK-3 Selectively Reduces Glucose-6-Phosphatase and Phosphoenolpyruvate Carboxykinase Gene Expression

¹ Division of Cell Signalling, School of Life Sciences, University of Dundee, Dundee; and the Departments of
² Vascular Biology and
³ Gene Expression Sciences, GlaxoSmithKline Pharmaceuticals, Harlow, Essex, U.K.

A major action of insulin is to regulate the transcription rate of specific genes. The expression of these genes is dramatically altered in type 2 diabetes. For example, the expression of two hepatic genes, glucose-6-phosphatase and PEPCK, is normally inhibited by insulin, but in type 2 diabetes, their expression is insensitive to insulin. An agent that mimics the effect of insulin on the expression of these genes would reduce gluconeogenesis and hepatic glucose output, even in the presence of insulin resistance. The repressive actions of insulin on these genes are dependent on phosphatidylinositol (PI) 3-kinase. However, the molecules that lie between this lipid kinase and the two gene promoters are unknown. Glycogen synthase kinase-3 (GSK-3) is inhibited following activation of PI 3-kinase and protein kinase B. In hepatoma cells, we find that selectively reducing GSK-3 activity strongly reduces the expression of both gluconeogenic genes. The effect is at the level of transcription and is observed with induced or basal gene expression. In addition, GSK-3 inhibition does not result in the subsequent activation of protein kinase B or inhibition of the transcription factor FKHR, which are candidate regulatory molecules for these promoters. Thus, GSK-3 activity is required for basal activity of each promoter. Inhibitors of GSK-3 should therefore reduce hepatic glucose output, as well as increase the synthesis of glycogen from L-glucose. These findings indicate that GSK-3 inhibitors may have greater therapeutic potential for lowering blood glucose levels and treating type 2 diabetes than previously realized.

CiteULike

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				L. Logie, A. J. Ruiz-Alcaraz, M. Keane, Y. L. Woods, J. Bain, R. Marquez, D. R. Alessi, and C. Sutherland Characterization of a Protein Kinase B Inhibitor In Vitro and in Insulin-Treated Liver Cells Diabetes, September 1, 2007; 56(9): 2218 - 2227. [Abstract] [Full Text] [PDF]

				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]

				M.-H. Liang and D.-M. Chuang Regulation and Function of Glycogen Synthase Kinase-3 Isoforms in Neuronal Survival J. Biol. Chem., February 9, 2007; 282(6): 3904 - 3917. [Abstract] [Full Text] [PDF]

				E. I. Danek, J. Tcherkezian, I. Triki, M. Meriane, and N. Lamarche-Vane Glycogen Synthase Kinase-3 Phosphorylates CdGAP at a Consensus ERK 1 Regulatory Site J. Biol. Chem., February 9, 2007; 282(6): 3624 - 3631. [Abstract] [Full Text] [PDF]

				D. Finlay, A. J Ruiz-Alcaraz, C. Lipina, S. Perrier, and C. Sutherland A temporal switch in the insulin-signalling pathway that regulates hepatic IGF-binding protein-1 gene expression. J. Mol. Endocrinol., October 1, 2006; 37(2): 227 - 237. [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]

				A. di Palma, G. Matarese, V. Leone, T. Di Matola, F. Acquaviva, A. M. Acquaviva, and P. Ricchi Aspirin reduces the outcome of anticancer therapy in Meth A-bearing mice through activation of AKT-glycogen synthase kinase signaling Mol. Cancer Ther., May 1, 2006; 5(5): 1318 - 1324. [Abstract] [Full Text] [PDF]

				S. Chevalier, S. C. Burgess, C. R. Malloy, R. Gougeon, E. B. Marliss, and J. A. Morais The Greater Contribution of Gluconeogenesis to Glucose Production in Obesity Is Related to Increased Whole-Body Protein Catabolism Diabetes, March 1, 2006; 55(3): 675 - 681. [Abstract] [Full Text] [PDF]

				H. Lohi, L. Ianzano, X.-C. Zhao, E. M. Chan, J. Turnbull, S. W. Scherer, C. A. Ackerley, and B. A. Minassian Novel glycogen synthase kinase 3 and ubiquitination pathways in progressive myoclonus epilepsy Hum. Mol. Genet., September 15, 2005; 14(18): 2727 - 2736. [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]

				S. Schinner, A. Barthel, C. Dellas, R. Grzeskowiak, S. K. Sharma, E. Oetjen, R. Blume, and W. Knepel Protein Kinase B Activity Is Sufficient to Mimic the Effect of Insulin on Glucagon Gene Transcription J. Biol. Chem., February 25, 2005; 280(8): 7369 - 7376. [Abstract] [Full Text] [PDF]

				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]

				S. M. Rahman, A. Dobrzyn, S.-H. Lee, P. Dobrzyn, M. Miyazaki, and J. M. Ntambi Stearoyl-CoA desaturase 1 deficiency increases insulin signaling and glycogen accumulation in brown adipose tissue Am J Physiol Endocrinol Metab, February 1, 2005; 288(2): E381 - E387. [Abstract] [Full Text] [PDF]

				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]

				P. Vuguin, E. Raab, B. Liu, N. Barzilai, and R. Simmons Hepatic Insulin Resistance Precedes the Development of Diabetes in a Model of Intrauterine Growth Retardation Diabetes, October 1, 2004; 53(10): 2617 - 2622. [Abstract] [Full Text] [PDF]

