Key points are not available for this paper at this time.
Insulin stimulation produced a reliable 3-fold increase in glucose uptake in primary neonatal rat myotubes, which was accompanied by a similar effect on GLUT4 translocation to plasma membrane. Tumor necrosis factor (TNF)-α caused insulin resistance on glucose uptake and GLUT4 translocation by impairing insulin stimulation of insulin receptor (IR) and IR substrate (IRS)-1 and IRS-2 tyrosine phosphorylation, IRS-associated phosphatidylinositol 3-kinase activation, and Akt phosphorylation. Because this cytokine produced sustained activation of stress and proinflammatory kinases, we have explored the hypothesis that insulin resistance by TNF-α could be mediated by these pathways. In this study we demonstrate that pretreatment with PD169316 or SB203580, inhibitors of p38 MAPK, restored insulin signaling and normalized insulin-induced glucose uptake in the presence of TNF-α. However, in the presence of PD98059 or SP600125, inhibitors of p42/p44 MAPK or JNK, respectively, insulin resistance by TNF-α was still produced. Moreover, TNF-α produced inhibitor κB kinase (IKK)-β activation and inhibitor κB-β and -α degradation in a p38 MAPK-dependent manner, and treatment with salicylate (an inhibitor of IKK) completely restored insulin signaling. Furthermore, TNF-α produced serine phosphorylation of IR and IRS-1 (total and on Ser307 residue), and these effects were completely precluded by pretreatment with either PD169316 or salicylate. Consequently, TNF-α, through activation of p38 MAPK and IKK, produces serine phosphorylation of IR and IRS-1, impairing its tyrosine phosphorylation by insulin and the corresponding activation of phosphatidylinositol 3-kinase and Akt, leading to insulin resistance on glucose uptake and GLUT4 translocation. Insulin stimulation produced a reliable 3-fold increase in glucose uptake in primary neonatal rat myotubes, which was accompanied by a similar effect on GLUT4 translocation to plasma membrane. Tumor necrosis factor (TNF)-α caused insulin resistance on glucose uptake and GLUT4 translocation by impairing insulin stimulation of insulin receptor (IR) and IR substrate (IRS)-1 and IRS-2 tyrosine phosphorylation, IRS-associated phosphatidylinositol 3-kinase activation, and Akt phosphorylation. Because this cytokine produced sustained activation of stress and proinflammatory kinases, we have explored the hypothesis that insulin resistance by TNF-α could be mediated by these pathways. In this study we demonstrate that pretreatment with PD169316 or SB203580, inhibitors of p38 MAPK, restored insulin signaling and normalized insulin-induced glucose uptake in the presence of TNF-α. However, in the presence of PD98059 or SP600125, inhibitors of p42/p44 MAPK or JNK, respectively, insulin resistance by TNF-α was still produced. Moreover, TNF-α produced inhibitor κB kinase (IKK)-β activation and inhibitor κB-β and -α degradation in a p38 MAPK-dependent manner, and treatment with salicylate (an inhibitor of IKK) completely restored insulin signaling. Furthermore, TNF-α produced serine phosphorylation of IR and IRS-1 (total and on Ser307 residue), and these effects were completely precluded by pretreatment with either PD169316 or salicylate. Consequently, TNF-α, through activation of p38 MAPK and IKK, produces serine phosphorylation of IR and IRS-1, impairing its tyrosine phosphorylation by insulin and the corresponding activation of phosphatidylinositol 3-kinase and Akt, leading to insulin resistance on glucose uptake and GLUT4 translocation. Insulin increases glucose transport into cells of target tissues, primarily muscle (skeletal and cardiac) and fat (white and brown). Acute insulin treatment stimulates glucose transport in adipocytes and myocytes largely by mediating translocation of GLUT4 from an intracellular compartment to the plasma membrane, as reviewed previously (1Pessin J.E. Saltiel A.R. J. Clin. Investig. 