Skip to main content

Advertisement

Log in

Adipokines and vascular disease in diabetes

  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

Adipokines, in particular adiponectin, have been highlighted in the pathogenesis of obesity-related illnesses, including type 2 diabetes, because of their role in the regulation of insulin sensitivity as well as vascular endothelial function. Since cardiovascular disease accounts for an overwhelming proportion of the morbidity and mortality suffered by patients with diabetes, researchers are actively seeking a better understanding of the role that adipokines play in the vasculature with the hope that the use of these agents, or activation of their signaling pathways, might help prevent micro-and macrovascular complications. This brief review highlights recent work on the vascular effects of circulating adipokines, focusing on adiponectin, and includes some recent findings with leptin and resistin. This highly active area of investigation has identified novel hormonal mechanisms by which the adipose tissue mass can influence vascular function with important consequences for cardiovascular risk.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Ogden CL, Carroll MD, Curtin LR, et al.: Prevalence of overweight and obesity in the United States, 1999–2004. JAMA 2006, 295:1549–1555.

    Article  PubMed  CAS  Google Scholar 

  2. Ford ES, Giles WH, Mokdad AH: Increasing prevalence of the metabolic syndrome among U.S. Adults. Diabetes Care 2004, 27:2444–2449.

    Article  PubMed  Google Scholar 

  3. Kershaw EE, Flier JS: Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 2004, 89:2548–2556.

    Article  PubMed  CAS  Google Scholar 

  4. Berg AH, Scherer PE: Adipose tissue, inflammation, and cardiovascular disease. Circ Res 2005, 96:939–949.

    Article  PubMed  CAS  Google Scholar 

  5. Greenberg AS, Obin MS: Obesity and the role of adipose tissue in inflammation and metabolism. Am J Clin Nutr 2006, 83:461S–465S.

    PubMed  CAS  Google Scholar 

  6. Goldstein BJ, Scalia R: Adiponectin: a novel adipokine linking adipocytes and vascular function. J Clin Endocrinol Metab 2004, 89:2563–2568.

    Article  PubMed  CAS  Google Scholar 

  7. Scherer PE: Adipose tissue: from lipid storage compartment to endocrine organ. Diabetes 2006, 55:1537–1545.

    Article  PubMed  CAS  Google Scholar 

  8. Kadowaki T, Yamauchi T, Kubota N, et al.: Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest 2006, 116:1784–1792.

    Article  PubMed  CAS  Google Scholar 

  9. Matsuzawa Y: Therapy insight: adipocytokines in metabolic syndrome and related cardiovascular disease. Nat Clin Pract Cardiovasc Med 2006, 3:35–42.

    Article  PubMed  CAS  Google Scholar 

  10. Fruebis J, Tsao TS, Javorschi S, et al.: Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci U S A 2001, 98:2005–2010.

    Article  PubMed  CAS  Google Scholar 

  11. Wang Y, Lam KSL, Chan L, et al.: Posttranslational modifications on the four conserved lysine residues within the collagenous domain of adiponectin are required for the formation of its high-molecular-weight oligomeric complex. J Biol Chem 2006, 281:16391–16400.

    Article  PubMed  CAS  Google Scholar 

  12. Combs TP, Berg AH, Obici S, et al.: Endogenous glucose production is inhibited by the adipose-derived protein Acrp30. J Clin Invest 2001, 108:1875–1881.

    Article  PubMed  CAS  Google Scholar 

  13. Yamauchi T, Kamon J, Ito Y, et al.: Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 2003, 423:762–769.

    Article  PubMed  CAS  Google Scholar 

  14. Motoshima H, Wu X, Mahadev K, Goldstein BJ: Adiponectin suppresses proliferation and superoxide generation and enhances eNOS activity in endothelial cells treated with oxidized LDL. Biochem Biophys Res Commun 2004, 315:264–271.

    Article  PubMed  CAS  Google Scholar 

  15. Tan KC, Xu A, Chow WS, et al.: Hypoadiponectinemia is associated with impaired endothelium-dependent vasodilation. J Clin Endocrinol Metab 2004, 89:765–769.

    Article  PubMed  CAS  Google Scholar 

  16. Hug C, Wang J, Ahmad NS, et al.: T-cadherin is a receptor for hexameric and high-molecular-weight forms of Acrp30/adiponectin. Proc Natl Acad Sci U S A 2004, 101:10308–10313.

