Skip to main content
SpringerLink
Log in
Book cover

The Metabolic Syndrome pp 189–204Cite as

Insulin Signaling in Adipocytes and the Role of Inflammation

  • Chapter

  • 1517 Accesses

Part of the book series: Contemporary Endocrinology ((COE))

Abstract

Type 2 diabetes has during the last 20 years increased dramatically and taken epidemic-like proportions. One major cause is the highly increased incidence of obesity, which in tum is caused by a sedentary lifestyle as well as an increased consumption of a more energy-dense diet containing high levels of sugar and saturated fats. Obesity is associated with insulin resistance and an impaired intracellular insulin signaling. Current knowledge about the adipose cells and the role of inflammation are reviewed in this chapter.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Martin BC, Warram JH, Krolewski AS, Bergman RN, Soeldner JS, Kahn CR. Role of glucose and insulin resistance in development of type 2 diabetes mellitus: Results of a 25-year follow-up study. Lancet 1992; 340:925–929.

    Article  CAS  PubMed  Google Scholar 

  2. Köbberling J, Tillil H. Empirical risk figures for first-degree relatives of non-insulin-dependent diabetics. In: The Genetics of Diabetes Mellitus, Kobberling J, Tattersall R (eds.), Academic Press, London, 1982, pp. 201–209.

    Google Scholar 

  3. Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK. Increased insulin concentrations in nondiabetic offspring of diabetic parents. N Engl J Med 1988; 319:1297–1301.

    Article  CAS  PubMed  Google Scholar 

  4. Eriksson J, Franssila-Kallunki A, Ekstrand A, Saloranta C, Widen E, Schalin C, Groop L. Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus. N Engl J Med 1989; 321:337–343.

    CAS  PubMed  Google Scholar 

  5. Eriksson JW, Smith U, Waagstein F, Wysocki M, Jansson PA. Glucose turnover and adipose tissue lipolysis are insulin-resistant in healthy relatives of type 2 diabetes patients: Is cellular insulin resistance a secondary phenomenon? Diabetes 1999; 48:1572–1578.

    Article  CAS  PubMed  Google Scholar 

  6. Vaag A, Henriksen JE, Beck-Nielsen H. Decreased insulin activation of glycogen synthase in skeletal muscles in young nonobese Caucasian first-degree relatives of patients with non-insulin-dependent diabetes mellitus. J Clin Invest 1992; 89:782–788.

    Article  CAS  PubMed  Google Scholar 

  7. Henriksen JE, Alford F, Handberg A, Vaag A, Ward GM, Kalfas A, Beck-Nielsen H. Increased glucose effectiveness in normoglycemic but insulin-resistant relatives of patients with noninsulin-dependent diabetes mellitus: A novel compensatory mechanism. J Clin Invest 1994; 94: 1196–1204.

    Article  CAS  PubMed  Google Scholar 

  8. Perseghin G, Ghosh S, Gerow K, Shulman GI. Metabolic defects in lean nondiabetic offspring of NIDDM parents: A cross-sectional study. Diabetes 1997; 46:1001–1009.

    Article  CAS  PubMed  Google Scholar 

  9. Groop L, Forsblom C, Lehtovirta M, Tuomi T, Karanko S, Nissen M, Ehrnstrom BO, Forsen B, Isomaa B, Snickars B, Taskinen MR. Metabolic consequences of a family history of NIDDM (the Botnia study): Evidence for sex-specific parental effects. Diabetes 1996; 45: 1585–1593.

    Article  CAS  PubMed  Google Scholar 

  10. Johanson EH, Jansson PA, Lonn L, Matsuzawa Y, Funahashi T, Taskinen MR, Smith U, Axelsen M. Fat distribution, lipid accumulation in the liver, and exercise capacity do not explain the insulin resistance in healthy males with a family history for type 2 diabetes. J Clin Endocrinol Metab 2003; 88:4232–4238.

    Article  CAS  PubMed  Google Scholar 

  11. Goldfine AB, Bouche C, Parker RA, Kim C, Kerivan A, Soeldner JS, Martin BC, Warram JH, Kahn CR. Insulin resistance is a poor predictor of type 2 diabetes in individuals with no family history of disease. Proc Natl Acad Sci USA 2003; 100:2724–2729.

    Article  CAS  PubMed  Google Scholar 

  12. Grill V, Persson G, Carlsson S, Norman A, Alvarsson M, Ostensson CG, Svanstrom L, Efendic S. Family history of diabetes in middle-aged Swedish men is a gender unrelated factor which associates with insulinopenia in newly diagnosed diabetic subjects. Diabetologia 1999; 42:15–23.

