title: Pathogenesis of insulin resistance in skeletal muscle.
abstract: Insulin resistance in skeletal muscle is manifested by decreased insulin-stimulated glucose uptake and results from impaired insulin signaling and multiple post-receptor intracellular defects including impaired glucose transport, glucose phosphorylation, and reduced glucose oxidation and glycogen synthesis. Insulin resistance is a core defect in type 2 diabetes, it is also associated with obesity and the metabolic syndrome. Dysregulation of fatty acid metabolism plays a pivotal role in the pathogenesis of insulin resistance in skeletal muscle. Recent studies have reported a mitochondrial defect in oxidative phosphorylation in skeletal muscle in variety of insulin resistant states. In this review, we summarize the cellular and molecular defects that contribute to the development of insulin resistance in skeletal muscle.
authors.affiliation: Division of Diabetes, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229, USA. abdulghani@uthscsa.edu
authors.forename: Muhammad A
authors.initials: MA
authors.lastname: Abdul-Ghani
authors.forename: Ralph A
authors.initials: RA
authors.lastname: DeFronzo
mesh_terms: D000818:Animals; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000503:physiopathology*
references.citation: Diabetes. 1996 Jul;45(7):915-25
references.pmid: 8666143
references.citation: J Clin Invest. 1999 Sep;104(6):733-41
references.pmid: 10491408
references.citation: Diabetes. 1979 Dec;28(12):1095-101
references.pmid: 510806
references.citation: J Clin Invest. 1975 Mar;55(3):454-61
references.pmid: 1117064
references.citation: J Clin Invest. 1987 May;79(5):1330-7
references.pmid: 3033021
references.citation: Diabetes Care. 1990 Mar;13(3):198-208
references.pmid: 2407475
references.citation: Curr Opin Cell Biol. 2000 Apr;12(2):222-8
references.pmid: 10712920
references.citation: J Clin Invest. 1991 Oct;88(4):1323-30
references.pmid: 1918382
references.citation: Biochim Biophys Acta. 1999 Oct 18;1441(1):4-13
references.pmid: 10526223
references.citation: Nature. 1990 Nov 22;348(6299):302-8
references.pmid: 2123524
references.citation: Diabetes. 1989 Nov;38(11):1496-500
references.pmid: 2620783
references.citation: Diabetes. 2001 Sep;50(9):2069-79
references.pmid: 11522673
references.citation: Proc Nutr Soc. 2007 Feb;66(1):33-41
references.pmid: 17343770
references.citation: Diabetes. 2001 Nov;50(11):2572-8
references.pmid: 11679436
references.citation: J Clin Invest. 1979 May;63(5):939-46
references.pmid: 376552
references.citation: Cell Biochem Biophys. 2007;48(2-3):103-13
references.pmid: 17709880
references.citation: Diabet Med. 1988 Jan;5(1):27-31
references.pmid: 2964324
references.citation: J Clin Endocrinol Metab. 1994 Feb;78(2):471-7
references.pmid: 8106637
references.citation: Diabetes. 2002 Oct;51(10):2944-50
references.pmid: 12351431
references.citation: Diabetes. 2007 Jun;56(6):1592-9
references.pmid: 17351150
references.citation: J Hypertens. 1996 Apr;14(4):489-94
references.pmid: 8761899
references.citation: N Engl J Med. 1999 Jul 22;341(4):240-6
references.pmid: 10413736
references.citation: Diabetes. 1995 Aug;44(8):863-70
references.pmid: 7621989
references.citation: Nature. 2001 Dec 13;414(6865):799-806
references.pmid: 11742412
references.citation: Arch Physiol Biochem. 2006 Apr;112(2):105-13