2000; 106: 165-169Crossref PubMed Scopus (685) Google Scholar, 2Watson R.T. Pessin J.E. Exp. Cell Res. 2001; 271: 75-83Crossref PubMed Scopus (93) Google Scholar, 3Khan A.H. Pessin J.E. Diabetologia. 2002; 45: 1475-1483Crossref PubMed Scopus (317) Google Scholar). This effect is accomplished by activation of phosphatidylinositol 3-kinase (PI3K), 1The abbreviations used are: PI3K, phosphatidylinositol 3-kinase; TNF, tumor necrosis factor; IR, insulin receptor; IκB, inhibitor κB; IKK, inhibitor κB kinase; IRS, insulin receptor substrate; MAPK, mitogen-activated protein kinase; JNK, c-Jun NH2-terminal kinase; PBS, phosphate-buffered saline; MBP, myelin basic protein; PD, PD98059; PD*, PD169316; SP, SP600125; SB, SB203580; P, phospho. Akt, and the atypical protein kinase C isoforms ζ and λ in most cellular models (4Wang Q. Somwar R. Bilan P.J. Liu Z. Jin J. Woodgett J.R. Klip A. Mol. Cell. Biol. 1999; 19: 4008-4018Crossref PubMed Scopus (504) Google Scholar, 5Hajduch E. Alessi D.R. Hemmings B.A. Hundal H.S. Diabetes. 1998; 47: 1006-1013Crossref PubMed Scopus (296) Google Scholar, 6Vollenweider P. Menard B. Nicod P. Diabetes. 2002; 51: 1052-1059Crossref PubMed Scopus (101) Google Scholar), although other protein kinase C isoforms seem to play a role in skeletal muscle (7Braiman L. Sheffi-Friedman L. Bak A. Tennenbaum T. Sampson S.R. Diabetes. 1999; 48: 1922-1929Crossref PubMed Scopus (87) Google Scholar, 8Rosenzweig T. Braiman L. Bak A. Alt A. Kuroki T. Sampson S.R. Diabetes. 2002; 51: 1921-1930Crossref PubMed Scopus (52) Google Scholar). Recent discoveries have shown the presence of a second insulin signaling pathway leading to GLUT4 translocation in a PI3K-independent manner, involving the adaptor protein Cbl and the activation of a small GTP-binding protein, TC10 (3Khan A.H. Pessin J.E. Diabetologia. 2002; 45: 1475-1483Crossref PubMed Scopus (317) Google Scholar, 9Chiang S.H. Baumann C.A. Kanzaki M. Thurmond D.C. Watson R.T. Neudauer C.L. Macara I.G. Pessin J.E. Saltiel A.R. Nature. 2001; 410: 944-948Crossref PubMed Scopus (484) Google Scholar). Furthermore, insulin can activate glucose uptake without producing GLUT4 translocation; this effect involves activation of p38 mitogen-activated protein kinase (MAPK), as has been specifically reported for muscle cells (10Sweeney G. Somwar R. Ramlal T. Volchuk A. Ueyama A. Klip A. J. Biol. Chem. 1999; 274: 10071-10078Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar). Insulin resistance, defined as a smaller than normal response to a given amount of insulin, is an important contributor to the pathogenesis of type 2 diabetes mellitus. Both genetic and environmental factors can contribute to the development of insulin resistance. Targeted disruption of insulin-like growth factor I and insulin receptor (IR) or of GLUT4, selectively, in skeletal muscle causes insulin resistance and insulin intolerance (11Bruning J.C. Michael M.D. Winnay J.N. Hayashi T. Horsch D. Accili D. Goodyear L.J. Kahn C.R. Mol. Cell. 1998; 2: 559-569Abstract Full Text Full Text PDF PubMed Scopus (957) Google Scholar, 12Fernandez A.M. Kim J.K. Yakar S. Dupont J. Hernandez-Sanchez C. Castle A.L. Filmore J. Shulman G.I. Le Roith D. Genes Dev. 2001; 15: 1926-1934Crossref PubMed Scopus (308) Google Scholar, 13Zisman A. Peroni O.D. Abel E.D. Michael M.D. Mauvais-Jarvis F. Lowell B.B. Wojtaszewski J.F. Hirshman M.F. Virkamaki A. Goodyear L.J. Kahn C.R. Kahn B.B. Nat. Med. 2000; 6: 924-928Crossref PubMed Scopus (573) Google Scholar). Tumor necrosis factor (TNF)-α has been proposed as a link between adiposity and the development of insulin resistance because (a) the majority of type 2 diabetics are obese, (b) TNF-α is highly expressed in adipose tissues of obese animals and humans (14Hotamisligil G.S. Shargill N.S. Spiegelman B.M. Science. 