    Article  CAS  PubMed  Google Scholar 

  13. Laws A, Stefanick ML, Reaven GM. Insulin resistance and hypertriglyceridemia in nondiabetic relatives of patients with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1989; 69: 343–347.

    Article  CAS  PubMed  Google Scholar 

  14. Axelsen M, Smith U, Eriksson JW, Taskinen MR, Jansson PA. Postprandial hypertriglyceridemia and insulin resistance in normoglycemic first-degree relatives of patients with type 2 diabetes. Ann Intern Med 1999; 131:27–31.

    CAS  PubMed  Google Scholar 

  15. Johanson EH, Jansson PA, Gustafson B, Lonn L, Smith U, Taskinen MR, Axelsen M. Early alterations in the postprandial VLDL1 apoB-100 and apoB-48 metabolism in men with strong heredity for type 2 diabetes. J Intern Med 2004; 255:273–279.

    Article  CAS  PubMed  Google Scholar 

  16. Johanson EH, Jansson PA, Gustafson B, Sandqvist M, Taskinen MR, Smith U, Axelsen M. No acute effect of nateglinide on postprandial lipid and lipoprotein responses in subjects at risk for type 2 diabetes. Diabetes Metab Res Rev 2005; 21:376–381.

    Article  CAS  PubMed  Google Scholar 

  17. Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, McCullough AJ, Natale S, Forlani G, Melchionda N. Nonalcoholic fatty liver disease: A feature of the metabolic syndrome. Diabetes 2001; 50:1844–1850.

    Article  CAS  PubMed  Google Scholar 

  18. Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001; 7:941–946.

    Article  CAS  PubMed  Google Scholar 

  19. Pellme F, Smith U, Funahashi T, Matsuzawa Y, Brekke H, Wiklund O, Taskinen MR, Jansson PA. Circulating adiponectin levels are reduced in nonobese but insulin-resistant first-degree relatives of type 2 diabetic patients. Diabetes 2003; 52:1182–1186.

    Article  CAS  PubMed  Google Scholar 

  20. Smith U. Impaired (“diabetic”) insulin signaling and action occur in fat cells long before glucose intolerance: Is insulin resistance initiated in the adipose tissue? Int J Obes Relat Metab Disord 2002; 26:897–904.

    Article  CAS  PubMed  Google Scholar 

  21. Carvalho E, Jansson PA, Axelsen M, Eriksson JW, Huang X, Groop L, Rondinone C, Sjostrom L, Smith U. Low cellular IRS 1 gene and protein expression predict insulin resistance and NIDDM. Faseb J 1999; 13:2173–2178.

    CAS  PubMed  Google Scholar 

  22. Carvalho E, Jansson PA, Nagaev I, Wenthzel AM, Smith U. Insulin resistance with low cellular IRS-1 expression is also associated with low GLUT4 expression and impaired insulin-stimulated glucose transport. Faseb J 2001; 15:1101–1103.

    CAS  PubMed  Google Scholar 

  23. Abel ED, Peroni O, Kim JK, Kim YB, Boss O, Hadro E, Minnemann T, Shulman GI, Kahn BB. Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. Nature 2001; 409:729–733.

    Article  CAS  PubMed  Google Scholar 

  24. Yang Q, Graham TE, Mody N, Preitner F, Peroni OD, Zabolotny JM, Kotani K, Quadro L, Kahn BB. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature 2005; 436:356–362.

    Article  CAS  PubMed  Google Scholar 

  25. Jansson PA, Pellme F, Hammarstedt A, Sandqvist M, Brekke H, Caidahl K, Forsberg M, Volkmann R, Carvalho E, Funahashi T, Matsuzawa Y, Wiklund O, Yang X, Taskinen MR, Smith U. A novel cellular marker of insulin resistance and early atherosclerosis in humans is related to impaired fat cell differentiation and low adiponectin. Faseb J 2003; 17:1434–1440.

    Article  CAS  PubMed  Google Scholar 

  26. Hammarstedt A, Sopasakis VR, Gogg S, Jansson PA, Smith U. Improved insulin sensitivity and adipose tissue dysregulation after short-term treatment with pioglitazone in non-diabetic, insulinresistant subjects. Diabetologia 2005; 48:96–104.