references.pmid: 16931452
references.citation: J Biol Chem. 2005 Mar 18;280(11):10290-7
references.pmid: 15598661
references.citation: Diabetes Care. 1999 Aug;22(8):1325-9
references.pmid: 10480778
references.citation: J Clin Invest. 1983 Nov;72(5):1814-20
references.pmid: 6355186
references.citation: Cell. 2006 Dec 15;127(6):1109-22
references.pmid: 17112576
references.citation: Diabetes. 1999 Sep;48(9):1836-41
references.pmid: 10480616
references.citation: Diabetes. 2001 Jun;50(6):1389-96
references.pmid: 11375340
references.citation: Diabetes. 1992 Dec;41(12):1575-86
references.pmid: 1446799
references.citation: J Clin Invest. 1989 Jul;84(1):205-13
references.pmid: 2661589
references.citation: Am J Physiol Endocrinol Metab. 2008 Jan;294(1):E97-102
references.pmid: 17957036
references.citation: FEBS Lett. 2009 Jul 7;583(13):2294-300
references.pmid: 19527715
references.citation: J Clin Invest. 1999 Apr;103(7):931-43
references.pmid: 10194465
references.citation: Lancet. 1963 Apr 13;1(7285):785-9
references.pmid: 13990765
references.citation: Gynecol Endocrinol. 2009 Aug;25(8):504-7
references.pmid: 19499403
references.citation: J Biol Chem. 1996 Jul 12;271(28):16690-4
references.pmid: 8663315
references.citation: Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8466-71
references.pmid: 12832613
references.citation: Diabetes. 2008 Nov;57(11):2943-9
references.pmid: 18678616
references.citation: Diabetes. 2003 Aug;52(8):1888-96
references.pmid: 12882902
references.citation: Diabetes. 2002 Feb;51(2):462-8
references.pmid: 11812756
references.citation: N Engl J Med. 1990 Jan 25;322(4):223-8
references.pmid: 2403659
references.citation: J Clin Endocrinol Metab. 1986 May;62(5):922-7
references.pmid: 3514652
references.citation: Philos Trans R Soc Lond B Biol Sci. 1999 Feb 28;354(1382):485-95
references.pmid: 10212493
references.citation: Int J Sports Med. 2002 Jan;23(1):33-9
references.pmid: 11774064
references.citation: Diabetes. 1988 Aug;37(8):1020-4
references.pmid: 3292322
references.citation: Am J Clin Nutr. 2003 Feb;77(2):313-8
references.pmid: 12540388
references.citation: N Engl J Med. 1999 Jul 22;341(4):248-57
references.pmid: 10413738
references.citation: Curr Diab Rep. 2008 Jun;8(3):185-91
references.pmid: 18625114
references.citation: J Clin Endocrinol Metab. 2009 Sep;94(9):3535-42
references.pmid: 19549745
references.citation: Diabetes. 1999 Aug;48(8):1600-6
references.pmid: 10426379
references.citation: J Clin Invest. 1987 Jul;80(1):95-100
references.pmid: 3110217
references.citation: Diabetes. 1998 Mar;47(3):387-94
references.pmid: 9519744
references.citation: J Clin Endocrinol Metab. 1991 Jan;72(1):96-107
references.pmid: 1986032
references.citation: J Clin Invest. 2005 Dec;115(12):3587-93
references.pmid: 16284649
references.citation: Diabetologia. 1988 Aug;31(8):585-91
references.pmid: 3065112
references.citation: Diabetologia. 1995 Apr;38(4):461-6
references.pmid: 7796987
references.citation: Am J Physiol Endocrinol Metab. 2004 Oct;287(4):E696-705
references.pmid: 15186996
references.citation: Biochem J. 1994 Oct 1;303 ( Pt 1):21-6
references.pmid: 7945242
references.citation: J Biol Chem. 1995 Sep 1;270(35):20801-7
references.pmid: 7657664
references.citation: Metabolism. 1996 Aug;45(8):947-50
references.pmid: 8769349
references.citation: J Clin Invest. 1993 Jul;92(1):486-94