1993; 259: 87-91Crossref PubMed Scopus (6193) Google Scholar, 15Hotamisligil G.S. Arner P. Caro J.F. Atkinson R.L. Spiegelman B.M. J. Clin. Investig. 1995; 95: 2409-2415Crossref PubMed Scopus (2991) Google Scholar), and (c) obese mice lacking either TNF-α or TNF-α receptors showed protection against developing insulin resistance (16Uysal K.T. Wiesbrock S.M. Marino M.W. Hotamisligil G.S. Nature. 1997; 389: 610-614Crossref PubMed Scopus (1917) Google Scholar, 17Uysal K.T. Wiesbrock S.M. Hotamisligil G.S. Endocrinology. 1998; 139: 4832-4838Crossref PubMed Google Scholar). Infusion of TNF-α to adult rats reduces systemic insulin sensitivity associated with major changes in adipocyte gene expression, favoring free fatty acid release without changes on muscle gene expression (18Ruan H. Miles P.D. Ladd C.M. Ross K. Golub T.R. Olefsky J.M. Lodish H.F. Diabetes. 2002; 51: 3176-3188Crossref PubMed Scopus (228) Google Scholar). These data suggest that impaired activity of the insulin signaling transduction pathways rather than changes in gene expression may be contributing to the development of insulin resistance in the muscle of TNF-α-treated animals. Direct exposure of fat cells to TNF-α inhibits insulin-stimulated glucose uptake in several systems including 3T3-L1 cells, human primary adipocytes, and primary brown adipocytes (19Hotamisligil G.S. Murray D.L. Choy L.N. Spiegelman B.M. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 4854-4858Crossref PubMed Scopus (1052) Google Scholar, 20Teruel T. Hernandez R. Lorenzo M. Diabetes. 2001; 50: 2563-2571Crossref PubMed Scopus (200) Google Scholar). The mechanism proposed involves serine phosphorylation of IR substrate (IRS)-1 that converts IRS-1 into an inhibitor of the insulin receptor tyrosine kinase activity (21Hotamisligil G.S. Peraldi P. Budavari A. Ellis R. White M.F. Spiegelman B.M. Science. 1996; 271: 665-668Crossref PubMed Scopus (2223) Google Scholar). Furthermore, Ser307 has been identified as a site for TNF-α-induced phosphorylation of IRS-1, with activation of c-Jun NH2-terminal kinase (JNK) involved in the phosphorylation of this residue (22Rui L. Aguirre V. Kim J.K. Shulman G.I. Lee A. Corbould A. Dunaif A. White M.F. J. Clin. Investig. 2001; 107: 181-189Crossref PubMed Scopus (492) Google Scholar). Other studies suggest that p42/p44 and p38 MAPKs could inhibit insulin signaling by diverse mechanisms in 3T3-L1 adipocytes A.H. Mol. 2000; PubMed Google Scholar). In this an activation of MAPKs in adipocytes from type 2 has been reported S. C.M. Diabetes. PubMed Scopus Google Scholar). Moreover, other have inhibitor κB kinase activation by TNF-α on serine phosphorylation of IRS-1 Z. D. F. M. D. J. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar), with or disruption of produces of and insulin resistance M. Lee J. L. M. Science. 2001; PubMed Scopus Google Scholar). and fatty have been reported to insulin resistance in skeletal muscle E. A. Hundal H.S. Diabetologia. 2001; PubMed Scopus Google Scholar, C. D.L. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar, P. H. A. K. G. J. 1999; PubMed Scopus Google Scholar), and of insulin resistance could be a of or activation by TNF-α P. Hotamisligil G.S. White M.F. Spiegelman B.M. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, M.D. P. Diabetes. 1998; 47: PubMed Scopus Google Scholar). However, a effect of TNF-α on insulin resistance in which is for of the glucose of the is TNF-α on insulin-induced glucose although TNF-α highly glucose uptake S. 1996; 45: Full Text PDF PubMed Scopus Google Scholar, D. S. R. Clin. Sci. 2000; PubMed Scopus Google Scholar, J.M. Diabetes. 