    Article  CAS  PubMed  Google Scholar 

  27. Faraj M, Lu HL, Cianflone K. Diabetes, lipids, and adipocyte secretagogues. Biochem Cell Biol 2004; 82:170–190.

    Article  CAS  PubMed  Google Scholar 

  28. Meier U, Gressner AM. Endocrine regulation of energy metabolism: review of pathobiochemical and clinical chemical aspects of leptin, ghrelin, adiponectin, and resistin. Clin Chem 2004; 50: 1511–1525.

    Article  CAS  PubMed  Google Scholar 

  29. Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka M, Kishimoto K, Matsuki Y, Murakami M, Ichisaka T, Murakami H, Watanabe E, Takagi T, Akiyoshi M, Ohtsubo T, Kihara S, Yamashita S, Makishima M, Funahashi T, Yamanaka S, Hiramatsu R, Matsuzawa Y, Shimomura I. Visfatin: A protein secreted by visceral fat that mimics the effects of insulin. Science 2005; 307:426–430.

    Article  CAS  PubMed  Google Scholar 

  30. Giovannone B, Scaldaferri ML, Federici M, Porzio O, Lauro D, Fusco A, Sbraccia P, Borboni P, Lauro R, Sesti G. Insulin receptor substrate (IRS) transduction system: Distinct and overlapping signaling potential. Diabetes Metab Res Rev 2000; 16:434–441.

    Article  CAS  PubMed  Google Scholar 

  31. Backer JM, Myers MG, Jr., Shoelson SE, Chin DJ, Sun XJ, Miralpeix M, Hu P, Margolis B, Skolnik EY, Schlessinger J et al. Phosphatidylinositol 3′-kinase is activated by association with IRS-1 during insulin stimulation. Embo J 1992; 11:3469–3479.

    CAS  PubMed  Google Scholar 

  32. Cheatham B, Vlahos CJ, Cheatham L, Wang L, Blenis J, Kahn CR. Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp70 S6 kinase, DNA synthesis, and glucose transporter translocation. Mol Cell Biol 1994; 14:4902–4911.

    CAS  PubMed  Google Scholar 

  33. Dhand R, Hiles I, Panayotou G, Roche S, Fry MJ, Gout I, Totty NF, Truong O, Vicendo P, Yonezawa K et al. PI 3-kinase is a dual specificity enzyme: Autoregulation by an intrinsic protein-serine kinase activity. Embo J 1994; 13:522–533.

    CAS  PubMed  Google Scholar 

  34. Alessi DR, Deak M, Casamayor A, Caudwell FB, Morrice N, Norman DG, Gaffney P, Reese CB, MacDougall CN, Harbison D, Ashworth A, Bownes M. 3-Phosphoinositide-dependent protein kinase-1 (PDK1): Structural and functional homology with the Drosophila DSTPK61 kinase. Curr Biol 1997; 7:776–789.

    Article  CAS  PubMed  Google Scholar 

  35. Downward J. Mechanisms and consequences of activation of protein kinase B/Akt. Curr Opin Cell Biol 1998; 10:262–267.

    Article  CAS  PubMed  Google Scholar 

  36. Standaert ML, Galloway L, Karnam P, Bandyopadhyay G, Moscat J, Farese RV. Protein kinase C-zeta as a downstream effector of phosphatidylinositol 3-kinase during insulin stimulation in rat adipocytes: Potential role in glucose transport. J Biol Chem 1997; 272:30075–30082.

    Article  CAS  PubMed  Google Scholar 

  37. Lizunov VA, Matsumoto H, Zimmerberg J, Cushman SW, Frolov VA. Insulin stimulates the halting, tethering, and fusion of mobile GLUT4 vesicles in rat adipose cells. J Cell Biol 2005; 169:481–489.

    Article  CAS  PubMed  Google Scholar 

  38. Fasshauer M, Klein J, Kriauciunas KM, Ueki K, Benito M, Kahn CR. Essential role of insulin receptor substrate 1 in differentiation of brown adipocytes. Mol Cell Biol 2001; 21:319–329.

    Article  CAS  PubMed  Google Scholar 

  39. Miki H, Yamauchi T, Suzuki R, Komeda K, Tsuchida A, Kubota N, Terauchi Y, Kamon J, Kaburagi Y, Matsui J, Akanuma Y, Nagai R, Kimura S, Tobe K, Kadowaki T. Essential role of insulin receptor substrate 1 (IRS-1) and IRS-2 in adipocyte differentiation. Mol Cell Biol 2001; 21:2521–2532.