references.pmid: 8326013
references.citation: J Clin Invest. 2000 Feb;105(3):311-20
references.pmid: 10675357
references.citation: Diabetes. 1979 Jan;28 Suppl 1:66-70
references.pmid: 104895
references.citation: Am J Physiol. 1999 Dec;277(6):E1130-41
references.pmid: 10600804
references.citation: Diabetes. 2005 Nov;54(11):3148-53
references.pmid: 16249438
references.citation: Am J Physiol Endocrinol Metab. 2002 Oct;283(4):E682-91
references.pmid: 12217885
references.citation: Am J Physiol. 1995 Oct;269(4 Pt 1):E701-8
references.pmid: 7485484
references.citation: J Clin Invest. 1988 Oct;82(4):1398-406
references.pmid: 3170749
references.citation: J Clin Invest. 1987 Sep;80(3):655-63
references.pmid: 2957389
references.citation: Diabetes. 2003 Sep;52(9):2191-7
references.pmid: 12941756
references.citation: J Clin Invest. 1993 Jun;91(6):2342-50
references.pmid: 8514849
references.citation: Cell Signal. 1995 Mar;7(3):171-84
references.pmid: 7662506
references.citation: Diabetologia. 1995 May;38(5):617-22
references.pmid: 7489847
references.citation: Biochem J. 2001 Oct 1;359(Pt 1):1-16
references.pmid: 11563964
references.citation: Circulation. 2003 Jun 24;107(24):3040-6
references.pmid: 12810608
references.citation: Diabetes Care. 2000 Sep;23(9):1278-83
references.pmid: 10977060
references.citation: Int J Obes. 1982;6 Suppl 1:73-82
references.pmid: 6749725
references.citation: Biochem J. 1995 Jan 1;305 ( Pt 1):25-8
references.pmid: 7826337
references.citation: Diabetes. 1997 Feb;46(2):169-78
references.pmid: 9000691
references.citation: Diabetes Care. 2008 Feb;31(2):311-5
references.pmid: 18000182
references.citation: J Biol Chem. 2001 Nov 2;276(44):40567-73
references.pmid: 11504711
references.citation: J Clin Invest. 1984 Mar;73(3):800-5
references.pmid: 6368588
references.citation: Diabetes. 1991 Dec;40(12):1712-8
references.pmid: 1756912
references.citation: Diabetes. 1989 Dec;38(12):1579-84
references.pmid: 2684714
references.citation: Curr Opin Lipidol. 2006 Apr;17(2):162-9
references.pmid: 16531753
references.citation: Am J Physiol Endocrinol Metab. 2002 Apr;282(4):E974-6
references.pmid: 11882521
references.citation: Diabetes Care. 1991 Mar;14(3):173-94
references.pmid: 2044434
references.citation: Endocrinol Metab Clin North Am. 2008 Sep;37(3):713-31, x
references.pmid: 18775360
references.citation: Acta Physiol Scand. 2003 Aug;178(4):347-56
references.pmid: 12864739
references.citation: Diabetologia. 1992 Feb;35(2):143-7
references.pmid: 1547918
references.citation: Cell. 1986 Jun 6;45(5):721-32
references.pmid: 3518947
references.citation: Curr Diabetes Rev. 2005 May;1(2):167-74
references.pmid: 18220592
references.citation: Am J Physiol. 1999 Feb;276(2):E352-7
references.pmid: 9950796
references.citation: Diabetes. 2002 Jul;51(7):2005-11
references.pmid: 12086926
references.citation: J Clin Invest. 1991 Oct;88(4):1282-90
references.pmid: 1918378
references.citation: Scand J Clin Lab Invest. 1968;21(3):263-76
references.pmid: 5708695
references.citation: Diabetes. 1995 Mar;44(3):290-4
references.pmid: 7883116
references.citation: Diabetes. 1997 Jun;46(6):983-8
references.pmid: 9166669
references.citation: Diabetologia. 1996 Oct;39(10):1180-9
references.pmid: 8897005
references.citation: Proc Nutr Soc. 2004 May;63(2):239-44
references.pmid: 15294037
references.citation: Diabetes. 1999 Jun;48(6):1270-4