    Article  PubMed  CAS  Google Scholar 

  17. Bromhead C, Miller JH, McDonald FJ: Regulation of T-cadherin by hormones, glucocorticoid and EGF. Gene 2006, 374:58–67.

    Article  PubMed  CAS  Google Scholar 

  18. Lam KS, Xu A: Adiponectin: protection of the endothelium. Curr Diab Rep 2005, 5:254–259.

    PubMed  CAS  Google Scholar 

  19. Bobbert T, Rochlitz H, Wegewitz U, et al.: Changes of adiponectin oligomer composition by moderate weight reduction. Diabetes 2005, 54:2712–2719.

    Article  PubMed  CAS  Google Scholar 

  20. Abbasi F, Chang SA, Chu JW, et al.: Improvements in insulin resistance with weight loss, in contrast to rosiglitazone, are not associated with changes in plasma adiponectin or adiponectin multimeric complexes. Am J Physiol Regul Integr Comp Physiol 2006, 290:R139–R144.

    PubMed  CAS  Google Scholar 

  21. Pajvani UB, Hawkins M, Combs TP, et al.: Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity. J Biol Chem 2004, 279:12152–12162.

    Article  PubMed  CAS  Google Scholar 

  22. Tonelli J, Li W, Kishore P, et al.: Mechanisms of early insulin-sensitizing effects of thiazolidinediones in type 2 diabetes. Diabetes 2004, 53:1621–1629.

    Article  PubMed  CAS  Google Scholar 

  23. Nawrocki AR, Rajala MW, Tomas E, et al.: Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor gamma agonists. J Biol Chem 2006, 281:2654–2660.

    Article  PubMed  CAS  Google Scholar 

  24. Kubota N, Terauchi Y, Kubota T, et al.: Pioglitazone ameliorates insulin resistance and diabetes by both adiponectin dependent and independent pathway. J Biol Chem 2006, 281:8748–8755.

    Article  PubMed  CAS  Google Scholar 

  25. Fisher FF, Trujillo ME, Hanif W, et al.: Serum high molecular weight complex of adiponectin correlates better with glucose tolerance than total serum adiponectin in Indo-Asian males. Diabetologia 2005, 48:1084–1087.

    Article  PubMed  CAS  Google Scholar 

  26. Lara-Castro C, Luo N, Wallace P, et al.: Adiponectin multimeric complexes and the metabolic syndrome trait cluster. Diabetes 2006, 55:249–259.

    Article  PubMed  CAS  Google Scholar 

  27. Brownlee M: The pathobiology of diabetic complications: a unifying mechanism. Diabetes 2005, 54:1615–1625.

    Article  PubMed  CAS  Google Scholar 

  28. Costacou T, Zgibor JC, Evans RW, et al.: The prospective association between adiponectin and coronary artery disease among individuals with type 1 diabetes. The Pittsburgh Epidemiology of Diabetes Complications Study. Diabetologia 2005, 48:41–48.

    Article  PubMed  CAS  Google Scholar 

  29. Ouedraogo R, Wu X, Xu SQ, et al.: Adiponectin suppression of high-glucose-induced reactive oxygen species in vascular endothelial cells: evidence for involvement of a cAMP signaling pathway. Diabetes 2006, 55:1840–1846.

    Article  PubMed  CAS  Google Scholar 

  30. Okamoto Y, Kihara S, Funahashi T, et al.: Adiponectin: a key adipocytokine in metabolic syndrome. Clin Sci (Lond) 2006, 110:267–278.

    Article  CAS  Google Scholar 

  31. Ouchi N, Kobayashi H, Kihara S, et al.: Adiponectin stimulates angiogenesis by promoting cross-talk between AMP-activated protein kinase and Akt signaling in endothelial cells. J Biol Chem 2004, 279:1304–1309.

    Article  PubMed  CAS  Google Scholar 

  32. Brakenhielm E, Veitonmaki N, Cao R, et al.: Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis. Proc Natl Acad Sci U S A 2004, 101:2476–2481.

    Article  PubMed  CAS  Google Scholar 

  33. Granger DN, Vowinkel T, Petnehazy T: Modulation of the inflammatory response in cardiovascular disease. Hypertension 2004, 43:924–931.

    Article  PubMed  CAS  Google Scholar 

  34. Furukawa S, Fujita T, Shimabukuro M, et al.: Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 2004, 114:1752–1761.