1998; 47: PubMed Scopus Google Scholar). However, T. Braiman L. Bak A. Alt A. Kuroki T. Sampson S.R. Diabetes. 2002; 51: 1921-1930Crossref PubMed Scopus (52) Google Scholar, J. 1999; Google that TNF-α an effect on insulin without glucose uptake in muscle the other in most of these insulin stimulation of glucose uptake was because skeletal muscle have been to be in GLUT4 in this we have primary of neonatal rat to insulin by glucose uptake 3-fold and GLUT4 translocation to the plasma membrane. Both effects were impaired by treatment with TNF-α. This through activation of p38 MAPK and IKK, produces phosphorylation of the residue Ser307 in IRS-1, impairing the insulin signaling the of IR and IRS-1 tyrosine phosphorylation and and Akt fatty myelin basic protein and were from TNF-α was from PD169316 and PD98059 were from and were from phosphate-buffered and were from were were and protein were from The and were by The and MAPK, MAPK, and were from Cell against IRS-1, and were from against IR and were from The was from other used were of the Cell muscle cells were from from neonatal rats to the in L. Sheffi-Friedman L. Bak A. Tennenbaum T. Sampson S.R. Diabetes. 1999; 48: 1922-1929Crossref PubMed Scopus (87) Google Scholar, with rats were by The from the and were to fat and in to cells, and with the muscle was to a for with were of was and for The were and in growth the the was with a of in and with the were for The was with PBS, in growth and for in to the of The was and the were with growth to a of of cells to the and to of cells were in were cells in and cells in were in growth in a of the cells as cells were for an in cells and into were in with uptake was the of by of were used for protein and were expressed as protein, as previously for brown adipocytes R. T. Lorenzo M. 2001; PubMed Scopus Google Scholar). were expressed as of stimulation were with and into 2 2 and a cells were with of a a were by for and the was for The the The was and in for The was from the by for and plasma were protein and with GLUT4 and T. Hernandez R. Lorenzo M. Diabetes. 2001; 50: 2563-2571Crossref PubMed Scopus (200) Google Scholar). were with I and and with against IR, p38 MAPK, or activity was in by in phosphorylation of phosphatidylinositol as previously T. Hernandez R. Lorenzo M. Diabetes. 2001; 50: 2563-2571Crossref PubMed Scopus (200) Google Scholar). p38 and in were in MAPK and and as previously R. Lorenzo M. J. Cell. 2001; PubMed Scopus Google Scholar). were with and with kinase and The kinase was in a kinase of and of as a substrate for and by the of by for were in and were and to were in and cellular were to to in and and with several as in in and in and were the are or for from to was with a of by the of were In exposure were used to that were TNF-α in a p38 MAPK-dependent in neonatal muscle cells were in the of cells were to and for in the or presence of TNF-α stimulation for with uptake was the of by of and were expressed as the of stimulation Insulin stimulation for glucose with TNF-α for showed a 3-fold glucose uptake than cells, and this insulin stimulation glucose Because insulin stimulation of glucose transport is mediated by the translocation of GLUT4 to the plasma membrane, we to the data on glucose uptake by GLUT4 translocation. GLUT4 protein in plasma was by Insulin GLUT4 translocation to plasma this effect was produced cells were with TNF-α insulin In the of GLUT4 in produced by insulin was TNF-α was with an protein from was used as a protein of the plasma membrane, and its amount by the used Moreover, the increase in glucose uptake TNF-α treatment was the of GLUT4 as shown in However, the of protein and TNF-α treatment were with without the expression of GLUT4 protein Moreover, because