Targeting glycogen synthase kinase-3 (GSK-3) in the treatment of Type 2 diabetes.
BACKGROUND
In spite of its rather specific name, glycogen synthase kinase-3 (GSK-3) is an eclectic cellular regulator that modulates an array of processes from nuclear transcription, to neurological functions and metabolism. The enzyme is also a focal point for diverse signaling pathways that act to suppress its activity.


OBJECTIVE
To review recent evidence supporting the important role GSK-3 plays in glucose homeostasis and discuss the therapeutic potential of inhibiting this enzyme in the treatment of diabetes and insulin resistance.


CONCLUSIONS
Despite its pleiotropic nature, GSK-3 has significant promise as a target for diabetes due to functional partitioning of the enzyme, tissue-selectivity and acute dosage-dependency of effects of inhibition, suggesting useful therapeutic windows.
MacAulay
Katrina
K
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
Woodgett
James R
JR
D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000502:physiology; D007333:Insulin Resistance; D015398:Signal Transduction; D013379:Substrate Specificity
D004791:Enzyme Inhibitors; D007328:Insulin; D038362:Glycogen Synthase Kinase 3
Am J Physiol Endocrinol Metab. 2003 May;284(5):E892-900
12517738
Proc Soc Exp Biol Med. 1997 Sep;215(4):314-32
9270716
Cell Regul. 1989 Nov;1(1):37-44
2519616
Genes Dev. 2000 Aug 1;14(15):1837-51
10921899
J Biol Chem. 1991 Aug 5;266(22):14139-42
1650349
Science. 2005 Feb 18;307(5712):1098-101
15718470
Nature. 1995 Dec 21-28;378(6559):785-9
8524413
Mol Cell. 2001 Jun;7(6):1321-7
11430833
Nature. 2000 Jul 6;406(6791):86-90
10894547
Diabetes. 2001 May;50(5):937-46
11334436
BMC Mol Biol. 2004 Sep 06;5:15
15350195
EMBO J. 1990 Aug;9(8):2431-8
2164470
J Pharmacol Exp Ther. 2006 Jan;316(1):17-24
16169938
Can J Physiol Pharmacol. 2006 Jul;84(7):725-37
16998536
Am J Physiol. 1997 Sep;273(3 Pt 1):E514-20
9316440
J Cell Sci. 2003 Apr 1;116(Pt 7):1175-86
12615961
PLoS Biol. 2008 Feb;6(2):e37
18288891
Diabetes. 2003 Mar;52(3):588-95
12606497
Eur J Biochem. 1980 Jun;107(2):519-27
6249596
Genes Dev. 2002 May 1;16(9):1066-76
12000790
J Biol Chem. 1987 Oct 15;262(29):14042-8
2820993
FEBS Lett. 2007 Oct 2;581(24):4749-53
17870073
Diabetes. 1997 Jun;46(6):1017-24
9166674
J Biol Chem. 1999 Jun 18;274(25):17934-40
10364240
Arch Biochem Biophys. 1959 Apr;81(2):508-20
13638016
Dev Biol. 2002 Apr 1;244(1):1-8
11900454
J Clin Invest. 1990 Dec;86(6):1999-2007
2123890
Biochem J. 2005 Dec 15;392(Pt 3):633-9
16176184
Diabetes Care. 1990 Mar;13(3):327-39
2407480
Diabetes. 2003 Jun;52(6):1393-402
12765949
J Biol Chem. 2005 Feb 11;280(6):4422-8
15574412
Diabetes. 2002 Oct;51(10):2903-10
12351425
Biochem Biophys Res Commun. 2001 Jan 26;280(3):720-5
11162580
Biochem J. 2007 Dec 15;408(3):297-315
17850214
EMBO J. 1997 Jul 1;16(13):3797-804
9233789
Proc Natl Acad Sci U S A. 1996 Sep 17;93(19):10228-33
8816781
Eur J Biochem. 2003 Sep;270(18):3829-38
12950267
Curr Biol. 1998 May 7;8(10):573-81
9601641
Trends Biochem Sci. 2004 Feb;29(2):95-102
15102436
Recent Prog Horm Res. 2001;56:157-73
11237211
Cell Metab. 2007 Oct;6(4):329-37
17908561
J Neurochem. 2002 Jun;81(5):1073-83
12065620
J Clin Pathol. 2005 Mar;58(3):225-36
15735151
J Clin Endocrinol Metab. 2001 Sep;86(9):4307-14
11549666
FEBS Lett. 2003 Aug 14;549(1-3):72-6
12914928
Diabetes. 1994 Jul;43(7):903-7
8013755
Diabetes. 2002 Jul;51(7):2190-8
12086949
Metabolism. 2004 Oct;53(10):1322-30
15375789
Nature. 1993 Apr 8;362(6420):557-60
8385271
Biochem Biophys Res Commun. 2004 Jul 9;319(4):1235-40
15194499
Curr Mol Med. 2002 Mar;2(2):101-20
11949930
J Biol Chem. 2000 May 26;275(21):15765-72
10748179
Am J Physiol Endocrinol Metab. 2006 Aug;291(2):E207-13
16478771
Prog Neurobiol. 2001 Nov;65(4):391-426
11527574
Metabolism. 2007 Jul;56(7):931-8
17570255
Diabetes. 2001 Apr;50(4):720-6
11289034
Philos Trans R Soc Lond B Biol Sci. 1996 Feb 29;351(1336):191-9
8650266
Dev Cell. 2007 Jun;12(6):957-71
17543867
J Cell Sci. 2003 Aug 1;116(Pt 15):3037-40
12829733
Mol Cell Biol. 2008 Oct;28(20):6314-28
18694957
Diabetologia. 2007 Feb;50(2):452-60
17151860
EMBO J. 2005 Apr 20;24(8):1571-83
15791206
Proc Natl Acad Sci U S A. 1997 Sep 2;94(18):9660-4
9275179
Am J Physiol Endocrinol Metab. 2008 Jan;294(1):E28-35
18003720
Am J Physiol Endocrinol Metab. 2005 Jun;288(6):E1188-94
15671078
Cell. 1997 Feb 21;88(4):561-72
9038347
Mol Cell Biochem. 1983;56(2):183-9
6417471