    Article  PubMed  CAS  Google Scholar 

  35. Katsuki A, Suematsu M, Gabazza EC, et al.: Increased oxidative stress is associated with decreased circulating levels of adiponectin in Japanese metabolically obese, normal-weight men with normal glucose tolerance. Diabetes Res Clin Pract 2006, 73:310–314.

    Article  PubMed  CAS  Google Scholar 

  36. Nakanishi S, Yamane K, Kamei N, et al.: A protective effect of adiponectin against oxidative stress in Japanese Americans: the association between adiponectin or leptin and urinary isoprostane. Metabolism 2005, 54:194–199.

    Article  PubMed  CAS  Google Scholar 

  37. Steffes MW, Gross MD, Lee DH, et al.: Adiponectin, visceral fat, oxidative stress, and early macrovascular disease: the Coronary Artery Risk Development in Young Adults Study. Obes Res 2006, 14:319–326.

    Article  CAS  Google Scholar 

  38. Ouchi N, Kihara S, Arita Y, et al.: Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin. Circulation 1999, 100:2473–2476.

    PubMed  CAS  Google Scholar 

  39. Ouchi N, Kihara S, Arita Y, et al.: Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-kappaB signaling through a cAMP-dependent pathway. Circulation 2000, 102:1296–1301.

    PubMed  CAS  Google Scholar 

  40. Kobashi C, Urakaze M, Kishida M, et al.: Adiponectin inhibits endothelial synthesis of interleukin-8. Circ Res 2005, 97:1245–1252.

    Article  PubMed  CAS  Google Scholar 

  41. Stone JR, Yang S: Hydrogen peroxide: a signaling messenger. Antioxid Redox Signal 2006, 8:243–270.

    Article  PubMed  CAS  Google Scholar 

  42. Ruderman NB, Cacicedo JM, Itani S, et al.: Malonyl-CoA and AMP-activated protein kinase (AMPK): possible links between insulin resistance in muscle and early endothelial cell damage in diabetes. Biochem Soc Trans 2003, 31:202–206.

    Article  PubMed  CAS  Google Scholar 

  43. Jung TW, Lee JY, Shim WS, et al.: Adiponectin protects human neuroblastoma SH-SY5Y cells against MPP+-induced cytotoxicity. Biochem Biophys Res Commun 2006, 343:564–570.

    Article  PubMed  CAS  Google Scholar 

  44. Arita Y, Kihara S, Ouchi N, et al.: Adipocyte-derived plasma protein adiponectin acts as a platelet-derived growth factor-BB-binding protein and regulates growth factor-induced common postreceptor signal in vascular smooth muscle cell. Circulation 2002, 105:2893–2898.

    Article  PubMed  CAS  Google Scholar 

  45. Wang Y, Lam KSL, Xu JY, et al.: Adiponectin inhibits cell proliferation by interacting with several growth factors in an oligomerization-dependent manner. J Biol Chem 2005, 280:18341–18347.

    Article  PubMed  CAS  Google Scholar 

  46. Kobayashi K, Inoguchi T, Sonoda N, et al.: Adiponectin inhibits the binding of low-density lipoprotein to biglycan, a vascular proteoglycan. Biochem Biophys Res Commun 2005, 335:66–70.

    Article  PubMed  CAS  Google Scholar 

  47. Yokota T, Oritani K, Takahashi I, et al.: Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood 2000, 96:1723–1732.

    PubMed  CAS  Google Scholar 

  48. Ouchi N, Kihara S, Arita Y, et al.: Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages. Circulation 2001, 103:1057–1063.

    PubMed  CAS  Google Scholar 

  49. Yamaguchi N, Argueta JG, Masuhiro Y, et al.: Adiponectin inhibits Toll-like receptor family-induced signaling. FEBS Lett 2005, 579:6821–6826.

    Article  PubMed  CAS  Google Scholar 

  50. Neumeier M, Weigert J, Schaffler A, et al.: Different effects of adiponectin isoforms in human monocytic cells. J Leukoc Biol 2006, 79:803–808.

    Article  PubMed  CAS  Google Scholar 

  51. Mao X, Kikani CK, Riojas RA, et al.: APPL1 binds to adiponectin receptors and mediates adiponectin signalling and function. Nat Cell Biol 2006, 8:516–523.