TNF-α treatment was in myotubes, changes in the of of the cells were The mechanism by which TNF-α produced insulin resistance on glucose uptake is from and to the signaling pathways by TNF-α treatment in skeletal were of and for to in the presence of TNF-α. the of the cells were and protein were for activation of stress by the corresponding against and p38 and p42/p44 MAPK and TNF-α produced a phosphorylation of p38 MAPK and this activation was sustained for of Furthermore, TNF-α-induced phosphorylation of p42/p44 MAPK was for of these on MAPKs were phosphorylation by TNF-α was of and this kinase for The changes in the of phosphorylation of these seem to changes in because the protein are similar in the we which p38 MAPK was by TNF-α, in kinase of phosphorylation in against the p38 MAPK isoforms and for with TNF-α the p38 MAPK activity associated with the insulin, which has been shown to phosphorylation of p38 MAPK in cells R. A.M. M. Lorenzo M. J. Cell. 2001; PubMed Scopus Google Scholar), the Both isoforms were to a similar stimulation with the sustained activation of p38 MAPK, p42/p44 MAPK, and by TNF-α could contribute to insulin resistance, we to these pathways by the of inhibitors and TNF-α was to insulin resistance used to inhibit JNK, to inhibit and or as p38 MAPK inhibitors the and of these in neonatal muscle cells uptake was in cells for in the or presence of TNF-α with or without stimulation for with insulin cells were for in the presence of PD, SP, or changes in insulin or glucose uptake were However, treatment with either or completely restored insulin stimulation of glucose uptake in the presence of TNF-α, leading to a stimulation and to a increase TNF-α This effect was in the presence of or similar on insulin-induced translocation of GLUT4 from to the plasma was in the presence of and for this effect was in the presence of Furthermore, the presence of the inhibitors for the expression of GLUT4 or The data seem to that although TNF-α several MAPKs in skeletal MAPK could be the primary contributor to the TNF-α effect on insulin-stimulated glucose TNF-α the Insulin in a p38 MAPK-dependent was to which TNF-α was with the insulin signaling and that could be in the presence of the inhibitor of p38 or p42/p44 of were for in the or presence of TNF-α with or without or PD*, stimulation for with Insulin tyrosine phosphorylation of IR in IR an effect that was impaired by pretreatment with TNF-α However, treatment with PD*, PD, completely restored IR tyrosine phosphorylation by insulin in the presence of TNF-α. with TNF-α for tyrosine phosphorylation of IR by insulin produced serine phosphorylation of the IR, as in with and with IR However, serine phosphorylation of IR was in with PD*, contributing to on tyrosine phosphorylation tyrosine phosphorylation of IRS-1 and IRS-2 was impaired by pretreatment with TNF-α, without changes in expression and However, treatment with in the presence of TNF-α completely restored tyrosine phosphorylation by insulin the of IRS-1, with a effect the of with TNF-α for produced serine phosphorylation of IRS-1, and this phosphorylation was precluded by pretreatment with PD*, PD, as in with and with IRS-1 Moreover, TNF-α produced phosphorylation on the Ser307 residue of IRS-1 in a p38 MAPK-dependent manner, as by with activity associated with was in the with either the or TNF-α impaired insulin-induced activity in IRS-2 in IRS-1 this effect was produced in the presence of In were by with for and insulin Akt was highly serine and and effects were impaired by TNF-α pretreatment in a p38 MAPK-dependent these data that TNF-α impaired insulin activation of the signaling in a p38 manner, in a similar to that for glucose of by or Insulin by TNF-α in resistance by TNF-α in skeletal muscle can be