S-Adenosyl-L-methionine ameliorates TNFα-induced insulin resistance in 3T3-L1 adipocytes

다국어 초록 (Multilingual Abstract)

An association between inflammatory processes and the pathogenesis of insulin resistance has been increasingly suggested. The IκB kinase-β (IKK-β)/ nuclear factor-κB (NF-κB) pathway is a molecular mediator of insulin resistance. S-Adenosyl-L-methionine (SAM) has both antioxidative and anti-inflammatory properties. We investigated the effects of SAM on the glucose transport and insulin signaling impaired by the tumor necrosis factor α (TNFα) in 3T3-L1 adipocytes.
SAM partially reversed the basal and insulin stimulated glucose transport, which was impaired by TNFα. The TNFα-induced suppression of the tyrosine phosphorylation of the insulin receptor substrate-1(IRS-1) and Akt in 3T3-L1 adipocytes was also reversed by SAM. In addition, SAM significantly attenuated the TNFα-induced degradation of IκB-α and NF-κB activation. Interestingly, SAM directly inhibited the kinase activity of IKK-β in vitro. These results suggest that SAM can alleviate TNFα mediated-insulin resistance by inhibiting the IKK-β/NF-κB pathway and thus can have a beneficial role in the treatment of type 2 diabetes mellitus.

참고문헌 (Reference)

1 Goldfine AB, "Use of Salsalate to Target Inflammation in the Treatment of Insulin Resistance and Type 2 Diabetes" 1 : 36-43, 2008

2 Skulachev VP, "Uncoupling: new approaches to an old problem of bioenergetics" 1363 : 100-124, 1998

3 Sethi JK, "The role of TNF alpha in adipocyte metabolism" 10 : 19-29, 1999

4 Garcia-Roman R, "The differential NF-kB modulation by S-adenosyl- L-methionine, N-acetylcysteine and quercetin on the promotion stage of chemical hepatocarcinogenesis" 42 : 331-343, 2008

5 Aguirre V, "The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307)" 275 : 9047-9054, 2000

6 Yin MJ, "The anti-inflammatory agents aspirin and salicylate inhibit the activity of IκB kinase β" 396 : 77-80, 1998

7 Daosukho C, "Tamoxifen enhancement of TNF-alpha induced MnSOD expression: modulation of NF-kappaB dimerization" 21 : 3603-3610, 2002

8 김현주, "TNF-α-induced up-regulation of intercellular adhesion molecule-1 is regulated by a Rac-ROS-dependent cascade in human airway epithelial cells" 생화학분자생물학회 40 (40): 167-175, 2008

9 Cawthorn WP, "TNF-alpha and adipocyte biology" 582 : 117-131, 2008

10 Yamamoto Y, "Sulindac inhibits activation of the NF-kappaB pathway" 274 : 27307-27314, 1999

11 Baud V, "Signal transduction by tumor necrosis factor and its relatives" 11 : 372-377, 2001

12 Gao Z, "Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex" 277 : 48115-48121, 2002

13 Staiger K, "Saturated, but not unsaturated, fatty acids induce apoptosis of human coronary artery endothelial cells via nuclear factor-kappaB activation" 55 : 3121-3126, 2006

14 Ara AI, "S-adenosylmethionine inhibits lipopolysaccharide-induced gene expression via modulation of histone methylation" 47 : 1655-1666, 2008

15 di Padova C, "S-adenosylmethionine in the treatment of osteoarthritis. Review of the clinical studies" 83 : 60-65, 1987

16 Watson WH, "S-adenosylmethionine attenuates the lipopolysaccharide-induced expression of the gene for tumour necrosis factor alpha" 342 : 21-25, 1999

17 Friedel HA, "S-adenosyl-L-methionine. A review of its pharmacological properties and therapeutic potential in liver dysfunction and affective disorders in relation to its physiological role in cell metabolism" 38 : 389-416, 1989

18 Jin CJ, "S-adenosyl-L-methionine increases skeletal muscle mitochondrial DNA density and whole body insulin sensitivity in OLETF rats" 137 : 339-344, 2007

19 Najm WI, "S-adenosyl methionine (SAMe) versus celecoxib for the treatment of osteoarthritis symptoms: a double-blind cross-over trial. [ISRCTN36233495]" 5 : 6-, 2004

20 Cheng X, "S-Adenosylmethionine-dependent methyltransferases: structures and functions" World Scientific Publication Co 1999

21 Chiang PK, "S-Adenosylmethionine and methylation" 10 : 471-480, 1996

22 Purohit V, "Role of S-adenosylmethionine, folate, and betaine in the treatment of alcoholic liver disease: summary of a symposium" 86 : 14-24, 2007

23 Kim JK, "Prevention of fat-induced insulin resistance by salicylate" 108 : 437-446, 2001

24 Becker A, "Plasma homocysteine and S-adenosylmethionine in erythrocytes as determinants of carotid intima-media thickness: different effects in diabetic and non-diabetic individuals" 169 : 323-330, 2003

25 Evans JL, "Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes" 23 : 599-622, 2002

26 Schinner S, "Molecular mechanisms of insulin resistance" 22 : 674-682, 2005

27 Hundal RS, "Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes" 109 : 1321-1326, 2002

28 Rotter V, "Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects" 278 : 45777-45784, 2003

29 Veal N, "Inhibition of lipopolysaccharide-stimulated TNF-alpha promoter activity by S-adenosylmethionine and 5'-methylthioadenosine" 287 : G352-G362, 2004

30 Shoelson SE, "Inflammation and the IKK beta/I kappa B/NF-kappa B axis in obesity- and diet-induced insulin resistance" 27 : S49-S52, 2003

31 Shoelson SE, "Inflammation and insulin resistance" 116 : 1793-1801, 2006

32 De Bosscher K, "Glucocorticoid-mediated repression of nuclear factor-kappaB-dependent transcription involves direct interference with transactivation" 13504-13509, 1997

33 Udalova IA, "Functional consequences of a polymorphism affecting NF-kappaB p50-p50 binding to the TNF promoter region" 20 : 9113-9119, 2000

34 Hosea Blewett HJ, "Exploring the mechanisms behind S-adenosylmethionine (SAMe) in the treatment of osteoarthritis" 48 : 458-463, 2008

35 Su Ryeon Seo, "Calcium overload is essential for the acceleration of staurosporine-induced cell death following neuronal differentiation in PC12 cells" 생화학분자생물학회 41 (41): 269-276, 2009

36 Evans PJ, "Antioxidant properties of S-adenosyl-L-methionine: a proposed addition to organ storage fluids" 23 : 1002-1008, 1997

37 Dignam JD, "Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei" 11 : 1475-1489, 1983

38 Burgermeister E, "A novel partial agonist of peroxisome proliferator-activated receptor-gamma (PPARgamma) recruits PPARgamma-coactivator-1alpha, prevents triglyceride accumulation, and potentiates insulin signaling in vitro" 20 : 809-830, 2006