    Article  PubMed  CAS  Google Scholar 

  52. Wu X, Motoshima H, Mahadev K, et al.: Involvement of AMP-activated protein kinase in glucose uptake stimulated by the globular domain of adiponectin in primary rat adipocytes. Diabetes 2003, 52:1355–1363.

    Article  PubMed  CAS  Google Scholar 

  53. Chen H, Montagnani M, Funahashi T, et al.: Adiponectin stimulates production of nitric oxide in vascular endothelial cells. J Biol Chem 2003, 278:45021–45026.

    Article  PubMed  CAS  Google Scholar 

  54. Kobayashi H, Ouchi N, Kihara S, et al.: Selective suppression of endothelial cell apoptosis by the high molecular weight form of adiponectin. Circ Res 2004, 94:e27–e31.

    Article  PubMed  CAS  Google Scholar 

  55. Xi W, Satoh H, Kase H, et al.: Stimulated HSP90 binding to eNOS and activation of the PI3-Akt pathway contribute to globular adiponectin-induced NO production: Vasorelaxation in response to globular adiponectin. Biochem Biophys Res Commun 2005, 332:200–205.

    Article  PubMed  CAS  Google Scholar 

  56. Zhao T, Hou M, Xia M, et al.: Globular adiponectin decreases leptin-induced tumor necrosis factor-alpha expression by murine macrophages: Involvement of cAMP-PKA and MAPK pathways. Cell Immunol 2005, 238:19–30.

    Article  PubMed  CAS  Google Scholar 

  57. Collins SP, Reoma JL, Gamm DM, Uhler MD: LKB1, a novel serine/threonine protein kinase and potential tumour suppressor, is phosphorylated by cAMP-dependent protein kinase (PKA) and prenylated in vivo. Biochem J 2000, 345(Pt 3):673–680.

    Article  PubMed  CAS  Google Scholar 

  58. Kimball SR, Siegfried BA, Jefferson LS: Glucagon represses signaling through the mammalian target of rapamycin in rat liver by activating AMP-activated protein kinase. J Biol Chem 2004, 279:54103–54109.

    Article  PubMed  CAS  Google Scholar 

  59. Yin W, Mu J, Birnbaum MJ: Role of AMP-activated protein kinase in cyclic AMP-dependent lipolysis In 3T3-L1 adipocytes. J Biol Chem 2003, 278:43074–43080.

    Article  PubMed  CAS  Google Scholar 

  60. Kato H, Kashiwagi H, Shiraga M, et al.: Adiponectin acts as an endogenous antithrombotic factor. Arterioscler Thromb Vasc Biol 2006, 26:224–230.

    Article  PubMed  CAS  Google Scholar 

  61. Rothenbacher D, Brenner H, Marz W, Koenig W: Adiponectin, risk of coronary heart disease and correlations with cardiovascular risk markers. Eur Heart J 2005, 26:1640–1646.

    Article  PubMed  CAS  Google Scholar 

  62. van der Vleuten GM, van Tits LJ, den Heijer M, et al.: Decreased adiponectin levels in familial combined hyperlipidemia patients contribute to the atherogenic lipid profile. J Lipid Res 2005, 46:2398–2404.

    Article  PubMed  CAS  Google Scholar 

  63. Schneider JG, von EM, Schiekofer S, et al.: Low plasma adiponectin levels are associated with increased hepatic lipase activity in vivo. Diabetes Care 2005, 28:2181–2186.

    Article  PubMed  CAS  Google Scholar 

  64. Verges B, Petit JM, Duvillard L, et al.: Adiponectin is an important determinant of ApoA-I catabolism. Arterioscler Thromb Vasc Biol 2006, 26:1364–1369.

    Article  PubMed  CAS  Google Scholar 

  65. Farvid MS, Ng TW, Chan DC, et al.: Association of adiponectin and resistin with adipose tissue compartments, insulin resistance and dyslipidaemia. Diabetes Obes Metab 2005, 7:406–413.

    Article  PubMed  CAS  Google Scholar 

  66. Ouchi N, Shibata R, Walsh K: Cardioprotection by adiponectin. Trends Cardiovasc Med 2006, 16:141–146.

    Article  PubMed  CAS  Google Scholar 

  67. Kougias P, Chai H, Lin PH, et al.: Effects of adipocyte-derived cytokines on endothelial functions: implication of vascular disease. J Surg Res 2005, 126:121–129.

