nach oben

Diabetologia

Erschienen in:

01.04.2007 | Article

C-reactive protein induces phosphorylation of insulin receptor substrate-1 on Ser³⁰⁷ and Ser⁶¹² in L6 myocytes, thereby impairing the insulin signalling pathway that promotes glucose transport

verfasst von: C. D’Alessandris, R. Lauro, I. Presta, G. Sesti

Erschienen in: Diabetologia | Ausgabe 4/2007

Einloggen, um Zugang zu erhalten

Abstract

Aims/hypothesis

C-reactive protein (CRP) is associated with insulin resistance and predicts development of type 2 diabetes. However, it is unknown whether CRP directly affects insulin signalling action. To this aim, we determined the effects of human recombinant CRP (hrCRP) on insulin signalling involved in glucose transport in L6 myotubes.

Materials and methods

L6 myotubes were exposed to endotoxin-free hrCRP and insulin-stimulated activation of signal molecules, glucose uptake and glycogen synthesis were assessed.

Results

We found that hrCRP stimulates both c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK)1/2 activity. These effects were paralleled by a concomitant increase in IRS-1 phosphorylation at Ser³⁰⁷ and Ser⁶¹², respectively. The stimulatory effects of hrCRP on IRS-1 phosphorylation at Ser³⁰⁷ and Ser⁶¹² were partially reversed by treatment with specific JNK and ERK1/2 inhibitors, respectively. Exposure of L6 myotubes to hrCRP reduced insulin-stimulated phosphorylation of IRS-1 at Tyr⁶³², a site essential for engaging p85 subunit of phosphatidylinositol-3 kinase (PI-3K), protein kinase B (Akt) activation and glycogen synthase kinase-3 (GSK-3) phosphorylation. These events were accompanied by a decrease in insulin-stimulated glucose transporter (GLUT) 4 translocation to the plasma membrane, glucose uptake and glucose incorporation into glycogen. The inhibitory effects of hrCRP on insulin signalling and insulin-stimulated GLUT4 translocation were reversed by treatment with JNK inhibitor I and the mitogen-activated protein kinase inhibitor, PD98059.

Conclusions/interpretation

Our data suggest that hrCRP may cause insulin resistance by increasing IRS-1 phosphorylation at Ser³⁰⁷ and Ser⁶¹² via JNK and ERK1/2, respectively, leading to impaired insulin-stimulated glucose uptake, GLUT4 translocation, and glycogen synthesis mediated by the IRS-1/PI-3K/Akt/GSK-3 pathway.

Pickup JC, Mattock MB, Chusney GD, Burt D (2004) Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care 27:813–823PubMed

Fernandez-Real JM, Ricart J (2003) Insulin resistance and chronic cardiovascular inflammatory syndrome. Endocr Rev 24:278–301PubMedCrossRef

Schmidt MI, Duncan BB, Sharrett AR et al (1999) Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis risk in communities study): a cohort study. Lancet 353:1649–1652PubMedCrossRef

Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM (2001) C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 286:327–334PubMedCrossRef

Festa A, D’Agostino R, Howard G, Mykkanen L, Tracey RP, Haffner SM (2000) Chronic subclinical inflammation as part of the insulin resistance syndrome. The Insulin Resistance Atherosclerosis Study (IRAS). Circulation 101:42–47

Ford ES (1999) Body mass index, diabetes, and C-reactive protein among US adults. Diabetes 22:1971–1977

Temelkova-Kurktschiev T, Henkel E, Koehler C, Karrei K, Hanefield M (2002) Subclinical inflammation in newly detected type II diabetes and impaired glucose tolerance. Diabetologia 45:151PubMedCrossRef

Festa A, D’Agostino R, Tracy RP, Haffner SM (2002) Elevated levels of acute-phase proteins and plasminogen activator inhibitor−1 predict the development of type 2 diabetes. The Insulin Resistance Atherosclerosis Study. Diabetes 51:1131–1137PubMed

De Fea K, Roth RA (1997) Modulation of insulin receptor substrate-1 tyrosine phosphorylation and function by mitogen-activated protein kinase. J Biol Chem 272:31400–31406PubMedCrossRef

10.