impaired by of p38 However, TNF-α, stress kinases, proinflammatory as that have been in the development of insulin resistance. we to the of in insulin resistance by TNF-α and was with the activation of p38 of were for to in the or presence of TNF-α, and activation was by degradation of and by TNF-α and degradation of and this effect was for of Insulin stimulation for effect on and degradation by TNF-α. However, this effect was in the presence of PD*, in the presence of PD, that TNF-α activation of was on p38 MAPK, as by in kinase in as as by However, p38 MAPK activation by TNF-α was of activation because in the presence of an inhibitor p38 MAPK phosphorylation was still we to activation by TNF-α by with salicylate to was to insulin signaling for in the presence of TNF-α with salicylate showed a of insulin signaling the of IR and IRS-1 tyrosine phosphorylation, with activation associated with IRS-1 and Akt phosphorylation on and as shown in Furthermore, of TNF-α-induced activation by salicylate completely Ser307 phosphorylation of IRS-1 by TNF-α, that the phosphorylation of this residue by TNF-α a major role in the development of insulin resistance in neonatal and insulin resistance by TNF-α in skeletal were for in the or presence of TNF-α without or with salicylate and for with insulin or were with against IR and with or with the against the of were with or and with or with the against with the is activity was in were by with the corresponding against Akt, and of are from from and C are expressed in and are was and between in the presence of I are by between in the presence of I are by and between are by TNF-α has been reported to insulin resistance in several cellular as and brown adipocytes, and in skeletal muscle T. Braiman L. Bak A. Alt A. Kuroki T. Sampson S.R. Diabetes. 2002; 51: 1921-1930Crossref PubMed Scopus (52) Google Scholar, G.S. Murray D.L. Choy L.N. Spiegelman B.M. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 4854-4858Crossref PubMed Scopus (1052) Google Scholar, 20Teruel T. Hernandez R. Lorenzo M. Diabetes. 2001; 50: 2563-2571Crossref PubMed Scopus (200) Google Scholar, J. 1999; Google Scholar). However, insulin stimulation of glucose uptake in these cells including and myotubes, was we have primary of neonatal skeletal muscle that a for the of TNF-α-induced insulin resistance. muscle cells were in the of and in the these insulin stimulation produced a reliable 3-fold increase in glucose which was accompanied by a similar effect on GLUT4 from and translocation to plasma membrane. primary neonatal rat to insulin to a similar as primary rat brown adipocytes T. Hernandez R. Lorenzo M. Diabetes. 2001; 50: 2563-2571Crossref PubMed Scopus (200) Google Scholar, R. T. Lorenzo M. 2001; PubMed Scopus Google Scholar). exposure to TNF-α impaired insulin-stimulated glucose uptake and GLUT4 without the expression of GLUT4 or the of of the in primary neonatal are in with in muscle in (18Ruan H. Miles P.D. Ladd C.M. Ross K. Golub T.R. Olefsky J.M. Lodish H.F. Diabetes. 2002; 51: 3176-3188Crossref PubMed Scopus (228) Google and that insulin resistance by TNF-α to be the of an in the activation of the insulin signaling from IR to Akt rather than changes on muscle gene Furthermore, the increase in glucose uptake produced by TNF-α treatment in primary skeletal muscle cells was to GLUT4 translocation to the plasma and to be associated with expression, as has been previously in several muscle cells P. H. A. K. G. J. 1999; PubMed Scopus Google Scholar, L. S. Endocrinology. 