references.pmid: 10342815
references.citation: Diabetologia. 2006 Aug;49(8):1924-36
references.pmid: 16736133
references.citation: Toxicol Appl Pharmacol. 2006 Apr 15;212(2):167-78
references.pmid: 16490224
references.citation: Diabetes. 1991 Feb;40(2):280-9
references.pmid: 1991575
references.citation: Diabetes. 2006 Jan;55(1):136-40
references.pmid: 16380486
references.citation: Diabetes. 1995 Jan;44(1):90-7
references.pmid: 7813820
references.citation: J Clin Invest. 1987 Jan;79(1):240-50
references.pmid: 3540010
references.citation: Diabetologia. 1999 Mar;42(3):358-64
references.pmid: 10096790
references.citation: Diabetologia. 1991 Apr;34(4):239-45
references.pmid: 1906024
references.citation: Am J Cardiol. 1999 Jul 8;84(1A):21J-24J
references.pmid: 10418854
references.citation: J Biol Chem. 1999 Sep 17;274(38):26761-6
references.pmid: 10480880
references.citation: J Appl Physiol (1985). 2001 May;90(5):1663-70
references.pmid: 11299253
references.citation: J Clin Invest. 1986 Jul;78(1):249-58
references.pmid: 3522628
references.citation: J Biol Chem. 2008 Feb 15;283(7):4228-40
references.pmid: 18079123
references.citation: J Clin Endocrinol Metab. 2004 Feb;89(2):463-78
references.pmid: 14764748
references.citation: Metabolism. 1990 Nov;39(11):1204-10
references.pmid: 2122177
references.citation: Diabetologia. 1995 Dec;38(12):1466-74
references.pmid: 8786021
references.citation: J Clin Invest. 1993 Feb;91(2):484-94
references.pmid: 8432857
references.citation: Obesity (Silver Spring). 2009 Aug;17(8):1609-14
references.pmid: 19197256
references.citation: FASEB J. 2004 Jul;18(10):1144-6
references.pmid: 15132977
references.citation: Diabetes. 1995 Mar;44(3):347-53
references.pmid: 7883123
references.citation: Diabetes. 1991 Dec;40(12):1740-5
references.pmid: 1756915
references.citation: Diabetes. 1997 Jun;46(6):1001-9
references.pmid: 9166672
references.citation: Science. 2003 May 16;300(5622):1140-2
references.pmid: 12750520
references.citation: Diabetes. 1995 Nov;44(11):1310-7
references.pmid: 7589829
references.citation: J Biol Chem. 1992 Nov 5;267(31):22662-72
references.pmid: 1385403
references.citation: J Clin Invest. 1983 Oct;72(4):1246-54
references.pmid: 6355180
references.citation: J Clin Invest. 1993 Oct;92(4):1787-94
references.pmid: 7691886
references.citation: Am J Physiol. 1997 Nov;273(5):E915-21
references.pmid: 9374677
references.citation: Diabetes. 2002 Jan;51(1):7-18
references.pmid: 11756317
references.citation: Biochem Genet. 1975 Dec;13(11-12):857-66
references.pmid: 1239274
references.citation: Diabetes. 1992 Jun;41(6):698-706
references.pmid: 1587397
references.citation: J Clin Invest. 1992 Mar;89(3):782-8
references.pmid: 1541672
references.citation: J Clin Invest. 1985 Jul;76(1):149-55
references.pmid: 3894418
references.citation: Diabetes. 2008 Oct;57(10):2644-51
references.pmid: 18633112
references.citation: J Am Coll Cardiol. 1997 Aug;30(2):527-32
references.pmid: 9247528
references.citation: J Clin Invest. 1990 Feb;85(2):522-9
references.pmid: 2105341
references.citation: Diabetes. 2005 Jan;54(1):8-14
references.pmid: 15616005
references.citation: Diabetes. 1992 May;41(5):598-604
references.pmid: 1568529
references.citation: Science. 2005 Jan 21;307(5708):384-7
references.pmid: 15662004
references.citation: J Lipid Res. 1967 Jul;8(4):366-73