    Article  PubMed  CAS  Google Scholar 

  68. Beltowski J: Leptin and atherosclerosis. Atherosclerosis 2006, 189:47–60.

    Article  PubMed  CAS  Google Scholar 

  69. Rahmouni K, Haynes WG: Endothelial effects of leptin: implications in health and diseases. Curr Diab Rep 2005, 5:260–266.

    PubMed  CAS  Google Scholar 

  70. Kotani K, Sakane N, Saiga K, Kurozawa Y: Leptin: adiponectin ratio as an atherosclerotic index in patients with type 2 diabetes: relationship of the index to carotid intima-media thickness. Diabetologia 2005, 48:2684–2686.

    Article  PubMed  CAS  Google Scholar 

  71. Knudson JD, Dincer UD, Zhang C, et al.: Leptin receptors are expressed in coronary arteries and hyperleptinemia causes significant coronary endothelial dysfunction. Am J Physiol Heart Circ Physiol 2005, 289:H48–H56.

    Article  PubMed  CAS  Google Scholar 

  72. Knudson JD, Dincer UD, Dick GM, et al.: Leptin resistance extends to the coronary vasculature in prediabetic dogs and provides a protective adaptation against endothelial dysfunction. Am J Physiol Heart Circ Physiol 2005, 289:H1038–H1046.

    Article  PubMed  CAS  Google Scholar 

  73. Momin AU, Melikian N, Shah AM, et al.: Leptin is an endothelial-independent vasodilator in humans with coronary artery disease: evidence for tissue specificity of leptin resistance. Eur Heart J 2006, 27:2294–2299.

    Article  PubMed  CAS  Google Scholar 

  74. Banerjee RR, Rangwala SM, Shapiro JS, et al.: Regulation of fasted blood glucose by resistin. Science 2004, 303:1195–1198.

    Article  PubMed  CAS  Google Scholar 

  75. Reilly MP, Lehrke M, Wolfe ML, et al.: Resistin is an inflammatory marker of atherosclerosis in humans. Circulation 2005, 111:932–939.

    Article  PubMed  CAS  Google Scholar 

  76. Burnett MS, Lee CW, Kinnaird TD, et al.: The potential role of resistin in atherogenesis. Atherosclerosis 2005, 182:241–248.

    Article  PubMed  CAS  Google Scholar 

  77. Kougias P, Chai H, Lin PH, et al.: Adipocyte-derived cytokine resistin causes endothelial dysfunction of porcine coronary arteries. J Vasc Surg 2005, 41:691–698.

    Article  PubMed  Google Scholar 

  78. Dick GM, Katz PS, Farias III, et al.: Resistin impairs endothelium-dependent dilation to bradykinin, but not acetylcholine, in the coronary circulation. Am J Physiol Heart Circ Physiol 2006, 291:H2997–H3002.

    Article  PubMed  CAS  Google Scholar 

  79. Verma S, Li SH, Wang CH, et al.: Resistin promotes endothelial cell activation: further evidence of adipokine-endothelial interaction. Circulation 2003, 108:736–740.

    Article  PubMed  CAS  Google Scholar 

  80. Shen YH, Zhang L, Gan Y, et al.: Up-regulation of PTEN (phosphatase and tensin homolog deleted on chromosome ten) mediates p38 MAPK stress signal-induced inhibition of insulin signaling: a cross-talk between stress signaling and insulin signaling in resistin-treated human endothelial cells. J Biol Chem 2006, 281:7727–7736.

    Article  PubMed  CAS  Google Scholar 

  81. Calabro P, Samudio I, Willerson JT, Yeh ETH: Resistin promotes smooth muscle cell proliferation through activation of extracellular signal-regulated kinase 1/2 and phosphatidylinositol 3-kinase pathways. Circulation 2004, 110:3335–3340.

    Article  PubMed  CAS  Google Scholar 

  82. Kawanami D, Maemura K, Takeda N, et al.: Direct reciprocal effects of resistin and adiponectin on vascular endothelial cells: a new insight into adipocytokine-endothelial cell interactions. Biochem Biophys Res Commun 2004, 314:415–419.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Barry J. Goldstein MD, PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Goldstein, B.J., Scalia, R. Adipokines and vascular disease in diabetes. Curr Diab Rep 7, 25–33 (2007). https://doi.org/10.1007/s11892-007-0006-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11892-007-0006-6

Keywords

Navigation