title: Glycogen synthase kinase 3 beta mediates high glucose-induced ubiquitination and proteasome degradation of insulin receptor substrate 1.
abstract: High glucose (HG) has been shown to induce insulin resistance in both type 1 and type 2 diabetes. However, the molecular mechanism behind this phenomenon is unknown. Insulin receptor substrate (IRS) proteins are the key signaling molecules that mediate insulin's intracellular actions. Genetic and biological studies have shown that reductions in IRS1 and/or IRS2 protein levels are associated with insulin resistance. In this study we have shown that proteasome degradation of IRS1, but not of IRS2, is involved in HG-induced insulin resistance in Chinese hamster ovary (CHO) cells as well as in primary hepatocytes. To further investigate the molecular mechanism by which HG induces insulin resistance, we examined various molecular candidates with respect to their involvement in the reduction in IRS1 protein levels. In contrast to the insulin-induced degradation of IRS1, HG-induced degradation of IRS1 did not require IR signaling or phosphatidylinositol 3-kinase/Akt activity. We have identified glycogen synthase kinase 3beta (GSK3 beta or GSK3B as listed in the MGI Database) as a kinase required for HG-induced serine(332) phosphorylation, ubiquitination, and degradation of IRS1. Overexpression of IRS1 with mutation of serine(332) to alanine partially prevents HG-induced IRS1 degradation. Furthermore, overexpression of constitutively active GSK3 beta was sufficient to induce IRS1 degradation. Our data reveal the molecular mechanism of HG-induced insulin resistance, and support the notion that activation of GSK3 beta contributes to the induction of insulin resistance via phosphorylation of IRS1, triggering the ubiquitination and degradation of IRS1.
authors.affiliation: The Section of Endocrinology, The University of Chicago, 900 East 57th Street, Chicago, Illinois 60637, USA.
authors.forename: Sanhua
authors.initials: S
authors.lastname: Leng
authors.forename: Wenshuo
authors.initials: W
authors.lastname: Zhang
authors.forename: Yanbin
authors.initials: Y
authors.lastname: Zheng
authors.forename: Ziva
authors.initials: Z
authors.lastname: Liberman
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Rhodes
authors.forename: Hagit
authors.initials: H
authors.lastname: Eldar-Finkelman
authors.forename: Xiao Jian
authors.initials: XJ
authors.lastname: Sun
mesh_terms: D000818:Animals; D016466:CHO Cells / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D005947:Glucose / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D022781:Hepatocytes / Q000378:metabolism; D015151:Immunoblotting; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D007333:Insulin Resistance; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D015398:Signal Transduction; D054875:Ubiquitination
chemical_list: D055504:Insulin Receptor Substrate Proteins; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D046988:Proteasome Endopeptidase Complex; D005947:Glucose
references.citation: J Biol Chem. 2000 Jul 7;275(27):20880-6
references.pmid: 10764799
references.citation: J Biol Chem. 2005 Feb 11;280(6):4422-8
references.pmid: 15574412
references.citation: Vitam Horm. 2009;80:351-87
references.pmid: 19251044
references.citation: Cell Metab. 2007 Oct;6(4):329-37
references.pmid: 17908561
references.citation: Nature. 2001 Nov 29;414(6863):514-21
references.pmid: 11734846
references.citation: Diabetes. 1997 Oct;46(10):1572-8
references.pmid: 9313752
references.citation: Biochem Biophys Res Commun. 1994 May 30;201(1):71-7
references.pmid: 8198614
references.citation: Proc Natl Acad Sci U S A. 1997 Sep 2;94(18):9660-4
references.pmid: 9275179
references.citation: Mol Cell Biol. 2007 Jun;27(12):4328-39
references.pmid: 17371841
references.citation: J Biol Chem. 2006 Dec 22;281(51):39071-80
references.pmid: 17068339
references.citation: Diabetes. 1999 Jul;48(7):1359-64
references.pmid: 10389839
references.citation: Nature. 1995 Dec 21-28;378(6559):785-9
references.pmid: 8524413