    Article  CAS  PubMed  Google Scholar 

  40. El-Jack AK, Hamm JK, Pilch PF, Farmer SR. Reconstitution of insulin-sensitive glucose transport in fibroblasts requires expression of both PPARgamma and CIEBPalpha. J Biol Chem 1999; 274:7946–7951.

    Article  CAS  PubMed  Google Scholar 

  41. Wu Z, Rosen ED, Brun R, Hauser S, Adelmant G, Troy AE, McKeon C, Darlington GJ, Spiegelman BM. Cross-regulation of CIEBP alpha and PPAR gamma controls the transcriptional pathway of adipogenesis and insulin sensitivity. Mol Cell 1999; 3:151–158.

    Article  CAS  PubMed  Google Scholar 

  42. Zierath JR, Krook A, Wallberg-Henriksson H. Insulin action and insulin resistance in human skeletal muscle. Diabetologia 2000; 43:821–835.

    Article  CAS  PubMed  Google Scholar 

  43. Rondinone CM, Wang LM, Lonnroth P, Wesslau C, Pierce JH, Smith U. 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 1997; 94:4171–4175.

    Article  CAS  PubMed  Google Scholar 

  44. Aguirre V, Werner ED, Giraud J, Lee YH, Shoelson SE, White MF. Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. J Biol Chem 2002; 277:1531–1537.

    Article  CAS  PubMed  Google Scholar 

  45. Greene MW, Sakaue H, Wang L, Alessi DR, Roth RA. Modulation of insulin-stimulated degradation of human insulin receptor substrate-1 by Serine 312 phosphorylation. J Biol Chem 2003; 278:8199–8211.

    Article  CAS  PubMed  Google Scholar 

  46. Gao Z, Zhang X, Zuberi A, Hwang D, Quon MJ, Lefevre M, Ye J. Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3-Ll adipocytes. Mol Endocrinol 2004; 18:2024–2034.

    Article  CAS  PubMed  Google Scholar 

  47. Carlson CJ, Koterski S, Sciotti RJ, Poccard GB, Rondinone CM. 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 2003; 52:634–641.

    Article  CAS  PubMed  Google Scholar 

  48. Rondinone CM, Carvalho E, Wesslau C, Smith UP. Impaired glucose transport and protein kinase B activation by insulin, but not okadaic acid, in adipocytes from subjects with type II diabetes mellitus. Diabetologia 1999; 42:819–825.

    Article  CAS  PubMed  Google Scholar 

  49. Carvalho E, Eliasson B, Wesslau C, Smith U. Impaired phosphorylation and insulin-stimulated translocation to the plasma membrane of protein kinase B/Akt in adipocytes from type II diabetic subjects. Diabetologia 2000; 43:1107–1115.

    Article  CAS  PubMed  Google Scholar 

  50. Ducluzeau PH, Perretti N, Laville M, Andreelli F, Vega N, Riou JP, Vidal H. Regulation by insulin of gene expression in human skeletal muscle and adipose tissue: Evidence for specific defects in type 2 diabetes. Diabetes 2001; 50: 1134–1142.

    Google Scholar 

  51. Hammarstedt A, Jansson PA, Wesslau C, Yang X, Smith U. Reduced expression of PGC-1 and insulin-signaling molecules in adipose tissue is associated with insulin resistance. Biochem Biophys Res Commun 2003; 301:578–582.

    Article  CAS  PubMed  Google Scholar 

  52. Semple RK, Crowley VC, Sewter CP, Laudes M, Christodoulides C, Considine RV, Vidal-Puig A, O’Rahilly S. Expression of the thermogenic nuclear hormone receptor coactivator PGC-1 alpha is reduced in the adipose tissue of morbidly obese subjects. Int J Obes Relat Metab Disord 2004; 8:176–179.

    Article  CAS  Google Scholar 

  53. Yang X, Enerback S, Smith U. Reduced expression of FOXC2 and brown adipogenic genes in human subjects with insulin resistance. Obes Res 2003; 11:1182–1191.

    Article  CAS  PubMed  Google Scholar 

  54. Yang X, Jansson PA, Nagaev I, Jack MM, Carvalho E, Sunnerhagen KS, Cam MC, Cushman SW, Smith U. Evidence of impaired adipogenesis in insulin resistance. Biochem Biophys Res Commun 2004; 317:1045–1051.