1998; 139: PubMed Google Scholar). The mechanism insulin resistance could activation of by TNF-α, and in this MAPKs and as as were by TNF-α in fat cells M. H. H. T. M. H. M. M. T. Mol. PubMed Scopus Google Scholar). In this we that TNF-α produced a sustained phosphorylation of JNK, p38 MAPK, and p42/p44 MAPK the of Acute insulin stimulation produces a phosphorylation of as we reported previously R. A.M. M. Lorenzo M. J. Cell. 2001; PubMed Scopus Google Scholar, R. C. M. A. Lorenzo M. 2002; PubMed Scopus Google Scholar), insulin MAPK, TNF-α the as we demonstrate in this the of sustained activation of these to insulin resistance, we used the inhibitors SP, and PD, which specifically activation of these pathways by TNF-α in primary muscle of p38 MAPK with either or completely restored insulin-stimulated glucose uptake and insulin of p42/p44 MAPK or TNF-α-induced insulin resistance. activation of isoforms of p38 MAPK by insulin has been proposed to activate glucose uptake without producing GLUT4 translocation (10Sweeney G. Somwar R. Ramlal T. Volchuk A. Ueyama A. Klip A. J. Biol. Chem. 1999; 274: 10071-10078Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar, R. M. S. C. G. Ramlal T. Kim J. Klip A. A. Diabetes. 2000; PubMed Scopus Google Scholar), other that p38 MAPK could play a role in of glucose transport in muscle cells E. Hundal H.S. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). Furthermore, of MAPK kinase in has been reported to glucose transport by insulin of GLUT4 gene expression M. H. H. T. M. H. M. K. M. T. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). we identified p38 MAPK as the kinase by which TNF-α was producing insulin resistance, we explored in with the insulin signaling treatment with TNF-α was producing serine phosphorylation of IRS-1 and IR in a p38 MAPK-dependent this serine phosphorylation was the tyrosine phosphorylation by insulin and impairing the normal response to insulin on glucose Both p42/p44 MAPK and have been proposed to TNF-α phosphorylation of IRS-1 in fat cells (22Rui L. Aguirre V. Kim J.K. Shulman G.I. Lee A. Corbould A. Dunaif A. White M.F. J. Clin. Investig. 2001; 107: 181-189Crossref PubMed Scopus (492) Google Scholar). have that p42/p44 MAPK, to a than p38 MAPK and JNK, could inhibit insulin signaling the of IRS-1 and IRS-2 in 3T3-L1 adipocytes M. H. H. T. M. H. M. M. T. Mol. PubMed Scopus Google Scholar), could the effect of insulin J. White M.F. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). data that p38 MAPK, p42/p44 MAPK or JNK, could be the major in TNF-α-induced insulin resistance in neonatal skeletal Furthermore, Ser307 of IRS-1 to be of the by TNF-α p38 MAPK, although we the that other in either IRS-1 or IRS-2 or IR could be a target for TNF-α-induced insulin resistance in skeletal have activation by TNF-α on serine phosphorylation of IRS-1 Z. D. F. M. D. J. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, M. Lee J. L. M. Science. 2001; PubMed Scopus Google Scholar), and a has that insulin-induced glucose uptake in 3T3-L1 adipocytes with TNF-α Z. A. Z. J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In this activation of by or degradation or by in kinase in was the treatment with this activation was on the of p38 of activation with salicylate completely insulin signaling to normal the presence of TNF-α. Furthermore, salicylate p38 MAPK activation by TNF-α. These data seem to that could of p38 MAPK and TNF-α-induced insulin resistance on skeletal are with the for p38 MAPK in the activation of factor in response to M.W. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). TNF-α treatment impaired insulin stimulation of glucose uptake and GLUT4 translocation to the plasma membrane. This through activation of in a p38 MAPK-dependent manner, produces phosphorylation of the residue Ser307 in IRS-1, impairing the insulin signaling the of IR and IRS-1 tyrosine phosphorylation and and Akt the in the of and on and in the from the and the from for
Álvaro et al. (Thu,) studied this question.