references.pmid: 6033603
references.citation: Diabetes. 2009 Apr;58(4):773-95
references.pmid: 19336687
references.citation: Menopause. 2010 Mar;17(2):321-5
references.pmid: 19745772
references.citation: Diabetologia. 2007 Apr;50(4):790-6
references.pmid: 17334651
references.citation: Proc Natl Acad Sci U S A. 1995 Feb 14;92(4):983-7
references.pmid: 7862678
references.citation: J Biol Chem. 2002 Mar 15;277(11):8854-60
references.pmid: 11729182
references.citation: J Lipid Res. 1999 May;40(5):881-92
references.pmid: 10224157
references.citation: Diabetes. 2007 May;56(5):1376-81
references.pmid: 17287462
references.citation: Diabetes. 1983 Aug;32(8):748-54
references.pmid: 6347772
references.citation: J Appl Physiol Respir Environ Exerc Physiol. 1984 Apr;56(4):831-8
references.pmid: 6373687
references.citation: N Engl J Med. 1987 Aug 6;317(6):350-7
references.pmid: 3299096
references.citation: Nature. 2006 Dec 14;444(7121):840-6
references.pmid: 17167471
references.citation: Am J Physiol Endocrinol Metab. 2008 Mar;294(3):E568-75
references.pmid: 18171910
references.citation: Diabetes. 1990 Jul;39(7):865-70
references.pmid: 2354749
references.citation: N Engl J Med. 2004 Feb 12;350(7):664-71
references.pmid: 14960743
references.citation: J Clin Invest. 1999 Jan;103(2):253-9
references.pmid: 9916137
references.citation: Am J Med. 2006 May;119(5 Suppl 1):S10-6
references.pmid: 16563942
references.citation: Am J Physiol Endocrinol Metab. 2006 May;290(5):E998-1005
references.pmid: 16352678
references.citation: J Clin Endocrinol Metab. 2006 Aug;91(8):3224-7
references.pmid: 16684829
references.citation: Acta Physiol Scand. 2003 Aug;178(4):357-65
references.pmid: 12864740
references.citation: Curr Opin HIV AIDS. 2008 Nov;3(6):660-5
references.pmid: 19373039
references.citation: Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7522-7
references.pmid: 11390966
references.citation: Am J Physiol. 1992 Jul;263(1 Pt 1):E79-84
references.pmid: 1636701
references.citation: Diabetes. 2001 May;50(5):1134-42
references.pmid: 11334418
references.citation: Med Clin North Am. 2004 Jul;88(4):787-835, ix
references.pmid: 15308380
references.citation: Am J Med. 1998 Oct;105(4):331-45
references.pmid: 9809695
references.citation: Am J Physiol Endocrinol Metab. 2005 Apr;288(4):E818-25
references.pmid: 15585590
references.citation: Diabetes. 1977 Jul;26(7):680-8
references.pmid: 873075
references.citation: J Clin Endocrinol Metab. 2004 Sep;89(9):4649-55
references.pmid: 15356076
references.citation: Diabetes. 1988 Jun;37(6):667-87
references.pmid: 3289989
references.citation: Am J Physiol Endocrinol Metab. 2001 Jul;281(1):E72-80
references.pmid: 11404224
references.citation: J Clin Invest. 2000 Jul;106(2):165-9
references.pmid: 10903329
references.citation: J Clin Invest. 1978 Jul;62(1):204-13
references.pmid: 350903
references.citation: Diabetes. 2006 Dec;55 Suppl 2:S9-S15
references.pmid: 17130651
references.citation: Curr Opin Pharmacol. 2009 Dec;9(6):753-62
references.pmid: 19683471
references.citation: Curr Diab Rep. 2008 Jun;8(3):173-8
references.pmid: 18625112
references.citation: Nat Med. 2001 Aug;7(8):941-6
references.pmid: 11479627
references.citation: Am J Physiol Endocrinol Metab. 2003 Apr;284(4):E741-7
references.pmid: 12626325
references.citation: J Biol Chem. 2002 Dec 27;277(52):50230-6
references.pmid: 12006582
