Role of reactive oxygen species in injury-induced insulin resistance.
Acute insulin resistance is common after injury, infection, and critical illness. To investigate the role of reactive oxygen species (ROS) in critical illness diabetes, we measured hepatic ROS, which rapidly increased in mouse liver. Overexpression of superoxide dismutase 2, which decreased mitochondrial ROS levels, protected mice from the development of acute hepatic insulin resistance. Insulin-induced intracellular signaling was dramatically decreased, and cellular stress signaling was rapidly increased after injury, resulting in the hyperglycemia of critical illness diabetes. Insulin-induced intracellular signaling, activation of stress (c-Jun N-terminal kinase) signaling, and glucose metabolism were all normalized by superoxide dismutase 2 overexpression or by pretreatment with antioxidants. Thus, ROS play an important role in the development of acute hepatic insulin resistance and activation of stress signaling after injury.
Department of Pathology, The University of Alabama at Birmingham, 1670 University Boulevard, Birmingham, Alabama 35294-0019, USA.
Lidong
L
Zhai
Scott W
SW
Ballinger
Joseph L
JL
Messina
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D005838:Genotype; D005951:Glucose Tolerance Test; D006470:Hemorrhage / Q000503:physiopathology; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D014947:Wounds and Injuries / Q000503:physiopathology; D000099156:Superoxide Dismutase 2
D000975:Antioxidants; D001786:Blood Glucose; D007328:Insulin; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2
Antioxid Redox Signal. 2007 Sep;9(9):1317-28
17627464
Crit Care. 2006;10(5):R146
17040563
Stroke. 2009 May;40(5):1644-52
19286596
Nutr Rev. 1998 Jan;56(1 Pt 2):S170-6
9481140
J Trauma. 2006 Apr;60(4):873-7; discussion 878-9
16612311
Heart Lung. 1985 Sep;14(5):470-2
3897133
Circ Shock. 1989 Jan;27(1):63-72
2917373
Circulation. 2004 Mar 30;109(12):1497-502
15006999
Endocrinology. 2008 May;149(5):2369-82
18187553
J Clin Invest. 2004 Dec;114(12):1752-61
15599400
Methods Enzymol. 1996;269:37-41
8791635
Mol Cell. 2007 Apr 13;26(1):1-14
17434122
J Pediatr Endocrinol Metab. 1999;12 Suppl 3:721-31
10626262
N Engl J Med. 2006 May 11;354(19):2069-71; author reply 2069-71
16696141
Nature. 2000 Apr 13;404(6779):787-90
10783895
Science. 2008 Dec 5;322(5907):1539-43
19056984
Endocrinology. 2004 Nov;145(11):5168-76
15297437
Biochem Pharmacol. 2005 Mar 1;69(5):719-23
15710349
Am J Respir Cell Mol Biol. 1998 Apr;18(4):538-47
9533942
Diabetes. 2008 Aug;57(8):2083-91
18487450
J Endocrinol. 2009 Dec;203(3):365-74
19752148
Shock. 2003 Apr;19(4):345-51
12688546
J Biol Chem. 1995 Jun 2;270(22):13399-405
7768942
N Engl J Med. 2001 Nov 8;345(19):1359-67
11794168
J Clin Endocrinol Metab. 2003 Mar;88(3):1082-8
12629088
Proc Natl Acad Sci U S A. 2006 Jul 11;103(28):10741-6
16818881
Diabetes. 1998 Oct;47(10):1549-54
9753291
J Clin Invest. 2008 Feb;118(2):789-800
18188455
Annu Rev Physiol. 2006;68:123-58
16460269
N Engl J Med. 2006 Feb 2;354(5):449-61
16452557
Diabetologia. 1997 Jul;40 Suppl 2:S2-17
9248696
Endocrinology. 2009 Jan;150(1):24-32
18801909
Diabetes. 2009 Mar;58(3):590-9
19074988
Crit Care Med. 2009 May;37(5):1769-76
19325461
Am J Physiol Heart Circ Physiol. 2000 Aug;279(2):H791-7
10924079
N Engl J Med. 2009 Mar 26;360(13):1283-97
19318384
Cell Metab. 2009 Oct;10(4):260-72
19808019
Cell. 2005 Mar 11;120(5):649-61
15766528
Nature. 2006 Apr 13;440(7086):944-8
16612386
Diabetologia. 2009 Apr;52(4):574-82
19183935
Am J Physiol Gastrointest Liver Physiol. 2003 Jan;284(1):G107-15
12388175
J Pediatr (Rio J). 2007 Nov;83(5 Suppl):S128-36
18038018
J Biol Chem. 1994 Nov 25;269(47):29405-8
7961919
Nature. 2002 Nov 21;420(6913):333-6
12447443
J Clin Invest. 2000 Jul;106(2):165-9
10903329
Mol Med. 2008 Nov-Dec;14(11-12):715-23
19009015
J Biol Chem. 2004 Oct 29;279(44):45803-9
15331609
Br J Pharmacol. 2003 Oct;140(3):445-60
14522841
Shock. 2007 Sep;28(3):270-7
17545941
Bioorg Med Chem. 2002 Sep;10(9):3013-21
12110324