Free fatty acid-induced muscle insulin resistance and glucose uptake dysfunction: evidence for PKC activation and oxidative stress-activated signaling pathways.
In the present study, we examined the effects of free fatty acids (FFAs) on insulin sensitivity and signaling cascades in the C2C12 skeletal muscle cell culture system. Our data clearly manifested that the inhibitory effects of PKC on insulin signaling may at least in part be explained by the serine/threonine phosphorylation of IRS-1. Both oleate and palmitate treatment were able to increase the Serine(307) phosphorylation of IRS-1. IRS-1 Serine(307) phosphorylation is inducible which causes the inhibition of IRS-1 tyrosine phosphorylation by either IkappaB-kinase (IKK) or c-jun N-terminal kinase (JNK) as seen in our proteomic kinases screen. Furthermore, our proteomic data have also manifested that the two FFAs activate the IKKalpha/beta, the stress kinases S6 kinase p70 (p70SK), stress-activated protein kinase (SAPK), JNK, as well as p38 MAP kinase (p38MAPK). On the other hand, the antioxidant, Taurine at 10mM concentrations was capable of reversing the oleate-induced insulin resistance in myocytes as manifested from the glucose uptake data. Our current data point out the importance of FFA-induced insulin resistance via multiple signaling mechanisms.
Ragheb
Rafik
R
University of Ain Shams, Department of Biochemistry, Faculty of Science, Cairo 11566, Egypt. rafik.ragheb@utoronto.ca
Shanab
Gamila M L
GM
Medhat
Amina M
AM
Seoudi
Dina M
DM
Adeli
K
K
Fantus
I G
IG
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002460:Cell Line; D004789:Enzyme Activation; D005230:Fatty Acids, Nonesterified / Q000378:metabolism* / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D051379:Mice; D032448:Myoblasts, Skeletal / Q000187:drug effects / Q000378:metabolism*; D019301:Oleic Acid / Q000378:metabolism / Q000494:pharmacology; D018384:Oxidative Stress; D019308:Palmitic Acid / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D013654:Taurine / Q000494:pharmacology
D000975:Antioxidants; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D013654:Taurine; D019301:Oleic Acid; D019308:Palmitic Acid; D012694:Serine; D011493:Protein Kinase C; D005947:Glucose
Diabetes. 1990 May;39(5):570-4
2185108
Endocrinology. 2006 Jan;147(1):552-61
16223857
Mol Endocrinol. 1992 Mar;6(3):337-45
1584210
Metabolism. 2001 May;50(5):613-8
11319727
J Biol Chem. 2002 Jan 4;277(1):793-803
11598116
J Biol Chem. 2001 Mar 9;276(10):6905-8
11238443
J Biol Chem. 1999 Aug 20;274(34):24202-10
10446195
J Biol Chem. 2002 Dec 13;277(50):48115-21
12351658
Diabetes. 2001 Oct;50(10):2210-8
11574400
Diabetes. 1998 Aug;47(8):1281-6
9703329
Biochem J. 2000 Mar 15;346 Pt 3:561-76
10698680
J Biol Chem. 1995 Oct 6;270(40):23780-4
7559552
FEBS Lett. 1993 Jul 12;326(1-3):117-23
8325359
J Biol Chem. 1994 Feb 25;269(8):6051-7
8119950
J Biol Chem. 2003 Jul 4;278(27):24944-50
12714600
Lancet. 1963 Apr 13;1(7285):785-9
13990765
Biochem J. 1998 Aug 1;333 ( Pt 3):471-90
9677303
J Biol Chem. 2002 Jan 11;277(2):1531-7
11606564
Ann N Y Acad Sci. 2002 Jun;967:146-57
12079844
J Biol Chem. 2000 Mar 24;275(12):9047-54
10722755
Science. 1992 Oct 30;258(5083):766-70
1439783
Diabetes. 1997 Jan;46(1):3-10
8971073
Diabetes. 1999 Jun;48(6):1270-4
10342815
J Biol Chem. 2005 Sep 23;280(38):32693-9
16055440
Am J Physiol Endocrinol Metab. 2002 Sep;283(3):E514-24
12169445
Mol Cell. 2002 Apr;9(4):695-6
11983159
J Clin Endocrinol Metab. 2002 Jan;87(1):226-34
11788651
Diabetologia. 1995 Oct;38(10):1213-7
8690174
Diabetes. 2008 Oct;57(10):2644-51
18633112
Cell Metab. 2007 Oct;6(4):320-8
17908560
J Clin Invest. 2000 Jul;106(2):165-9
10903329
Curr Opin Cell Biol. 1999 Apr;11(2):219-25
10209156
Proc Natl Acad Sci U S A. 1986 Aug;83(16):5822-4
3526339