De Fea K, Roth RA (1997) Protein kinase C modulation of insulin receptor substrate-1 tyrosine phosphorylation requires serine 612. Biochemistry 36:12939–12947PubMedCrossRef

11.

Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM (1996) IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science 271:665–668PubMedCrossRef

12.

Aguirre V, Uchida T, Yenush L, Davis R, White MF (2000) The c-Jun NH(2)-termrinal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307). J Biol Chem 275:9047–9054PubMedCrossRef

13.

Hirosumi J, Tuncman G, Chang L et al (2002) A central role for JNK in obesity and insulin resistance. Nature 420:333–336PubMedCrossRef

14.

Tuncman G, Hirosumi J, Solinas G, Chang L, Karin M, Hotamisligil GS (2006) Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance. Proc Natl Acad Sci USA 103:10741–10746PubMedCrossRef

15.

Araki E, Lipes MA, Patti ME et al (1994) Alternative pathways of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature 372:186–190PubMedCrossRef

16.

Tamemoto H, Kadowaki T, Tobe K et al (1994) Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature 372:182–186PubMedCrossRef

17.

Withers DJ, Gutierrez JS, Towery H et al (1998) Disruption of IRS-2 causes type 2 diabetes in mice. Nature 391:900–903PubMedCrossRef

18.

Goodyear LJ, Giorgino F, Sherman LA, Carey J, Smith RJ, Dohm GL (1995) Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects. J Clin Invest 95:2195–2204PubMed

19.

Rondinone CM, Wang LM, Lonnroth P, Wesslau C, Pierce JH, Smith U (1997) Insulin receptor substrate (IRS) 1 is reduced and IRS-2 is the main docking protein for phosphatidylinositol 3-kinase in adipocytes from subjects with non-insulin-dependent diabetes mellitus. Proc Natl Acad Sci USA 94:4171–4175PubMedCrossRef

20.

Bjornholm M, Kawano Y, Lehtihet M, Zierath JR (1997) Insulin receptor substrate-1 phosphorylation and phosphatidylinositol 3-kinase activity in skeletal muscle from NIDDM subjects after in vivo insulin stimulation. Diabetes 46:524–527PubMed

21.

Sesti G, Federici M, Hribal ML, Lauro D, Sbraccia P, Lauro R (2001) Defects of the insulin receptor substrate (IRS) system in human metabolic disorders. FASEB J 15:2099–2111PubMedCrossRef

22.

Almind K, Bjorbaek C, Vestergaard H, Hansen T, Echwald SM, Pedersen O (1993) Amino acid polymorphism in insulin receptor substrate-1 in non-insulin-dependent diabetes mellitus. Lancet 342:828–832PubMedCrossRef

23.

Marini MA, Frontoni S, Mineo D et al (2003) The Arg⁹⁷² variant in insulin receptor substrate-1 is associated with an atherogenic profile in offspring of type 2 diabetic patients. J Clin Endocrinol Metab 88:3368–3371PubMedCrossRef

24.

Verma S, Wang CH, Li SH et al (2002) A self-fulfilling prophecy: C-reactive protein attenuates nitric oxide production and inhibits angiogenesis. Circulation 106:913–919PubMedCrossRef

25.

Verma S, Badiwala MV, Weisel RD et al (2003) C-reactive protein activates the nuclear factor-kB signal transduction pathway in saphenous vein endothelial cells: implications for atherosclerosis and restenosis. J Thorac Cardiovasc Surg 126:1886–1891PubMedCrossRef

26.

Hattori Y, Matsumura M, Kasai K (2003) Vascular smooth muscle cell activation by C-reactive protein. Cardiovasc Res 58:186–195PubMedCrossRef

27.