    Article  CAS  PubMed  Google Scholar 

  55. Hammarstedt A, Andersson CX, Rotter Sopasakis V, Smith U. The effect of PPARgamma ligands on the adipose tissue in insulin resistance. Prostaglandins Leukot Essent Fatly Acids 2005; 73:65–75.

    Article  CAS  Google Scholar 

  56. O’Brien KD, Brehm BJ, Seeley RJ, Bean J, Wener MH, Daniels S, D’ Alessio DA. Diet-induced weight loss is associated with decreases in plasma serum amyloid a and C-reactive protein independent of dietary macronutrient composition in obese subjects. J Clin Endocrinol Metab 2005; 90:2244–2249.

    Article  PubMed  CAS  Google Scholar 

  57. Park HS, Park JY, Yu R. Relationship of obesity and visceral adiposity with serum concentrations of CRP, TNF-alpha and IL-6. Diabetes Res Clin Pract 2005; 69:29–35.

    Article  CAS  PubMed  Google Scholar 

  58. Pai JK, Pischon T, Ma J, Manson JE, Hankinson SE, Joshipura K, Curhan GC, Rifai N, Cannuscio CC, Stampfer MJ, Rimm EB. Inflammatory markers and the risk of coronary heart disease in men and women. N Engl J Med 2004; 351:2599–2610.

    Article  CAS  PubMed  Google Scholar 

  59. Giugliano G, Nicoletti G, Grella E, Giugliano F, Esposito K, Scuderi N, D’ Andrea F. Effect of liposuction on insulin resistance and vascular inflammatory markers in obese women. Br J Plast Surg 2004; 57:190–194.

    Article  CAS  PubMed  Google Scholar 

  60. Ziccardi P, Nappo F, Giugliano G, Esposito K, Marfella R, Cioffi M, D’Andrea F, Molinari AM, Giugliano D. Reduction of inflammatory cytokine concentrations and improvement of endothelial functions in obese women after weight loss over one year. Circulation 2002; 105:804–809.

    Article  CAS  PubMed  Google Scholar 

  61. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003; 112:1821–1830.

    CAS  PubMed  Google Scholar 

  62. Wellen KE, Hotamisligil GS. Obesity-induced inflammatory changes in adipose tissue. J Clin Invest 2003; 112:1785–1788.

    CAS  PubMed  Google Scholar 

  63. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW, Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003; 112:1796–1808.

    CAS  PubMed  Google Scholar 

  64. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993; 259:87–91.

    Article  CAS  PubMed  Google Scholar 

  65. Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest 1995; 95:2409–2415.

    Article  CAS  PubMed  Google Scholar 

  66. Kern PA, Saghizadeh M, Ong JM, Bosch RJ, Deem R, Simsolo RB. The expression of tumor necrosis factor in human adipose tissue: Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J Clin Invest 1995; 95:2111–2119.

    Article  CAS  PubMed  Google Scholar 

  67. Xu H, Uysal KT, Becherer JD, Arner P, Hotamisligil GS. Altered tumor necrosis factor-alpha (TNF-alpha) processing in adipocytes and increased expression of transmembrane TNF-alpha in obesity. Diabetes 2002; 51:1876–1883.

    Article  CAS  PubMed  Google Scholar 

  68. Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab 2001; 280:E745–751.

    CAS  PubMed  Google Scholar 

  69. Kado S, Nagase T, Nagata N. Circulating levels of interleukin-6, its soluble receptor and interleukin6/ interleukin-6 receptor complexes in patients with type 2 diabetes mellitus. Acta Diabetol 1999; 36:67–72.

    Article  CAS  PubMed  Google Scholar 

  70. Rotter V, Nagaev I, Smith U. Interleukin-6 (IL-6) induces insulin resistance in 3T3-Ll adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects. J Biol Chem 2003; 278:45777–45784.

    Article  CAS  PubMed  Google Scholar 

  71. Sopasakis VR, Sandqvist M, Gustafson B, Hammarstedt A, Schmelz M, Yang X, Jansson PA, Smith U. High local concentrations and effects on differentiation implicate interleukin-6 as a paracrine regulator. Obes Res 2004; 12:454–460.

    Article  CAS  PubMed  Google Scholar 

  72. Fasshauer M, Kralisch S, Klier M, Lossner U, Bluher M, Klein J, Paschke R. Adiponectin gene expression and secretion is inhibited by interleukin-6 in 3T3-Ll adipocytes. Biochem Biophys Res Commun 2003; 301:1045–1050.