				W. T. O'Brien, A. D. Harper, F. Jove, J. R. Woodgett, S. Maretto, S. Piccolo, and P. S. Klein Glycogen Synthase Kinase-3{beta} Haploinsufficiency Mimics the Behavioral and Molecular Effects of Lithium J. Neurosci., July 28, 2004; 24(30): 6791 - 6798. [Abstract] [Full Text] [PDF]

				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]

				H. Ono, H. Shimano, H. Katagiri, N. Yahagi, H. Sakoda, Y. Onishi, M. Anai, T. Ogihara, M. Fujishiro, A. Y.I. Viana, et al. Hepatic Akt Activation Induces Marked Hypoglycemia, Hepatomegaly, and Hypertriglyceridemia With Sterol Regulatory Element Binding Protein Involvement Diabetes, December 1, 2003; 52(12): 2905 - 2913. [Abstract] [Full Text] [PDF]

				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]

				S. M. Rahman, A. Dobrzyn, P. Dobrzyn, S.-H. Lee, M. Miyazaki, and J. M. Ntambi Stearoyl-CoA desaturase 1 deficiency elevates insulin-signaling components and down-regulates protein-tyrosine phosphatase 1B in muscle PNAS, September 16, 2003; 100(19): 11110 - 11115. [Abstract] [Full Text] [PDF]

				F. Zhang, C. J. Phiel, L. Spece, N. Gurvich, and P. S. Klein Inhibitory Phosphorylation of Glycogen Synthase Kinase-3 (GSK-3) in Response to Lithium: EVIDENCE FOR AUTOREGULATION OF GSK-3 J. Biol. Chem., August 29, 2003; 278(35): 33067 - 33077. [Abstract] [Full Text] [PDF]

				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]

				B. W. Doble and J. R. Woodgett GSK-3: tricks of the trade for a multi-tasking kinase J. Cell Sci., April 1, 2003; 116(7): 1175 - 1186. [Abstract] [Full Text] [PDF]

				B. T. Vander Kooi, R. S. Streeper, C. A. Svitek, J. K. Oeser, D. R. Powell, and R. M. O'Brien The Three Insulin Response Sequences in the Glucose-6-phosphatase Catalytic Subunit Gene Promoter Are Functionally Distinct J. Biol. Chem., March 28, 2003; 278(14): 11782 - 11793. [Abstract] [Full Text] [PDF]

				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]

				R. J. Gum, L. L. Gaede, S. L. Koterski, M. Heindel, J. E. Clampit, B. A. Zinker, J. M. Trevillyan, R. G. Ulrich, M. R. Jirousek, and C. M. Rondinone Reduction of Protein Tyrosine Phosphatase 1B Increases Insulin-Dependent Signaling in ob/ob Mice Diabetes, January 1, 2003; 52(1): 21 - 28. [Abstract] [Full Text] [PDF]

				M. J. Pagliassotti, Y. Wei, and M. E. Bizeau Glucose-6-Phosphatase Activity Is Not Suppressed but the mRNA Level Is Increased by a Sucrose-Enriched Meal in Rats J. Nutr., January 1, 2003; 133(1): 32 - 37. [Abstract] [Full Text] [PDF]

				G. W. Cline, K. Johnson, W. Regittnig, P. Perret, E. Tozzo, L. Xiao, C. Damico, and G. I. Shulman Effects of a Novel Glycogen Synthase Kinase-3 Inhibitor on Insulin-Stimulated Glucose Metabolism in Zucker Diabetic Fatty (fa/fa) Rats Diabetes, October 1, 2002; 51(10): 2903 - 2910. [Abstract] [Full Text] [PDF]

				C. Anderwald, G. Muller, G. Koca, C. Furnsinn, W. Waldhausl, and M. Roden Short-Term Leptin-Dependent Inhibition of Hepatic Gluconeogenesis Is Mediated by Insulin Receptor Substrate-2 Mol. Endocrinol., July 1, 2002; 16(7): 1612 - 1628. [Abstract] [Full Text] [PDF]

				Y. Sun, S. Liu, S. Ferguson, L. Wang, P. Klepcyk, J. S. Yun, and J. E. Friedman Phosphoenolpyruvate Carboxykinase Overexpression Selectively Attenuates Insulin Signaling and Hepatic Insulin Sensitivity in Transgenic Mice J. Biol. Chem., June 21, 2002; 277(26): 23301 - 23307. [Abstract] [Full Text] [PDF]

				S. Patel, P. A. Lochhead, G. Rena, S. Fumagalli, M. Pende, S. C. Kozma, G. Thomas, and C. Sutherland Insulin Regulation of Insulin-like Growth Factor-binding Protein-1 Gene Expression Is Dependent on the Mammalian Target of Rapamycin, but Independent of Ribosomal S6 Kinase Activity J. Biol. Chem., March 15, 2002; 277(12): 9889 - 9895. [Abstract] [Full Text] [PDF]

				C. Yu, G. Krystal, L. Varticovksi, R. McKinstry, M. Rahmani, P. Dent, and S. Grant Pharmacologic Mitogen-activated Protein/Extracellular Signal-regulated Kinase Kinase/Mitogen-activated Protein Kinase Inhibitors Interact Synergistically with STI571 to Induce Apoptosis in Bcr/Abl-expressing Human Leukemia Cells Cancer Res., January 1, 2002; 62(1): 188 - 199. [Abstract] [Full Text] [PDF]