Tortorella LL, Pilch PF (2002) C₂C₁₂ myocytes lack an insulin-responsive vescicular compartment despite dexamethasone-induced GLUT4 expression. Am J Physiol Endocrinol Metab 283:E514–E524PubMed

28.

Lewis TS, Shapiro PS, Ahn NG (1998) Signal transduction through MAP kinase cascades. Adv Cancer Res 74:49–139PubMedCrossRef

29.

Davis RJ (1999) Signal transduction by the c-Jun N terminal kinase. Biochem Soc Symp 64:1–12PubMed

30.

Esposito DL, Li Y, Cama A (2001) Tyr(612) and Tyr(632) in human insulin receptor substrate-1 are important for full activation of insulin-stimulated phosphatidylinositol 3-kinase activity and translocation of GLUT4 in adipose cells. Endocrinology 142:2833–2840PubMedCrossRef

31.

Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378:785–789PubMedCrossRef

32.

Hajduch E, Alessi DR, Hemmings BA, Hundal HS (1998) Constitutive activation of protein kinase B α by membrane targeting promotes glucose and system A amino acid transport, protein synthesis, and inactivation of glycogen synthase kinase 3 in L6 muscle cells. Diabetes 47:1006–1013PubMed

33.

Klip A, Ramlal T, Douen AG, Bilan PJ, Skoreck L (1998) Inhibition by forskolin of insulin-stimulated glucose transport in L6 muscle cells. Biochem J 255:1023–1029

34.

Pedrini MT, Kranebitter M, Niederwanger A et al (2005) Human triglyceride-rich lipoproteins impair glucose metabolism and insulin signaling in L6 muscle cells independently of non-esterified fatty acid levels. Diabetologia 48:756–766PubMedCrossRef

35.

Marnell LL, Mold C, Volzer MA, Burlingame RW, Du Clos TW (1995) C-reactive protein binds to FcγRI in transfected COS cells. J Immunol 155:2185–2193PubMed

36.

Bharadwaj D, Stein P, Volzer M, Mold C, Du Clos TW (1999) The major receptor for C-reactive protein on leukocytes is Fcγ receptor II. J Exp Med 190:585–590PubMedCrossRef

37.

Williams TN, Zhang CX, Game BA, He L, Huang Y (2004) C-reactive protein stimulates MMP-1 expression in U937 histocytes through FcγRII and extracellular signal-regulated kinase pathway: an implication of CRP involvement in plaque destabilization. Arterioscler Thromb Vasc Biol 24:61–66PubMedCrossRef

38.

Oriente F, Formisano P, Miele C et al (2001) Insulin receptor substrate-2 phosphorylation is necessary for protein kinase C zeta activation by insulin in L6hIR cells. J Biol Chem 276:37109–37119PubMedCrossRef

39.

Kaneto H, Nakatani Y, Miyatsuka T et al (2004) Possible novel therapy for diabetes with cell-permeable JNK-inhibitory peptide. Nat Med 10:1128–1132PubMedCrossRef

40.

Bouzakri K, Roques M, Gual P et al (2003) Reduced activation of phosphatidylinositol-3 kinase and increased serine 636 phosphorylation of insulin receptor substrate-1 in primary culture of skeletal muscle cells from patients with type 2 diabetes. Diabetes 52:1319–1325PubMed

41.

Carlson CJ, Koterski S, Sciotti RJ, Poccard GB, Rondinone CM (2003) Enhanced basal activation of mitogen-activated protein kinases in adipocytes from type 2 diabetes: potential role of p38 in the downregulation of GLUT4 expression. Diabetes 52:634–641PubMed

42.

Morino K, Petersen KF, Dufour S et al (2005) Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. J Clin Invest 115:3587–3593PubMedCrossRef

43.

Bost F, Aouadi M, Caron L et al (2005) The extracellular signal-regulated kinase isoform ERK1 is specifically required for in vitro and in vivo adipogenesis. Diabetes 54:402–411PubMed

44.