references.citation: Diabetes. 2001 Jul;50(7):1612-7
references.pmid: 11423483
references.citation: J Clin Invest. 1995 Sep;96(3):1261-8
references.pmid: 7657800
references.citation: Am J Physiol Endocrinol Metab. 2002 Jul;283(1):E187-92
references.pmid: 12067860
references.citation: PLoS Med. 2005 Sep;2(9):e233
references.pmid: 16089501
references.citation: J Biol Chem. 1999 Jul 2;274(27):19055-62
references.pmid: 10383407
references.citation: J Clin Endocrinol Metab. 2010 Jan;95(1):422-9
references.pmid: 19864449
references.citation: J Clin Invest. 1988 May;81(5):1528-36
references.pmid: 3366906
references.citation: Diabetologia. 2007 Jan;50(1):113-20
references.pmid: 17093944
references.citation: Am J Physiol. 1986 Oct;251(4 Pt 1):E489-96
references.pmid: 3094377
references.citation: Physiol Rev. 2006 Jan;86(1):205-43
references.pmid: 16371598
references.citation: Cell. 2007 Nov 2;131(3):476-91
references.pmid: 17981116
references.citation: Diabetologia. 1995 Apr;38(4):481-6
references.pmid: 7796990
references.citation: Curr Pharm Des. 2008;14(19):1887-99
references.pmid: 18691100
references.citation: Diabetes. 2000 Feb;49(2):284-92
references.pmid: 10868945
references.citation: Am J Physiol Endocrinol Metab. 2004 Sep;287(3):E537-46
references.pmid: 15126243
references.citation: Diabetes. 1994 Mar;43(3):447-53
references.pmid: 7508875
references.citation: PLoS Med. 2007 May;4(5):e154
references.pmid: 17472434
references.citation: Best Pract Res Clin Endocrinol Metab. 2005 Sep;19(3):391-403
references.pmid: 16150382
references.citation: J Biol Chem. 1987 Feb 5;262(4):1842-7
references.pmid: 3100537
references.citation: Diabetes. 2005 Jun;54(6):1640-8
references.pmid: 15919784
references.citation: Diabetes. 1988 Dec;37(12):1595-607
references.pmid: 3056758
references.citation: J Physiol. 1993 Sep;469:459-78
references.pmid: 8271208
references.citation: Metabolism. 2000 Jun;49(6):814-8
references.pmid: 10877213
references.citation: Diabetes. 2000 Dec;49(12):1967-77
references.pmid: 11117996
references.citation: Diabetes. 1990 Nov;39(11):1381-90
references.pmid: 2121568
references.citation: Diabetes. 1995 Sep;44(9):1099-105
references.pmid: 7657035
references.citation: Rev Endocr Metab Disord. 2004 May;5(2):127-34
references.pmid: 15041788
references.citation: Diabetologia. 1996 Mar;39(3):314-21
references.pmid: 8721777
references.citation: Obes Res. 1995 Sep;3(5):459-64
references.pmid: 8521165
references.citation: Diabetes. 1982 Nov;31(11):957-63
references.pmid: 6757014
references.citation: J Clin Invest. 1995 Feb;95(2):690-8
references.pmid: 7860750
references.citation: Diabetologia. 1999 Jan;42(1):113-6
references.pmid: 10027589
references.citation: Diabetologia. 1996 Nov;39(11):1345-50
references.pmid: 8933003
references.citation: Int J Obes (Lond). 2005 Sep;29 Suppl 2:S111-5
references.pmid: 16385762
references.citation: Diabetes. 2002 Jan;51(1):144-51
references.pmid: 11756334
references.citation: Diabetes. 2006 Dec;55(12):3309-19
references.pmid: 17130474
references.citation: J Nucl Cardiol. 2003 May-Jun;10(3):311-23
references.pmid: 12794631
references.citation: J Am Soc Nephrol. 2006 May;17(5):1388-94
references.pmid: 16611720
references.citation: J Clin Invest. 1999 Aug;104(4):447-57
references.pmid: 10449437
references.citation: Diabetes. 1994 Aug;43(8):976-83
references.pmid: 8039605