references.citation: Diabetes. 2000 Jun;49(6):981-91
references.pmid: 10866051
references.citation: Nature. 2000 Jul 6;406(6791):86-90
references.pmid: 10894547
references.citation: BMC Mol Biol. 2004 Sep 06;5:15
references.pmid: 15350195
references.citation: Diabetologia. 2004 Oct;47(10):1661-7
references.pmid: 15480539
references.citation: EMBO J. 1990 Aug;9(8):2431-8
references.pmid: 2164470
references.citation: J Clin Invest. 2005 Mar;115(3):718-27
references.pmid: 15711641
references.citation: Can J Physiol Pharmacol. 2006 Jul;84(7):725-37
references.pmid: 16998536
references.citation: Diabetes. 2000 Feb;49(2):263-71
references.pmid: 10868943
references.citation: Arch Pharm Res. 2004 Apr;27(4):361-70
references.pmid: 15180298
references.citation: J Clin Invest. 1995 Jul;96(1):132-40
references.pmid: 7615783
references.citation: Am J Physiol Endocrinol Metab. 2008 Jun;294(6):E1169-77
references.pmid: 18430969
references.citation: J Cell Biol. 1969 Dec;43(3):506-20
references.pmid: 4900611
references.citation: Diabetes. 1994 Aug;43(8):1066-84
references.pmid: 8039601
references.citation: FEBS Lett. 2006 Apr 3;580(8):1932-40
references.pmid: 16530186
references.citation: J Clin Invest. 1999 Apr;103(7):931-43
references.pmid: 10194465
references.citation: Nature. 1994 Nov 10;372(6502):186-90
references.pmid: 7526222
references.citation: Diabetes Res Clin Pract. 2007 Sep;77 Suppl 1:S49-57
references.pmid: 17478001
references.citation: J Biol Chem. 1994 Feb 4;269(5):3381-6
references.pmid: 7508912
references.citation: Biochem J. 2007 Dec 15;408(3):297-315
references.pmid: 17850214
references.citation: Diabetes. 1999 Aug;48(8):1662-6
references.pmid: 10426388
references.citation: J Am Soc Nephrol. 2006 Oct;17(10):2812-20
references.pmid: 16943306
references.citation: Mol Cell Biol. 1993 Dec;13(12):7418-28
references.pmid: 7504175
references.citation: Eur J Endocrinol. 2003 Jan;148(1):157-67
references.pmid: 12534369
references.citation: Am J Physiol Endocrinol Metab. 2002 Mar;282(3):E497-506
references.pmid: 11832350
references.citation: FEBS Lett. 1997 Oct 27;416(3):307-11
references.pmid: 9373175
references.citation: Biochem J. 2001 Oct 1;359(Pt 1):1-16
references.pmid: 11563964
references.citation: J Biol Chem. 2000 Jul 21;275(29):22558-62
references.pmid: 10811632
references.citation: J Diabetes Complications. 2002 Jan-Feb;16(1):69-71
references.pmid: 11872371
references.citation: Diabetes. 2002 Jul;51(7):2190-8
references.pmid: 12086949
references.citation: Mol Cell Biol. 2002 Feb;22(4):1016-26
references.pmid: 11809794
references.citation: Metabolism. 2004 Oct;53(10):1322-30
references.pmid: 15375789
references.citation: Nat Rev Mol Cell Biol. 2006 Feb;7(2):85-96
references.pmid: 16493415
references.citation: Ann N Y Acad Sci. 1999 Nov 18;892:187-203
references.pmid: 10842663
references.citation: J Clin Invest. 1996 Feb 1;97(3):613-20
references.pmid: 8609215
references.citation: Am J Physiol Endocrinol Metab. 2000 Jan;278(1):E103-12
references.pmid: 10644543
references.citation: Diabetes. 1982 Sep;31(9):795-801
references.pmid: 6761214
references.citation: Mol Cell Biol. 2000 Mar;20(5):1489-96
references.pmid: 10669726
references.citation: Am J Physiol Endocrinol Metab. 2003 Dec;285(6):E1267-72
references.pmid: 12954597
references.citation: J Biol Chem. 2002 Nov 1;277(44):42394-8
references.pmid: 12228220
references.citation: Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):4171-5
references.pmid: 9108124
references.citation: Diabetes. 1992 May;41(5):571-80
references.pmid: 1568526
references.citation: Cell. 1997 Feb 21;88(4):561-72
references.pmid: 9038347
references.citation: Diabetologia. 1994 Oct;37(10):1025-35
references.pmid: 7851681
references.citation: Nature. 1991 Jul 4;352(6330):73-7
references.pmid: 1648180
references.citation: J Investig Med. 2000 Jul;48(4):251-8
references.pmid: 10916283
references.citation: J Clin Invest. 1992 Nov;90(5):1839-49
references.pmid: 1331176
references.citation: Cardiovasc Diabetol. 2005 Oct 05;4:16
references.pmid: 16207378