Gual P, Gremeaux T, Gonzalez T, Le Marchand-Brustel Y, Tanti JF (2003) MAP kinases and mTOR mediate insulin-induced phosphorylation of insulin receptor substrate-1 on serine residues 307, 612 and 632. Diabetologia 46:1532–1542PubMedCrossRef

45.

van den Berg CW, Taylor KE, Lang D (2004) C-reactive protein-induced in vitro vasorelaxation is an artefact caused by the presence of sodium azide in commercial preparations. Arterioscler Thromb Vasc Biol 24:e168–e171PubMedCrossRef

46.

Liu C, Wang S, Deb A et al (2005) Proapoptotic, antimigratory, antiproliferative, and antiangiogenic effects of commercial C-reactive protein on various human endothelial cell types: in vitro implications of contaminating presence of sodium azide in commercial preparation. Circ Res 97:135–143PubMedCrossRef

47.

Taylor KE, Giddings JC, van den Berg CW (2005) C-Reactive protein-induced in vitro endothelial cell activation is an artefact caused by azide and lipopolysaccharide. Arterioscler Thromb Vasc Biol 25:1225–1230PubMedCrossRef

48.

The Diabetes Prevention Program Research Group (2005) Intensive lifestyle intervention or metformin on inflammation and coagulation in participants with impaired glucose tolerance. Diabetes 54:1566–1572

49.

Haffner SM, Greenberg AS, Weston WM, Chen H, Williams K, Freed MI (2002) Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 106:679–684PubMedCrossRef

50.

Satoh N, Ogawa Y, Usui T et al (2003) Anti-atherogenic effect of pioglitazone in type 2 diabetic patients irrespective of the responsiveness to its antidiabetic effect. Diabetes Care 26:2493–2499PubMed

Titel: C-reactive protein induces phosphorylation of insulin receptor substrate-1 on Ser307 and Ser612 in L6 myocytes, thereby impairing the insulin signalling pathway that promotes glucose transport
verfasst von: C. D’Alessandris
R. Lauro
I. Presta
G. Sesti
Publikationsdatum: 01.04.2007
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 4/2007
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-006-0522-y

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

C-reactive protein induces phosphorylation of insulin receptor substrate-1 on Ser³⁰⁷ and Ser⁶¹² in L6 myocytes, thereby impairing the insulin signalling pathway that promotes glucose transport

Abstract

Aims/hypothesis

Materials and methods

Results

Conclusions/interpretation

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Erhebliches Risiko für Kehlkopfkrebs bei mäßiger Dysplasie

Nach Herzinfarkt mit Typ-1-Diabetes schlechtere Karten als mit Typ 2?

15% bedauern gewählte Blasenkrebs-Therapie

Costims – das nächste heiße Ding in der Krebstherapie?

Update Innere Medizin

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Abstract

Aims/hypothesis

Materials and methods

Results

Conclusions/interpretation

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 4/2007

Inappropriate suppression of glucagon during OGTT but not during isoglycaemic i.v. glucose infusion contributes to the reduced incretin effect in type 2 diabetes mellitus

A novel mechanism of action for statins against diabetes-induced oxidative stress

Prevalence and incidence rate of diabetes mellitus in a Swedish community during 30 years of follow-up

Inhibition of histone deacetylases prevents cytokine-induced toxicity in beta cells

Sphingosine kinase 1 participates in insulin signalling and regulates glucose metabolism and homeostasis in KK/Ay diabetic mice

Effect of type 2 diabetes mellitus on exercise intolerance and the physiological responses to exercise in peripheral arterial disease

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Erhebliches Risiko für Kehlkopfkrebs bei mäßiger Dysplasie

Nach Herzinfarkt mit Typ-1-Diabetes schlechtere Karten als mit Typ 2?

15% bedauern gewählte Blasenkrebs-Therapie

Costims – das nächste heiße Ding in der Krebstherapie?

Update Innere Medizin