    Article  CAS  PubMed  Google Scholar 

  73. Gustafson B, Jack MM, Cushman SW, Smith U. Adiponectin gene activation by thiazolidinediones requires PPAR gamma 2, but not CIEBP alpha: Evidence for differential regulation of the aP2 and adiponectin genes. Biochem Biophys Res Commun 2003; 308:933–939.

    Article  CAS  PubMed  Google Scholar 

  74. Starr R, Willson TA, Viney EM, Murray LJ, Rayner JR, Jenkins BJ, Gonda TJ, Alexander WS, Metcalf D, Nicola NA, Hilton DJ. A family of cytokine-inducible inhibitors of signalling. Nature 1997; 387:917–921.

    Article  CAS  PubMed  Google Scholar 

  75. Ueki K, Kondo T, Kahn CR. Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Mol Cell Biol 2004; 24:5434–5446.

    Article  CAS  PubMed  Google Scholar 

  76. Lee YH, Giraud J, Davis RJ, White MF. c-Jun N-terminal kinase (JNK) mediates feedback inhibition of the insulin signaling cascade. J Biol Chem 2003; 278:2896–2902.

    Article  CAS  PubMed  Google Scholar 

  77. Rotter Sopasakis V, Larsson BM, Johansson A, Holmang A, Smith U. Short-term infusion of interleukin-6 does not induce insulin resistance in vivo or impair insulin signalling in rats. Diabetologia 2004; 47:1879–1887.

    Article  CAS  PubMed  Google Scholar 

  78. Yang X, Jansson PA, Pellme F, Laakso M, Smith U. Effect of the interleukin-6 (−174) g/c promoter polymorphism on adiponectin and insulin sensitivity. Obes Res 2005; 13:813–817.

    Article  CAS  PubMed  Google Scholar 

  79. Ruan H, Hacohen N, Golub TR, Van Parijs L, Lodish HF. Tumor necrosis factor-alpha suppresses adipocyte-specific genes and activates expression of preadipocyte genes in 3T3-Ll adipocytes: Nuclear factor-kappaB activation by TNF-alpha is obligatory. Diabetes 2002; 51:1319–1336.

    Article  CAS  PubMed  Google Scholar 

  80. Uysal KT, Wiesbrock SM, Hotamisligil GS. Functional analysis of tumor necrosis factor (TNF) receptors in TNF-alpha-mediated insulin resistance in genetic obesity. Endocrinology 1998; 139:4832–4838.

    Article  CAS  PubMed  Google Scholar 

  81. Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 1997; 389:610–614.

    Article  CAS  PubMed  Google Scholar 

  82. Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM, Wynshaw-Boris A, Poli G, Olefsky J, Karin M. IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 2005; 11:191–198.

    Article  CAS  PubMed  Google Scholar 

  83. Sopasakis VR, Nagaev I, Smith U. Cytokine release from adipose tissue of nonobese individuals. Int J Obes Relat Metab Disord 2005; 29:1144–1147

    Article  CAS  Google Scholar 

  84. Gerhardt CC, Romero lA, Cancello R, Camoin L, Strosberg AD. Chemokines control fat accumulation and leptin secretion by cultured human adipocytes. Mol Cell Endocrinol 2001; 175:81–92.

    Article  CAS  PubMed  Google Scholar 

  85. Bokarewa M, Nagaev I, Dahlberg L, Smith U, Tarkowski A. Resistin, an adipokine with potent proinflammatory properties. J Immunol 2005; 174:5789–5795.

    CAS  PubMed  Google Scholar 

  86. Banerjee RR, Lazar MA. Resistin: molecular history and prognosis. J Mol Med 2003; 81:218–226.

    CAS  PubMed  Google Scholar 

  87. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA. The hormone resistin links obesity to diabetes. Nature 2001; 409:307–312.

    Article  CAS  PubMed  Google Scholar 

  88. Nagaev I, Smith U. Insulin resistance and type 2 diabetes are not related to resistin expression in human fat cells or skeletal muscle. Biochem Biophys Res Commun 2001; 285:561–564.

    Article  CAS  PubMed  Google Scholar 

  89. Li SP, Liu TY, Goldman ND. Cis-acting elements responsible for interleukin-6 inducible C-reactive protein gene expression. J Biol Chem 1990; 265:4136–4142.

    CAS  PubMed  Google Scholar 

  90. Ramadori G, Van Damme J, Rieder H, Meyer zum Buschenfelde KH. Interleukin 6, the third mediator of acute-phase reaction, modulates hepatic protein synthesis in human and mouse: Comparison with interleukin 1 beta and tumor necrosis factor-alpha. Eur J Immunol 1988; 18:1259–1264.

    Article  CAS  PubMed  Google Scholar 

  91. Benigni F, Fantuzzi G, Sacco S, Sironi M, Pozzi P, Dinarello CA, Sipe JD, Poli V, Cappelletti M, Paonessa G, Pennica D, Panayotatos N, Ghezzi P. Six different cytokines that share GP130 as a receptor subunit, induce serum amyloid A and potentiate the induction of interleukin-6 and the activation of the hypothalamus-pituitary-adrenal axis by interleukin-1. Blood 1996; 87:1851–1854.

    CAS  PubMed  Google Scholar 

  92. Tillett WS, Francis T. Serological reactions in pneumonia with a nonprotein somatic fraction of pneumococcus. J Exp Med 1930; 52:561–585.

    Article  CAS  PubMed  Google Scholar 

  93. Kroop IG, Shackman NH. Level of C-reactive protein as a measure of acute myocardial infarction. Proc Soc Exp Biol Med 1954; 86:95–97.

    CAS  PubMed  Google Scholar 

  94. Chang MK, Binder CJ, Torzewski M, Witztum JL. C-reactive protein binds to both oxidized LDL and apoptotic cells through recognition of a common ligand: Phosphorylcholine of oxidized phospholipids. Proc Natl Acad Sci USA 2002; 99:13043–13048.

    Article  CAS  PubMed  Google Scholar 

  95. Torzewski J, Torzewski M, Bowyer DE, Frohlich M, Koenig W, Waltenberger J, Fitzsimmons C, Hombach V. C-reactive protein frequently colocalizes with the terminal complement complex in the intima of early atherosclerotic lesions of human coronary arteries. Arterioscler Thromb Vasc Biol 1998; 18:1386–1392.

    CAS  PubMed  Google Scholar 

  96. Agrawal A. CRP after 2004. Mollmmunol 2005; 42:927–930.

    CAS  Google Scholar 

  97. Taskinen S, Hyvonen M, Kovanen PT, Meri S, Pentikainen MO. C-reactive protein binds to the 3beta-OH group of cholesterol in LDL particles. Biochem Biophys Res Commun 2005; 329:1208–1216.

    Article  CAS  PubMed  Google Scholar 

  98. Paul A, Ko KW, Li L, Yechoor V, McCrory MA, Szalai AJ, Chan L. C-reactive protein accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice. Circulation 2004; 109:647–655.

    Article  CAS  PubMed  Google Scholar 

  99. Hirschfield GM, Gallimore JR, Kahan MC, Hutchinson WL, Sabin CA, Benson GM, Dhillon AP, Tennent GA, Pepys MB. Transgenic human C-reactive protein is not proatherogenic in apolipoprotein E-deficient mice. Proc Natl Acad Sci USA 2005; 102:8309–8314.

    Article  CAS  PubMed  Google Scholar 

  100. Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: An 8-year follow-up of 14,719 initially healthy American women. Circulation 2003; 107:391–397.

    Article  PubMed  Google Scholar 

  101. Uhlar CM, Whitehead AS. Serum amyloid A: The major vertebrate acute-phase reactant. Eur J Biochem 1999; 265:501–523.

    Article  CAS  PubMed  Google Scholar 

  102. Meek RL, Eriksen N, Benditt EP. Murine serum amyloid A3 is a high density apolipoprotein and is secreted by macrophages. Proc Natl Acad Sci USA 1992; 89:7949–7952.

    Article  CAS  PubMed  Google Scholar 

  103. Lin Y, Rajala MW, Berger JP, Moller DE, Barzilai N, Scherer PE. Hyperglycemia-induced production of acute phase reactants in adipose tissue. J Biol Chem 2001; 276:42077–42083.

    Article  CAS  PubMed  Google Scholar 

  104. Cai L, de Beer MC, de Beer FC, van der Westhuyzen DR. Serum amyloid A is a ligand for scavenger receptor class B type I and inhibits high density lipoprotein binding and selective lipid uptake. J Biol Chem 2005; 280:2954–2961.

    Article  CAS  PubMed  Google Scholar 

  105. Fujiwara T, Yoshioka S, Yoshioka T, Ushiyama I, Horikoshi H. Characterization of new oral antidiabetic agent CS-045: Studies in KK and ob/ob mice and Zucker fatty rats. Diabetes 1988; 37:1549–1558.

    Article  CAS  PubMed  Google Scholar 

  106. Yki-Jarvinen H. Thiazolidinediones. N Engl J Med 2004; 351:1106–1118.

    Article  PubMed  Google Scholar 

  107. Ciaraldi TP, Kong AP, Chu NV, Kim DD, Baxi S, Loviscach M, Plodkowski R, Reitz R, Caulfield M, Mudaliar S, Henry RR. Regulation of glucose transport and insulin signaling by troglitazone or metformin in adipose tissue of type 2 diabetic subjects. Diabetes 2002; 51:30–36.

    Article  CAS  PubMed  Google Scholar 

  108. Jiang G, Dallas-Yang Q, Biswas S, Li Z, Zhang BB. Rosiglitazone, an agonist of peroxisome-proliferator-activated receptor gamma (PPARgamma), decreases inhibitory serine phosphorylation of IRS1 in vitro and in vivo. Biochem J 2004; 377:339–346.

    Article  CAS  PubMed  Google Scholar 

  109. Okuno A, Tamemoto H, Tobe K, Ueki K, Mori Y, Iwamoto K, Umesono K, Akanuma Y, Fujiwara T, Horikoshi H, Yazaki Y, Kadowaki T. Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats. J Clin Invest 1998; 101:1354–1361.

    Article  CAS  PubMed  Google Scholar 

  110. Mohanty P, Aljada A, Ghanim H, Hofmeyer D, Tripathy D, Syed T, Al-Haddad W, Dhindsa S, Dandona P. Evidence for a potent antiinflammatory effect of rosiglitazone. J Clin Endocrinol Metab 2004; 89:2728–2735.

    Article  CAS  PubMed  Google Scholar 

  111. Katsuki A, Sumida Y, Murata K, Furuta M, Araki-Sasaki R, Tsuchihashi K, Hori Y, Yano Y, Gabazza EC, Adachi Y. Troglitazone reduces plasma levels of tumour necrosis factor-alpha in obese patients with type 2 diabetes. Diabetes Obes Metab 2000; 2:189–191.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  113. Sigrist S, Bedoucha M, Boelsterli VA. Down-regulation by troglitazone of hepatic tumor necrosis factor-alpha and interleukin-6 mRNA expression in a murine model of non-insulin-dependent diabetes. Biochem PharmacoI 2000; 60:67–75.

    Article  CAS  Google Scholar 

  114. Peraldi P, Xu M, Spiegelman BM. Thiazolidinediones block tumor necrosis factor-alpha-induced inhibition of insulin signaling. J Clin Invest 1997; 100:1863–1869.

    Article  CAS  PubMed  Google Scholar 

  115. Lagathu C, Bastard JP, Auclair M, Maachi M, Capeau J, Caron M. Chronic interleukin-6 (IL-6) treatment increased IL-6 secretion and induced insulin resistance in adipocyte: Prevention by rosiglitazone. Biochem Biophys Res Commun 2003; 311:372–379.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Lundberg Laboratory for Diabetes Research, Sahlgrenska University Hospital at Gőteborg University, Gőteborg, Sweden

    Christian X. Andersson MD (Assistant Researcher), Ann Hammarstedt MD (Assistant Researcher), Per-Anders Jansson MD (Physician) & Ulf Smith MD (Professor of Internal Medicine)

Authors
  1. Christian X. Andersson MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ann Hammarstedt MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Per-Anders Jansson MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ulf Smith MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Obesity, Diabetes, and Aging Research Center, University of South Florida College of Medicine, Tampa, FL

    Barbara Caleen Hansen PhD (Professor of Internal Medicine and Pediatrics Director) (Professor of Internal Medicine and Pediatrics Director)

  2. Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA

    George A. Bray MD (Boyd Professor) (Boyd Professor)

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Humana Press, a part of Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Andersson, C.X., Hammarstedt, A., Jansson, PA., Smith, U. (2008). Insulin Signaling in Adipocytes and the Role of Inflammation. In: Hansen, B.C., Bray, G.A. (eds) The Metabolic Syndrome. Contemporary Endocrinology. Humana Press. https://doi.org/10.1007/978-1-60327-116-5_10

Download citation

  • DOI: https://doi.org/10.1007/978-1-60327-116-5_10

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-738-9

  • Online ISBN: 978-1-60327-116-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation