Signaling in Diabetes and Metabolic Syndrome



Diabetes mellitus is a condition in which an ­organism contains elevated blood sugar. This pathological state could be a result of two major abnormalities both related to the functioning of insulin, a hormone that regulates glucose metabolism. Type 1 diabetes (T1D) develops when β cells fail to produce insulin. The most common diabetes affecting 90–95% of the US diabetes population is Type 2 diabetes (T2D), which results from “insulin resistance”: cells lose sensitivity and respond weakly (or stop responding) to the insulin that is produced.

This chapter focuses on the signaling pathways triggered by insulin under normal conditions and describes the changes leading to the development of resistance of target cells to insulin. Also are described consequences of insulin resistance for the development of obesity, a number of signaling systems affected under other metabolic disorders that increase the risk of developing cardiovascular disease (components of metabolic syndrome (MetSyn), such as dyslipidemia and hyperinsulinemia) and genes polymorphisms associated with diabetes, resistance to insulin and MetSyn.


Diabetes signaling Metabolic syndrome Insulin Advance glycation end-products 


  1. 1.
    Zeng G, Quon MJ. Insulin-stimulated production of nitric oxide is inhibited by wortmannin. Direct measurement in vascular endothelial cells. J Clin Invest. 1996;98:894–8.PubMedCrossRefGoogle Scholar
  2. 2.
    Zeng G, Nystrom FH, Ravichandran LV, et al. Roles for insulin receptor, PI3-kinase, and Akt in insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells. Circulation. 2000;101:1539–45.PubMedGoogle Scholar
  3. 3.
    Montagnani M, Ravichandran LV, Chen H, Esposito DL, Quon MJ. Insulin receptor substrate-1 and phosphoinositide-dependent kinase-1 are required for insulin-stimulated production of nitric oxide in endothelial cells. Mol Endocrinol. 2002;16:1931–42.PubMedCrossRefGoogle Scholar
  4. 4.
    Trovati M, Massucco P, Mattiello L, et al. Human vascular smooth muscle cells express a constitutive nitric oxide synthase that insulin rapidly activates, thus increasing guanosine 3′:5′-cyclic monophosphate and adenosine 3′:5′-cyclic monophosphate concentrations. Diabetologia. 1999;42:831–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Sobrevia L, Nadal A, Yudilevich DL, Mann GE. Activation of L-arginine transport (system y+) and nitric oxide synthase by elevated glucose and insulin in human endothelial cells. J Physiol. 1996;490:775–81.PubMedGoogle Scholar
  6. 6.
    Lee JH, Ragolia L. AKT phosphorylation is essential for insulin-induced relaxation of rat vascular smooth muscle cells. Am J Physiol Cell Physiol. 2006;291:C1355–65.PubMedCrossRefGoogle Scholar
  7. 7.
    Surks HK, Mochizuki N, Kasai Y, et al. Regulation of myosin phosphatase by a specific interaction with cGMP-dependent protein kinase Iα. Science. 1999;286:1583–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Bolotina VM, Najibi S, Palacino JJ, Pagano PJ, Cohen RA. Nitric oxide directly activates calcium-dependent potassium channels in vascular smooth muscle. Nature. 1994;368:850–3.PubMedCrossRefGoogle Scholar
  9. 9.
    Kovacic S, Soltys CL, Barr AJ, Shiojima I, Walsh K, Dyck JR. Akt activity negatively regulates phosphorylation of AMP-activated protein kinase in the heart. J Biol Chem. 2003;278:39422–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Chabowski A, Coort SLM, Calles-Escandon J, et al. Insulin stimulates fatty acid transport by regulating expression of FAT/CD36 but not FABPpm. Am J Physiol Endocrinol Metab. 2004;287:E781–9.PubMedCrossRefGoogle Scholar
  11. 11.
    von Lewinski D, Bruns S, Walther S, Kogler H, Pieske B. Insulin causes [Ca2+]i-dependent and [Ca2+]i-independent positive inotropic effects in failing human myocardium. Circulation. 2005;111:2588–95.CrossRefGoogle Scholar
  12. 12.
    McDowell SA, McCall E, Matter WF, Estridge TB, Vlahos CJ. Phosphoinositide 3-kinase regulates excitation-contraction coupling in neonatal cardiomyocytes. Am J Physiol Heart Circ Physiol. 2004;286:H796–805.PubMedCrossRefGoogle Scholar
  13. 13.
    Rota M, Boni A, Urbanek K, et al. Nuclear targeting of Akt enhances ventricular function and myocyte contractility. Circ Res. 2005;97:1332–41.PubMedCrossRefGoogle Scholar
  14. 14.
    Walsh K. Akt signaling and growth of the heart. Circulation. 2006;113:2032–4.PubMedCrossRefGoogle Scholar
  15. 15.
    Samuelsson AM, Bollano E, Mobini R, et al. Hyperinsulinemia: effect on cardiac mass/function, angiotensin II receptor expression, and insulin signaling pathways. Am J Physiol Heart Circ Physiol. 2006;291:H787–96.PubMedCrossRefGoogle Scholar
  16. 16.
    DeBosch BJ, Muslin AJ. Insulin signaling pathways and cardiac growth. J Mol Cell Cardiol. 2008;44:855–64.PubMedCrossRefGoogle Scholar
  17. 17.
    Draznin B, Miles P, Kruszynska Y, et al. Effects of insulin on prenylation as a mechanism of potentially detrimental influence of hyperinsulinemia. Endocrinology. 2000;141:1310–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Golovchenko I, Goalstone ML, Watson P, Brownlee M, Draznin B. Hyperinsulinemia enhances transcriptional activity of nuclear factor-κB induced by angiotensin II, hyperglycemia, and advanced glycosylation end products in vascular smooth muscle cells. Circ Res. 2000;87:746–52.PubMedGoogle Scholar
  19. 19.
    Iwata K, Nishinaka T, Matsuno K, Kakehi T, Katsuyama M, Ibi M, et al. The activity of aldose reductase is elevated in diabetic mouse heart. J Pharmacol Sci. 2007;103:408–16.PubMedCrossRefGoogle Scholar
  20. 20.
    Cappiello M, Voltarelli M, Cecconi I, Vilardo PG, Dal Monte M, Marini I, et al. Specifically targeted modification of human aldose reductase by physiological disulfides. J Biol Chem. 1996;271:33539–44.PubMedCrossRefGoogle Scholar
  21. 21.
    Tan AL, Forbes JM, Cooper ME. AGE, RAGE, and ROS in diabetic nephropathy. Semin Nephrol. 2007;27:130–43.PubMedCrossRefGoogle Scholar
  22. 22.
    Coughlan MT, Cooper ME, Forbes JM. Renal microvascular injury in diabetes: RAGE and redox signaling. Antioxid Redox Signal. 2007;9:331–42.PubMedCrossRefGoogle Scholar
  23. 23.
    Goldin A, Beckman JA, Schmidt A, Creager MA. Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation. 2006;114:597–605.PubMedCrossRefGoogle Scholar
  24. 24.
    Kaneko M, Bucciarelli L, Hwang YC, Lee L, Yan SF, Schmidt AM, et al. Aldose reductase and AGE-RAGE pathways: key players in myocardial ischemic injury. Ann N Y Acad Sci. 2005;1043:702–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Hartog JW, Voors AA, Bakker SJ, Smit AJ, van Veldhuisen DJ. Advanced glycation end-products (AGEs) and heart failure: Pathophysiology and clinical implications. Eur J Heart Fail. 2007;9:1146–55.PubMedCrossRefGoogle Scholar
  26. 26.
    Koyama Y, Takeishi Y, Arimoto T, Niizeki T, Shishido T, Takahashi H, et al. High serum level of pentosidine, an advanced glycation end product (AGE), is a risk factor of patients with heart failure. J Card Fail. 2007;13:199–206.PubMedCrossRefGoogle Scholar
  27. 27.
    Liu J, Masurekar MR, Vatner DE, Jyothirmayi GN, Regan TJ, Vatner SF, et al. Glycation end-product cross-link breaker reduces collagen and improves cardiac function in aging diabetic heart. Am J Physiol Heart Circ Physiol. 2003;285:H2587–91.PubMedGoogle Scholar
  28. 28.
    Zieman S, Kass D. Advanced glycation end product cross-linking: pathophysiologic role and therapeutic target in cardiovascular disease. Congest Heart Fail. 2004;10:144–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Bidasee KR, Nallani K, Yu Y, Cocklin RR, Zhang Y, Wang M, et al. Chronic diabetes increases advanced glycation end products on cardiac ryanodine receptors/calcium-release channels. Diabetes. 2003;52:1825–36.PubMedCrossRefGoogle Scholar
  30. 30.
    Schäfer S, Huber J, Wihler C, Rütten H, Busch AE, Linz W. Impaired left ventricular relaxation in type 2 diabetic rats is related to myocardial accumulation of N(epsilon)-(carboxymethyl) lysine. Eur J Heart Fail. 2006;8:2–6.PubMedCrossRefGoogle Scholar
  31. 31.
    Cooper ME. Importance of advanced glycation end products in diabetes-associated cardiovascular and renal disease. Am J Hypertens. 2004;17:31S–8.PubMedCrossRefGoogle Scholar
  32. 32.
    van Heerebeek L, Hamdani N, Handoko ML, Falcao-Pires I, Musters RJ, Kupreishvili K, et al. Diastolic stiffness of the failing diabetic heart: importance of fibrosis, advanced glycation end products, and myocyte resting tension. Circulation. 2008;117:43–51.PubMedCrossRefGoogle Scholar
  33. 33.
    Kim JK, Kim YJ, Fillmore JJ, et al. Prevention of fat-induced insulin resistance by salicylate. J Clin Invest. 2001;108:437–46.PubMedGoogle Scholar
  34. 34.
    Schwartzbauer G, Robbins J. The tumor suppressor gene PTEN can regulate cardiac hypertrophy and survival. J Biol Chem. 2001;276:35786–93.PubMedCrossRefGoogle Scholar
  35. 35.
    Liu GX, Hanley PJ, Ray J, Daut J. Long-chain acyl-coenzyme A esters and fatty acids directly link metabolism to KATP channels in the heart. Circ Res. 2001;88:918–24.PubMedCrossRefGoogle Scholar
  36. 36.
    Tappia PS. Phospholipid-mediated signaling systems as novel targets for treatment of heart disease. Can J Physiol Pharmacol. 2007;85:25–41.PubMedCrossRefGoogle Scholar
  37. 37.
    Lamers JM, De Jonge HW, Panagia V, Van Heugten HA. Receptor-mediated signalling pathways acting through hydrolysis of membrane phospholipids in cardiomyocytes. Cardioscience. 1993;4:121–31.PubMedGoogle Scholar
  38. 38.
    Tappia PS, Dent MR, Dhalla NS. Oxidative stress and redox regulation of phospholipase D in myocardial disease. Free Radic Biol Med. 2006;41:349–61.PubMedCrossRefGoogle Scholar
  39. 39.
    Xu YJ, Panagia V, Shao Q, Wang X, Dhalla NS. Phosphatidic acid increases intracellular free Ca2+ and cardiac contractile force. Am J Physiol Heart Circ Physiol. 1996;271:H651–9.Google Scholar
  40. 40.
    Dhalla NS, Xu YJ, Sheu SS, Tappia PS, Panagia V. Phosphatidic acid: a potential signal transducer for cardiac hypertrophy. J Mol Cell Cardiol. 1997;29:2865–71.PubMedCrossRefGoogle Scholar
  41. 41.
    Pavoine C, Behforouz N, Gauthier C, et al. β2-adrenergic signaling in human heart: shift from the cyclic AMP to the arachidonic acid pathway. Mol Pharmacol. 2003;64:1117–25.PubMedCrossRefGoogle Scholar
  42. 42.
    Engelbrecht AM, Ellis B. Apoptosis is mediated by cytosolic phospholipase A2 during simulated ischaemia/reperfusion-induced injury in neonatal cardiac myocytes. Prostaglandins Leukot Essent Fatty Acids. 2007;77:37–43.PubMedCrossRefGoogle Scholar
  43. 43.
    Su X, Han X, Mancuso DJ, Abendschein DR, Gross RW. Accumulation of long-chain acylcarnitine and 3-hydroxy acylcarnitine molecular species in diabetic myocardium: identification of alterations in mitochondrial fatty acid processing in diabetic myocardium by shotgun lipidomics. Biochemistry. 2005;44:5234–45.PubMedCrossRefGoogle Scholar
  44. 44.
    Mancuso DJ, Abendschein DR, Jenkins CM, et al. Cardiac ischemia activates calcium-independent phospholipase A2β, precipitating ventricular tachyarrhythmias in transgenic mice: rescue of the lethal electrophysiologic phenotype by mechanism-based inhibition. J Biol Chem. 2003;278:22231–6.PubMedCrossRefGoogle Scholar
  45. 45.
    Morin CL, Eckel RH, Marcel T, Pagliassotti MJ. High fat diets elevate adipose tissue-derived tumor necrosis factor-α activity. Endocrinology. 1997;138:4665–71.PubMedCrossRefGoogle Scholar
  46. 46.
    Boden G, She P, Mozzoli M, et al. Free fatty acids produce insulin resistance and activate the proinflammatory nuclear factor-κB pathway in rat liver. Diabetes. 2005;54:3458–65.PubMedCrossRefGoogle Scholar
  47. 47.
    Ajuwon KM, Spurlock ME. Palmitate activates the NF-κB transcription factor and induces IL-6 and TNFα expression in 3T3-L1 adipocytes. J Nutr. 2005;135:1841–6.PubMedGoogle Scholar
  48. 48.
    Eringa EC, Stehouwer CD, Walburg K, et al. Physiological concentrations of insulin induce endothelin-dependent vasoconstriction of skeletal muscle resistance arteries in the presence of tumor necrosis factor-α dependence on c-Jun N-terminal kinase. Arterioscler Thromb Vasc Biol. 2006;26:274–80.PubMedCrossRefGoogle Scholar
  49. 49.
    Anderson HD, Rahmutula D, Gardner DG. Tumor necrosis factor-α inhibits endothelial nitric-oxide synthase gene promoter activity in bovine aortic endothelial cells. J Biol Chem. 2004;279:963–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Nguyen MT, Satoh H, Favelyukis S, et al. JNK and tumor necrosis factor-α mediate free fatty acid-induced insulin resistance in 3T3-L1 adipocytes. J Biol Chem. 2005;280:35361–71.PubMedCrossRefGoogle Scholar
  51. 51.
    Gao Z, Zuberi A, Quon MJ, Dong Z, Ye J. Aspirin inhibits serine phosphorylation of insulin receptor substrate 1 in tumor necrosis factor-treated cells through targeting multiple serine kinases. J Biol Chem. 2003;278:24944–50.PubMedCrossRefGoogle Scholar
  52. 52.
    de Alvaro C, Teruel T, Hernandez R, Lorenzo M. Tumor necrosis factor α produces insulin resistance in skeletal muscle by activation of inhibitor κB kinase in a p38 MAPK-dependent manner. J Biol Chem. 2004;279:17070–8.PubMedCrossRefGoogle Scholar
  53. 53.
    Xu JW, Morita I, Ikeda K, Miki T, Yamori Y. C-reactive protein suppresses insulin signaling in endothelial cells. Role of Syk tyrosine kinase. Mol Endocrinol. 2007;21:564–73.PubMedCrossRefGoogle Scholar
  54. 54.
    Arita Y, Kihara S, Ouchi N, et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun. 1999;257:79–83.PubMedCrossRefGoogle Scholar
  55. 55.
    Hotta K, Funahashi T, Arita Y, et al. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol. 2000;20:1595–9.PubMedCrossRefGoogle Scholar
  56. 56.
    Kojima S, Funahashi T, Sakamoto T, et al. The variation of plasma concentrations of a novel, adipocyte derived protein, adiponectin, in patients with acute myocardial infarction. Heart. 2003;89:667.PubMedCrossRefGoogle Scholar
  57. 57.
    Iwashima Y, Katsuya T, Ishikawa K, et al. Hypoadiponectinemia is an independent risk factor for hypertension. Hypertension. 2004;43:1318–23.PubMedCrossRefGoogle Scholar
  58. 58.
    Ouchi N, Kihara S, Funahashi T, et al. Reciprocal association of C-reactive protein with adiponectin in blood stream and adipose tissue. Circulation. 2003;107:671–4.PubMedCrossRefGoogle Scholar
  59. 59.
    Hulthe J, Hulten LM, Fagerberg B. Low adipocyte-derived plasma protein adiponectin concentrations are associated with the metabolic syndrome and small dense low-density lipoprotein particles: atherosclerosis and insulin resistance study. Metabolism. 2003;52:1612–4.PubMedCrossRefGoogle Scholar
  60. 60.
    Gilardini L, McTernan PG, Girola A, et al. Adiponectin is a candidate marker of metabolic syndrome in obese children and adolescents. Atherosclerosis. 2006;189:401–7.PubMedCrossRefGoogle Scholar
  61. 61.
    Ohashi K, Ouchi N, Kihara S, et al. Adiponectin I164T mutation is associated with the metabolic syndrome and coronary artery disease. J Am Coll Cardiol. 2004;43:1195–200.PubMedCrossRefGoogle Scholar
  62. 62.
    Yang WS, Chuang LM. Human genetics of adiponectin in the metabolic syndrome. J Mol Med. 2006;84:112–21.PubMedCrossRefGoogle Scholar
  63. 63.
    Hara K, Boutin P, Mori Y, et al. Genetic variation in the gene encoding adiponectin is associated with an increased risk of type 2 diabetes in the Japanese population. Diabetes. 2002;51:536–40.PubMedCrossRefGoogle Scholar
  64. 64.
    Vasseur F, Helbecque N, Dina C, et al. Single-nucleotide polymorphism haplotypes in the both proximal promoter and exon 3 of the APM1 gene modulate adipocyte-secreted adiponectin hormone levels and contribute to the genetic risk for type 2 diabetes in French Caucasians. Hum Mol Genet. 2002;11:2607–14.PubMedCrossRefGoogle Scholar
  65. 65.
    González-Sánchez JL, Zabena CA, Martínez-Larrad MT, et al. An SNP in the adiponectin gene is associated with decreased serum adiponectin levels and risk for impaired glucose tolerance. Obes Res. 2005;13:807–12.PubMedCrossRefGoogle Scholar
  66. 66.
    Xita N, Georgiou I, Chatzikyriakidou A, et al. Effect of adiponectin gene polymorphisms on circulating adiponectin and insulin resistance indexes in women with polycystic ovary syndrome. Clin Chem. 2005;51:416–23.PubMedCrossRefGoogle Scholar
  67. 67.
    Filippi E, Sentinelli F, Trischitta V, et al. Association of the human adiponectin gene and insulin resistance. Eur J Hum Genet. 2004;12:199–205.PubMedCrossRefGoogle Scholar
  68. 68.
    Filippi E, Sentinelli F, Romeo S, et al. The adiponectin gene SNP+276G>T associates with early-onset coronary artery disease and with lower levels of adiponectin in younger coronary artery disease patients (age ≤50 years). J Mol Med. 2005;83:711–9.PubMedCrossRefGoogle Scholar
  69. 69.
    Yang WS, Lee WJ, Funahashi T, et al. Weight reduction increases plasma levels of an adipose-derived anti-inflammatory protein, adiponectin. J Clin Endocrinol Metab. 2001;86:3815–9.PubMedCrossRefGoogle Scholar
  70. 70.
    Maeda N, Takahashi M, Funahashi T, et al. PPARγ ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes. 2001;50:2094–9.PubMedCrossRefGoogle Scholar
  71. 71.
    Juan CC, Chuang TY, Chang CL, Huang SW, Ho LT. Endothelin-1 regulates adiponectin gene expression and secretion in 3T3-L1 adipocytes via distinct signaling pathways. Endocrinology. 2007;148:1835–42.PubMedCrossRefGoogle Scholar
  72. 72.
    Delporte ML, Funahashi T, Takahashi M, Matsuzawa Y, Brichard SM. Pre- and post-translational negative effect of β-adrenoceptor agonists on adiponectin secretion: in vitro and in vivo studies. Biochem J. 2002;367:677–85.PubMedCrossRefGoogle Scholar
  73. 73.
    Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R. Adiponectin gene expression is inhibited by β-adrenergic stimulation via protein kinase A in 3T3-L1 adipocytes. FEBS Lett. 2001;507:142–6.PubMedCrossRefGoogle Scholar
  74. 74.
    Soares AF, Guichardant M, Cozzone D, et al. Effects of oxidative stress on adiponectin secretion and lactate production in 3T3-L1 adipocytes. Free Radic Biol Med. 2005;38:882–9.PubMedCrossRefGoogle Scholar
  75. 75.
    Fasshauer M, Kralisch S, Klier M, et al. Adiponectin gene expression and secretion is inhibited by interleukin-6 in 3T3-L1 adipocytes. Biochem Biophys Res Commun. 2003;301:1045–50.PubMedCrossRefGoogle Scholar
  76. 76.
    Degawa-Yamauchi M, Moss KA, Bovenkerk JE, et al. Regulation of adiponectin expression in human adipocytes: effects of adiposity, glucocorticoids, and tumor necrosis factor α. Obes Res. 2005;13:662–9.PubMedCrossRefGoogle Scholar
  77. 77.
    Wang B, Jenkins JR, Trayhurn P. Expression and secretion of inflammation-related adipokines by human adipocytes differentiated in culture: integrated response to TNF-α. Am J Physiol Endocrinol Metab. 2005;288:E731–40.PubMedCrossRefGoogle Scholar
  78. 78.
    Gable DR, Hurel SJ, Humphries SE. Adiponectin and its gene variants as risk factors for insulin resistance, the metabolic syndrome and cardiovascular disease. Atherosclerosis. 2006;188:231–44.PubMedCrossRefGoogle Scholar
  79. 79.
    Hopkins TA, Ouchi N, Shibata R, Walsh K. Adiponectin actions in the cardiovascular system. Cardiovasc Res. 2007;74:11–8.PubMedCrossRefGoogle Scholar
  80. 80.
    Karbowska J, Kochan Z. Role of adiponectin in the regulation of carbohydrate and lipid metabolism. J Physiol Pharmacol. 2006;57:103–13.PubMedGoogle Scholar
  81. 81.
    Yamauchi T, Kamon J, Ito Y, et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature. 2003;423:762–9.PubMedCrossRefGoogle Scholar
  82. 82.
    Yamauchi T, Kamon J, Waki H, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001;7:941–6.PubMedCrossRefGoogle Scholar
  83. 83.
    Tomas E, Tsao TS, Saha AK, et al. Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation. Proc Natl Acad Sci USA. 2002;99:16309–13.PubMedCrossRefGoogle Scholar
  84. 84.
    Yamauchi T, Kamon J, Minokoshi Y, et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002;8:1288–95.PubMedCrossRefGoogle Scholar
  85. 85.
    Onay-Besikci A, Altarejos JY, Lopaschuk GD. gAd-globular head domain of adiponectin increases fatty acid oxidation in newborn rabbit hearts. J Biol Chem. 2004;279:44320–6.PubMedCrossRefGoogle Scholar
  86. 86.
    Li L, Wu LL. Effect of AMP-activated protein kinase on cardiovascular protection of adiponectin. Sheng Li Xue Bao. 2007;59:614–8.PubMedGoogle Scholar
  87. 87.
    Combs TP, Berg AH, Obici S, Scherer PE, Rossetti L. Endogenous glucose production is inhibited by the adipose-derived protein Acrp30. J Clin Invest. 2001;108:1875–81.PubMedGoogle Scholar
  88. 88.
    Ouchi N, Kihara S, Funahashi T, Matsuzawa Y, Walsh K. Obesity, adiponectin and vascular inflammatory disease. Curr Opin Lipidol. 2003;14:561–6.PubMedCrossRefGoogle Scholar
  89. 89.
    Kumada M, Kihara S, Ouchi N, et al. Adiponectin specifically increased tissue inhibitor of metalloproteinase-1 through interleukin-10 expression in human macrophages. Circulation. 2004;109:2046–9.PubMedCrossRefGoogle Scholar
  90. 90.
    Chen H, Montagnani M, Funahashi T, Shimomura I, Quon MJ. Adiponectin stimulates production of nitric oxide in vascular endothelial cells. J Biol Chem. 2003;278:45021–6.PubMedCrossRefGoogle Scholar
  91. 91.
    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;279:1304–9.PubMedCrossRefGoogle Scholar
  92. 92.
    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:e27–31.PubMedCrossRefGoogle Scholar
  93. 93.
    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;105:2893–8.PubMedCrossRefGoogle Scholar
  94. 94.
    Wang Y, Lam KS, Xu JY, et al. Adiponectin inhibits cell proliferation by interacting with several growth factors in an oligomerization-dependent manner. J Biol Chem. 2005;280:18341–7.PubMedCrossRefGoogle Scholar
  95. 95.
    Okamoto Y, Kihara S, Ouchi N, et al. Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice. Circulation. 2002;106:2767–70.PubMedCrossRefGoogle Scholar
  96. 96.
    Yamauchi T, Kamon J, Waki H, et al. Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis. J Biol Chem. 2003;278:2461–8.PubMedCrossRefGoogle Scholar
  97. 97.
    Shibata R, Ouchi N, Ito M, et al. Adiponectin-mediated modulation of hypertrophic signals in the heart. Nat Med. 2004;10:1384–9.PubMedCrossRefGoogle Scholar
  98. 98.
    Chan AY, Soltys CL, Young ME, Proud CG, Dyck JR. Activation of AMP-activated protein kinase inhibits protein synthesis associated with hypertrophy in the cardiac myocyte. J Biol Chem. 2004;279:32771–9.PubMedCrossRefGoogle Scholar
  99. 99.
    Shibata R, Sato K, Pimentel DR, et al. Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2-dependent mechanisms. Nat Med. 2005;11:1096–103.PubMedCrossRefGoogle Scholar
  100. 100.
    Kudo N, Gillespie JG, Kung L, et al. Characterization of 5′-AMP-activated protein kinase activity in the heart and its role in inhibiting acetyl-CoA carboxylase during reperfusion following ischemia. Biochim Biophys Acta. 1996;1301:67–75.PubMedGoogle Scholar
  101. 101.
    Makinde AO, Gamble J, Lopaschuk GD. Upregulation of 5′-AMP-activated protein kinase is responsible for the increase in myocardial fatty acid oxidation rates following birth in the newborn rabbit. Circ Res. 1997;80:482–9.PubMedGoogle Scholar
  102. 102.
    Considine RV, Sinha MK, Heiman ML, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med. 1996;334:292–5.PubMedCrossRefGoogle Scholar
  103. 103.
    Löllmann B, Grüninger S, Stricker-Krongrad A, Chiesi M. Detection and quantification of the leptin receptor splice variants Ob-Ra, b, and, e in different mouse tissues. Biochem Biophys Res Commun. 1997;238:648–52.PubMedCrossRefGoogle Scholar
  104. 104.
    Bohlen F, Kratzsch J, Mueller M, et al. Leptin inhibits cell growth of human vascular smooth muscle cells. Vascul Pharmacol. 2007;46:67–71.PubMedCrossRefGoogle Scholar
  105. 105.
    Bouloumié A, Drexler HC, Lafontan M, Busse R. Leptin, the product of Ob gene, promotes angiogenesis. Circ Res. 1998;83:1059–66.PubMedGoogle Scholar
  106. 106.
    Sierra-Honigmann MR, Nath AK, Murakami C, et al. Biological action of leptin as an angiogenic factor. Science. 1998;281:1683–6.PubMedCrossRefGoogle Scholar
  107. 107.
    Smith CC, Mocanu MM, Davidson SM, Wynne AM, Simpkin JC, Yellon DM. Leptin, the obesity-associated hormone, exhibits direct cardioprotective effects. Br J Pharmacol. 2006;149:5–13.PubMedCrossRefGoogle Scholar
  108. 108.
    Matsui H, Motooka M, Koike H, et al. Ischemia/reperfusion in rat heart induces leptin and leptin receptor gene expression. Life Sci. 2007;80:672–80.PubMedCrossRefGoogle Scholar
  109. 109.
    Rajapurohitam V, Javadov S, Purdham DM, Kirshenbaum LA, Karmazyn M. An autocrine role for leptin in mediating the cardiomyocyte hypertrophic effects of angiotensin II and endothelin-1. J Mol Cell Cardiol. 2006;41:265–74.PubMedCrossRefGoogle Scholar
  110. 110.
    Yang R, Barouch LA. Leptin signaling and obesity: cardiovascular consequences. Circ Res. 2007;101:545–59.PubMedCrossRefGoogle Scholar
  111. 111.
    Shin HJ, Oh J, Kang SM, et al. Leptin induces hypertrophy via p38 mitogen-activated protein kinase in rat vascular smooth muscle cells. Biochem Biophys Res Commun. 2005;329:18–24.PubMedCrossRefGoogle Scholar
  112. 112.
    Rajapurohitam V, Gan XT, Kirshenbaum LA, Karmazyn M. The obesity-associated peptide leptin induces hypertrophy in neonatal rat ventricular myocytes. Circ Res. 2003;93:277–9.PubMedCrossRefGoogle Scholar
  113. 113.
    Gnanapavan S, Kola B, Bustin SA, et al. The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans (Abstract). J Clin Endocrinol Metab. 2002;87:2988.PubMedCrossRefGoogle Scholar
  114. 114.
    Cao JM, Ong H, Chen C. Effects of ghrelin and synthetic GH secretagogues on the cardiovascular system. Trends Endocrinol Metab. 2006;17:13–8.PubMedCrossRefGoogle Scholar
  115. 115.
    Iantorno M, Chen H, Kim JA, et al. Ghrelin has novel vascular actions that mimic PI3-kinase-dependent actions of insulin to stimulate production of NO from endothelial cells. Am J Physiol Endocrinol Metab. 2006;292:E756–64.PubMedCrossRefGoogle Scholar
  116. 116.
    Poykko SM, Kellokoski E, Horkko S, Kauma H, Kesaniemi YA, Ukkola O. Low plasma ghrelin is associated with insulin resistance, hypertension, and the prevalence of type 2 diabetes. Diabetes. 2003;52:2546–53.PubMedCrossRefGoogle Scholar
  117. 117.
    Mager U, Lindi V, Lindstrom J, et al. Association of the Leu72Met polymorphism of the ghrelin gene with the risk of type 2 diabetes in subjects with impaired glucose tolerance in the Finnish Diabetes Prevention Study. Diabet Med. 2006;23:685–9.PubMedCrossRefGoogle Scholar
  118. 118.
    Tesauro M, Schinzari F, Iantorno M, et al. Ghrelin improves endothelial function in patients with metabolic syndrome. Circulation. 2005;112:2986–92.PubMedGoogle Scholar
  119. 119.
    Fukuchi S, Hamaguchi K, Seike M, Himeno K, Sakata T, Yoshimatsu H. Role of fatty acid composition in the development of metabolic disorders in sucrose-induced obese rats. Exp Biol Med. 2004;229:486–93.Google Scholar
  120. 120.
    Weisberg S, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante Jr AW. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112:1796–808.PubMedGoogle Scholar
  121. 121.
    Hu E, Kim JB, Sarraf P, Spiegelman BM. Inhibition of adipogenesis through MAP kinase-mediated phosphorylation of PPARγ. Science. 1996;274:2100–3.PubMedCrossRefGoogle Scholar
  122. 122.
    Adams M, Reginato MJ, Shao D, Lazar MA, Chatterjee VK. Transcriptional activation by peroxisome proliferator-activated receptor γ is inhibited by phosphorylation at a consensus mitogen-activated protein kinase site. J Biol Chem. 1997;272:5128–32.PubMedCrossRefGoogle Scholar
  123. 123.
    Jain RG, Phelps KD, Pekala PH. Tumor necrosis factor-α initiated signal transduction in 3T3-L1 adipocytes. J Cell Physiol. 1999;179:58–66.PubMedCrossRefGoogle Scholar
  124. 124.
    Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-α- and obesity-induced insulin resistance. Science. 1996;271:665–8.PubMedCrossRefGoogle Scholar
  125. 125.
    Zick Y. Ser/Thr phosphorylation of IRS proteins: a molecular basis for insulin resistance. Sci STKE. 2005;2005(pe4):1–3.Google Scholar
  126. 126.
    Engelman JA, Berg AH, Lewis RY, Lisanti MP, Scherer PE. Tumor necrosis factor α-mediated insulin resistance, but not dedifferentiation, is abrogated by MEK1/2 inhibitors in 3T3-L1 adipocytes. Mol Endocrinol. 2000;14:1557–69.PubMedCrossRefGoogle Scholar
  127. 127.
    Aguirre V, Uchida T, Yenush L, Davis R, White MF. The c-Jun NH2-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser307. J Biol Chem. 2000;275:9047–54.PubMedCrossRefGoogle Scholar
  128. 128.
    Kellerer M, Mushack J, Seffer E, Mischak H, Ullrich A, Häring HU. Protein kinase C isoforms α, δ and θ require insulin receptor substrate-1 to inhibit the tyrosine kinase activity of the insulin receptor in human kidney embryonic cells (HEK 293 cells). Diabetologia. 1998;41:833–8.PubMedCrossRefGoogle Scholar
  129. 129.
    Gao Z, Hwang D, Bataille F, et al. Serine phosphorylation of insulin receptor substrate 1 by inhibitor κB kinase complex. J Biol Chem. 2002;277:48115–21.PubMedCrossRefGoogle Scholar
  130. 130.
    Nachiappan V, Curtiss D, Corkey BE, Kilpatrick L. Cytokines inhibit fatty acid oxidation in isolated rat hepatocytes: synergy among TNF, IL-6, and IL-1. Shock. 1994;1:123–9.PubMedCrossRefGoogle Scholar
  131. 131.
    Steinberg GR, Michell BJ, van Denderen BJ, et al. Tumor necrosis factor α-induced skeletal muscle insulin resistance involves suppression of AMP-kinase signaling. Cell Metab. 2006;4:465–74.PubMedCrossRefGoogle Scholar
  132. 132.
    Ioannidis I. The road from obesity to type 2 diabetes. Angiology. 2008;59 Suppl 2:39S–43.PubMedCrossRefGoogle Scholar
  133. 133.
    Haasch D, Berg C, Clampit JE, et al. PKCθ is a key player in the development of insulin resistance. Biochem Biophys Res Commun. 2006;343:361–8.PubMedCrossRefGoogle Scholar
  134. 134.
    Degawa-Yamauchi M, Moss KA, Bovenkerk JE, et al. Regulation of adiponectin expression in human adipocytes: effects of adiposity, glucocorticoids, and tumor necrosis factor α. Obes Res. 2005;13:662–9.PubMedCrossRefGoogle Scholar
  135. 135.
    Laffitte BA, Chao LC, Li J, et al. Activation of liver X receptor improves glucose tolerance through coordinate regulation of glucose metabolism in liver and adipose tissue. Proc Natl Acad Sci USA. 2003;100:5419–24.PubMedCrossRefGoogle Scholar
  136. 136.
    Peet DJ, Turley SD, Ma W, et al. Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXRα. Cell. 1998;93:693–704.PubMedCrossRefGoogle Scholar
  137. 137.
    Schultz JR, Tu H, Luk A, et al. Role of LXRs in control of lipogenesis. Genes Dev. 2000;14:2831–8.PubMedCrossRefGoogle Scholar
  138. 138.
    Xu H, Barnes GT, Yang Q, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003;112:1821–30.PubMedGoogle Scholar
  139. 139.
    Weisberg SP, McCann D, Desai M, et al. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112:1796–808.PubMedGoogle Scholar
  140. 140.
    Venkateswaran A, Lafitte BA, Joseph SB, et al. Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXRα. Proc Natl Acad Sci USA. 2000;97:12097–102.PubMedCrossRefGoogle Scholar
  141. 141.
    Lehmann JM, Moore LB, Smith-Oliver TA, et al. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor γ. J Biol Chem. 1995;270:12953–6.PubMedCrossRefGoogle Scholar
  142. 142.
    Willson TM, Cobb JE, Cowan DJ, et al. The structure-activity relationship between peroxisome proliferatoractivated receptor γ agonism and the antihyperglycemic activity of thiazolidinediones. J Med Chem. 1996;39:665–8.PubMedCrossRefGoogle Scholar
  143. 143.
    Forman BM, Chen J, Evans RM. Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors α and δ. Proc Natl Acad Sci USA. 1997;94:4312–7.PubMedCrossRefGoogle Scholar
  144. 144.
    Huss JM, Levy FH, Kelly DP. Hypoxia inhibits the peroxisome proliferator-activated receptor α/retinoid X receptor gene regulatory pathway in cardiac myocytes: a mechanism for O2-dependent modulation of mitochondrial fatty acid oxidation. J Biol Chem. 2001;276:27605–12.PubMedCrossRefGoogle Scholar
  145. 145.
    Gilde AJ, van der Lee KA, Willemsen PH, et al. Peroxisome proliferator-activated receptor (PPAR) α and PPARβ/δ, but not PPARγ, modulate the expression of genes involved in cardiac lipid metabolism. Circ Res. 2003;92:518–24.PubMedCrossRefGoogle Scholar
  146. 146.
    Aasum E, Belke DD, Severson DL, et al. Cardiac function and metabolism in Type 2 diabetic mice after treatment with BM 17.0744, a novel PPAR-α activator. Am J Physiol Heart Circ Physiol. 2002;283:H949–57.PubMedGoogle Scholar
  147. 147.
    Dashti N, Ontko JA. Alterations in rat serum lipids and apolipoproteins following clofibrate treatment. Atherosclerosis. 1983;49:255–66.PubMedCrossRefGoogle Scholar
  148. 148.
    Cheng L, Ding G, Qin Q, et al. Cardiomyocyte-restricted peroxisome proliferator-activated receptor δ deletion perturbs myocardial fatty acid oxidation and leads to cardiomyopathy. Nat Med. 2004;10:1245–50.PubMedCrossRefGoogle Scholar
  149. 149.
    Hevener A, He W, Barak Y, et al. Muscle-specific PPAR γ deletion causes insulin resistance. Nat Med. 2003;9:1491–7.PubMedCrossRefGoogle Scholar
  150. 150.
    He W, Barak Y, Hevener A, et al. Adipose-specific peroxisome proliferator-activated receptor γ knockout causes insulin resistance in fat and liver but not in muscle. Proc Natl Acad Sci USA. 2003;100:15712–7.PubMedCrossRefGoogle Scholar
  151. 151.
    Moore KJ, Rosen ED, Fitzgerald ML, et al. The role of PPAR-γ in macrophage differentiation and cholesterol uptake. Nat Med. 2001;7:41–7.PubMedCrossRefGoogle Scholar
  152. 152.
    Chawla A, Barak Y, Nagy L, et al. PPAR-γ dependent and independent effects on macrophage gene expression in lipid metabolism and inflammation. Nat Med. 2001;7:48–52.PubMedCrossRefGoogle Scholar
  153. 153.
    Lehman JJ, Barger PM, Kovacs A, Saffitz JE, Medeiros DM, Kelly DP. Peroxisome proliferator-activated receptor γ coactivator-1 promotes cardiac mitochondrial biogenesis. J Clin Invest. 2000;106:847–56.PubMedCrossRefGoogle Scholar
  154. 154.
    Huss JM, Torra IP, Staels B, Giguere V, Kelly DP. Estrogen-related receptor α directs peroxisome proliferator-activated receptor α signaling in the transcriptional control of energy metabolism in cardiac and skeletal muscle. Mol Cell Biol. 2004;24:9079–91.PubMedCrossRefGoogle Scholar
  155. 155.
    Russell LK, Mansfield CM, Lehman JJ, et al. Cardiac-specific induction of the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1α promotes mitochondrial biogenesis and reversible cardiomyopathy in a developmental stage-dependent manner. Circ Res. 2004;94:525–33.PubMedCrossRefGoogle Scholar
  156. 156.
    Arany Z, He H, Lin J, et al. Transcriptional coactivator PGC-1α controls the energy state and contractile function of cardiac muscle. Cell Metab. 2005;1:259–71.PubMedCrossRefGoogle Scholar
  157. 157.
    Sowers JR. Insulin resistance and hypertension. Am J Physiol Heart Circ Physiol. 2004;286:H1597–602.PubMedCrossRefGoogle Scholar
  158. 158.
    Manrique C, Lastra G, Whaley-Connell A, Sowers JR. Hypertension and the cardiometabolic syndrome. J Clin Hypertens. 2005;7:471–6.CrossRefGoogle Scholar
  159. 159.
    Wei Y, Stump CS, Habibi J, et al. NADPH oxidase activation contributes to vascular inflammation, insulin resistance, and remodeling in the transgenic (mRen2) rat. Hypertension. 2007;50:384–91.PubMedCrossRefGoogle Scholar
  160. 160.
    Nathan C. Specificity of a third kind: reactive oxygen and nitrogen intermediates in cell signaling. J Clin Invest. 2003;111:769–78.PubMedGoogle Scholar
  161. 161.
    Muller DN, Dechend R, Mervaala EM, et al. NF-κB inhibition ameliorates angiotensin II-induced inflammatory damage in rats. Hypertension. 2000;35:193–201.PubMedGoogle Scholar
  162. 162.
    Kim JA, Yeh DC, Ver M, et al. Phosphorylation of Ser24 in the pleckstrin homology domain of insulin receptor substrate-1 by mouse Pelle-like kinase/interleukin-1 receptor-associated kinase: cross-talk between inflammatory signaling and insulin signaling that may contribute to insulin resistance. J Biol Chem. 2005;280:23173–83.PubMedCrossRefGoogle Scholar
  163. 163.
    Reusch JE. Diabetes, microvascular complications, and cardiovascular complications: what is it about glucose? J Clin Invest. 2003;112:986–8.PubMedGoogle Scholar
  164. 164.
    Wang XL, Zhang L, Youker K, et al. Free fatty acids inhibit insulin signaling-stimulated endothelial nitric oxide synthase activation through upregulating PTEN or inhibiting Akt kinase. Diabetes. 2006;55:2301–10.PubMedCrossRefGoogle Scholar
  165. 165.
    Inoguchi T, Li P, Umeda F, et al. High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C-dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes. 2000;49:1939–45.PubMedCrossRefGoogle Scholar
  166. 166.
    Lastra G, Manrique CM, Stump CS, et al. Low-dose spironolactone reduces reactive oxygen species generation and improves insulin-stimulated glucose transport in skeletal muscle in TGR(mRen-2)27 rats. Am J Physiol Endocrinol Metab. 2008;295:E110–6.PubMedCrossRefGoogle Scholar
  167. 167.
    Seager MJ, Singal PK, Orchard R, Pierce GN, Dhalla NS. Cardiac cell damage: a primary myocardial disease in streptozotocin-induced chronic diabetes. Br J Exp Pathol. 1984;65:613–23.PubMedGoogle Scholar
  168. 168.
    Mokhtar N, Lavoie JP, Rousseau-Migneron S, Nadeau A. Physical training reverses defect in mitochondrial energy production in heart of chronically diabetic rats. Diabetes. 1993;42:682–7.PubMedCrossRefGoogle Scholar
  169. 169.
    Tomita M, Mukae S, Geshi E, Umetsu K, Nakatani M, Katagiri T. Mitochondrial respiratory impairment in streptozotocin induced diabetic rat heart. Jpn Circ J. 1996;60:673–82.PubMedCrossRefGoogle Scholar
  170. 170.
    Kong JY, Rabkin SW. Mitochondrial effects with ceramide-induced cardiac apoptosis are different from those of palmitate. Arch Biochem Biophys. 2003;412:196–206.PubMedCrossRefGoogle Scholar
  171. 171.
    Hickson-Bick DL, Buja ML, McMillin JB. Palmitate-mediated alterations in the fatty acid metabolism of rat neonatal cardiac myocytes. J Mol Cell Cardiol. 2000;32:511–9.PubMedCrossRefGoogle Scholar
  172. 172.
    Sparagna GC, Hickson-Bick DL, Buja LM, McMillin JB. Fatty acid-induced apoptosis in neonatal cardiomyocytes: redox signaling. Antioxid Redox Signal. 2001;3:71–9.PubMedCrossRefGoogle Scholar
  173. 173.
    Sparagna GC, Hickson-Bick DL, Buja LM, McMillin JB. A metabolic role for mitochondria in palmitate-induced cardiac myocyte apoptosis. Am J Physiol Heart Circ Physiol. 2000;279:H2124–32.PubMedGoogle Scholar
  174. 174.
    Hickson-Bick DL, Sparagna GC, Buja LM, McMillin JB. Palmitate-induced apoptosis in neonatal cardiomyocytes is not dependent on the generation of ROS. Am J Physiol Heart Circ Physiol. 2002;282:H656–64.PubMedGoogle Scholar
  175. 175.
    Williams SD, Gottlieb RA. Inhibition of mitochondrial calcium-independent phospholipase A2 (iPLA2) attenuates mitochondrial phospholipid loss and is cardioprotective. Biochem J. 2002;362:23–32.PubMedCrossRefGoogle Scholar
  176. 176.
    Nishikawa T, Edelstein D, Du XL, et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature. 2000;404:787–90.PubMedCrossRefGoogle Scholar
  177. 177.
    Verma S, Li SH, Badiwala MV, et al. Endothelin antagonism and interleukin-6 inhibition attenuate the proatherogenic effects of C-reactive protein. Circulation. 2002;105:1890–6.PubMedCrossRefGoogle Scholar
  178. 178.
    Du XL, Edelstein D, Rossetti L, et al. Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci USA. 2000;97:12222–6.PubMedCrossRefGoogle Scholar
  179. 179.
    Kohler HP, Grant PJ. Plasminogen-activator inhibitor type 1 and coronary artery disease. N Engl J Med. 2000;342:1792–801.PubMedCrossRefGoogle Scholar
  180. 180.
    Bobik A. Transforming growth factor-betas and vascular disorders. Arterioscler Thromb Vasc Biol. 2006;26:1712–20.PubMedCrossRefGoogle Scholar
  181. 181.
    Du X, Matsumura T, Edelstein D, et al. Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J Clin Invest. 2003;112:1049–57.PubMedGoogle Scholar
  182. 182.
    Mabile L, Meilhac O, Escargueil-Blanc I, et al. Mitochondrial function is involved in LDL oxidation mediated by human cultured endothelial cells. Arterioscler Thromb Vasc Biol. 1997;17:1575–82.PubMedCrossRefGoogle Scholar
  183. 183.
    Honda HM, Korge P, Weiss JN. Mitochondria and ischemia/reperfusion injury. Ann N Y Acad Sci. 2005;1047:248–58.PubMedCrossRefGoogle Scholar
  184. 184.
    Recchioni R, Marcheselli F, Moroni F, Pieri C. Apoptosis in human aortic endothelial cells induced by hyperglycemic condition involves mitochondrial depolarization and is prevented by N-acetyl-l-cysteine. Metabolism. 2002;51:1384–8.PubMedCrossRefGoogle Scholar
  185. 185.
    Koster JC, Permutt MA, Nichols CG. Diabetes and Insulin Secretion: The ATP-Sensitive K+ Channel (KATP) Connection. Diabetes. 2005;54:3065–72.PubMedCrossRefGoogle Scholar
  186. 186.
    Hattersley AT, Ashcroft FM. Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy. Diabetes. 2005;54:2503–13.PubMedCrossRefGoogle Scholar
  187. 187.
    Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, et al. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med. 2004;350:1838–49.PubMedCrossRefGoogle Scholar
  188. 188.
    Sperling MA. Neonatal diabetes mellitus: from understudy to center stage. Curr Opin Pediatr. 2005;17:512–8.PubMedCrossRefGoogle Scholar
  189. 189.
    Gloyn AL, Weedon MN, Owen KR, Turner MJ, Knight BA, Hitman G, et al. Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Diabetes. 2003;52:568–72.PubMedCrossRefGoogle Scholar
  190. 190.
    Riedel MJ, Steckley DC, Light PE. Current status of the E23K Kir6.2 polymorphism: implications for type-2 diabetes. Hum Genet. 2005;116:133–45.PubMedCrossRefGoogle Scholar
  191. 191.
    Riedel MJ, Boora P, Steckley D, de Vries G, Light PE. Kir6.2 polymorphisms sensitize beta-cell ATP-sensitive potassium channels to activation by acyl CoAs: a possible cellular mechanism for increased susceptibility to type 2 diabetes? Diabetes. 2003;52:2630–5.PubMedCrossRefGoogle Scholar
  192. 192.
    Slingerland AS, Hattersley AT. Mutations in the Kir6.2 subunit of the KATP channel and permanent neonatal diabetes: new insights and new treatment. Ann Med. 2005;37:186–95.PubMedCrossRefGoogle Scholar
  193. 193.
    Malecki MT. Genetics of type 2 diabetes mellitus. Diab Res Clin Pract. 2005;68:S10–21.CrossRefGoogle Scholar
  194. 194.
    Gupta RK, Kaestner KH. HNF-4alpha: from MODY to late-onset type 2 diabetes. Trends Mol Med. 2004;10:521–4.PubMedCrossRefGoogle Scholar
  195. 195.
    Gloyn AL. Glucokinase (GCK) mutations in hyper- and hypoglycemia: maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemia of infancy. Hum Mutat. 2003;22:353–62.PubMedCrossRefGoogle Scholar
  196. 196.
    Mitchell SM, Frayling TM. The role of transcription factors in maturity-onset diabetes of the young. Mol Genet Metab. 2002;77:35–43.PubMedCrossRefGoogle Scholar
  197. 197.
    George S, Rochford JJ, Wolfrum C, Gray SL, Schinner S, Wilson JC, et al. A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science. 2004;304:1325–8.PubMedCrossRefGoogle Scholar
  198. 198.
    Hone J, Accili D, al-Gazali LI, Lestringant G, Orban T, Taylor SI. Homozygosity for a new mutation (Ile119–>Met) in the insulin receptor gene in five sibs with familial insulin resistance. J Med Genet. 1994;31:715–6.PubMedCrossRefGoogle Scholar
  199. 199.
    Kusari J, Takata Y, Hatada E, Freidenberg G, Kolterman O, Olefsky JM. Insulin resistance and diabetes due to different mutations in the tyrosine kinase domain of both insulin receptor gene alleles. J Biol Chem. 1991;266:5260–7.PubMedGoogle Scholar
  200. 200.
    Musso C, Cochran E, Moran SA, Skarulis MC, Oral EA, Taylor S, et al. Clinical course of genetic diseases of the insulin receptor (type A and Rabson-Mendenhall syndromes): a 30-year prospective. Medicine. 2004;83:209–22.PubMedCrossRefGoogle Scholar
  201. 201.
    Shen X, Zheng S, Thongboonkerd V, Xu M, Pierce Jr WM, Klein JB, et al. Cardiac mitochondrial damage and biogenesis in a chronic model of type 1 diabetes. Am J Physiol Endocrinol Metab. 2004;287:E896–905.PubMedCrossRefGoogle Scholar
  202. 202.
    Ferreira FM, Seica R, Oliveira PJ, Coxito PM, Moreno AJ, Palmeira CM, et al. Diabetes induces metabolic adaptations in rat liver mitochondria: role of coenzyme Q and cardiolipin contents. Biochim Biophys Acta. 2003;1639:113–8.PubMedGoogle Scholar
  203. 203.
    Ritov VB, Menshikova EV, He J, Ferrell RE, Goodpaster BH, Kelley DE. Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes. Diabetes. 2005;54:8–14.PubMedCrossRefGoogle Scholar
  204. 204.
    Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med. 2004;350:664–71.PubMedCrossRefGoogle Scholar
  205. 205.
    Silva JP, Kohler M, Graff C, Oldfors A, Magnuson MA, Berggren PO, et al. Impaired insulin secretion and beta-cell loss in tissue-specific knockout mice with mitochondrial diabetes. Nat Genet. 2000;26:336–40.PubMedCrossRefGoogle Scholar
  206. 206.
    Brownlee M. A radical explanation for glucose-induced beta cell dysfunction. J Clin Invest. 2003;112:1788–90.PubMedGoogle Scholar
  207. 207.
    Lowell BB, Shulman GI. Mitochondrial dysfunction and type 2 diabetes. Science. 2005;307:384–7.PubMedCrossRefGoogle Scholar
  208. 208.
    Stumvoll M, Goldstein BJ, van Haeften TW. Type 2 diabetes: principles of pathogenesis and therapy. Lancet. 2005;365:1333–46.PubMedCrossRefGoogle Scholar
  209. 209.
    Malecki MT. Genetics of type 2 diabetes mellitus. Diab Res Clin Pract. 2005;68:S10–21.CrossRefGoogle Scholar
  210. 210.
    Kelly MA, Mijovic CH, Barnett AH. Genetics of type 1 diabetes. Best Pract Res Clin Endocrinol Metab. 2001;15:279–91.PubMedCrossRefGoogle Scholar
  211. 211.
    Achenbach P, Bonifacio E, Ziegler AG. Predicting type 1 diabetes. Curr Diab Rep. 2005;5:98–103.PubMedCrossRefGoogle Scholar
  212. 212.
    Kavvoura FK, Ioannidis JP. CTLA-4 gene polymorphisms and susceptibility to type 1 diabetes mellitus: a HuGE Review and meta-analysis. Am J Epidemiol. 2005;162:3–16.PubMedCrossRefGoogle Scholar
  213. 213.
    Bottini N, Musumeci L, Alonso A, Rahmouni S, Nika K, Rostamkhani M, et al. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet. 2004;36:337–8.PubMedCrossRefGoogle Scholar
  214. 214.
    Mathieu C, Badenhoop K. Vitamin D and type 1 diabetes mellitus: state of the art. Trends Endocrinol Metab. 2005;16:261–6.PubMedCrossRefGoogle Scholar
  215. 215.
    Luong K, Nguyen LT, Nguyen DN. The role of vitamin D in protecting type 1 diabetes mellitus. Diab Metab Res Rev. 2005;21:338–46.CrossRefGoogle Scholar
  216. 216.
    Pollex RL, Mamakeesick M, Zinman B, Harris SB, Hanley AJ, Hegele RA. Methylenetetrahydrofolate reductase polymorphism 677C>T is associated with peripheral arterial disease in type 2 diabetes. Cardiovasc Diabetol. 2005;4:17.PubMedCrossRefGoogle Scholar
  217. 217.
    Maeda S, Tsukada S, Kanazawa A, Sekine A, Tsunoda T, Koya D, et al. Genetic variations in the gene encoding TFAP2B are associated with type 2 diabetes mellitus. J Hum Genet. 2005;50:283–92.PubMedCrossRefGoogle Scholar
  218. 218.
    Vimaleswaran KS, Radha V, Ghosh S, Majumder PP, Deepa R, Babu HN, et al. Peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PGC-1alpha) gene polymorphisms and their relationship to Type 2 diabetes in Asian Indians. Diabet Med. 2005;22:1516–21.PubMedCrossRefGoogle Scholar
  219. 219.
    Ek J, Andersen G, Urhammer SA, Gaede PH, Drivsholm T, Borch-Johnsen K, et al. Mutation analysis of peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) and relationships of identified amino acid polymorphisms to Type II diabetes mellitus. Diabetologia. 2001;44:2220–6.PubMedCrossRefGoogle Scholar
  220. 220.
    Nicaud V, Raoux S, Poirier O, Cambien F, O’Reilly DS, Tiret L. The TNF alpha/G-308A polymorphism influences insulin sensitivity in offspring of patients with coronary heart disease: the European Atherosclerosis Research Study II. Atherosclerosis. 2002;161:317–25.PubMedCrossRefGoogle Scholar
  221. 221.
    Vendrell J, Fernandez-Real JM, Gutierrez C, Zamora A, Simon I, Bardaji A, et al. A polymorphism in the promoter of the tumor necrosis factor-alpha gene (-308) is associated with coronary heart disease in type 2 diabetic patients. Atherosclerosis. 2003;167:257–64.PubMedCrossRefGoogle Scholar
  222. 222.
    Florez JC, Burtt N, de Bakker PI, Almgren P, Tuomi T, Holmkvist J, et al. Haplo-type structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region. Diabetes. 2004;53:1360–8.PubMedCrossRefGoogle Scholar
  223. 223.
    Hayes MG, Del Bosque-Plata L, Tsuchiya T, Hanis CL, Bell GI, Cox NJ. Patterns of linkage disequilibrium in the type 2 diabetes gene calpain-10. Diabetes. 2005;54:3573–6.PubMedCrossRefGoogle Scholar
  224. 224.
    Evans JC, Frayling TM, Cassell PG, Saker PJ, Hitman GA, Walker M, et al. Studies of association between the gene for calpain-10 and type 2 diabetes mellitus in the United Kingdom. Am J Hum Genet. 2001;69:544–52.PubMedCrossRefGoogle Scholar
  225. 225.
    Liang H, Murase Y, Katuta Y, Asano A, Kobayashi J, Mabuchi H. Association of LMNA 1908C/T polymorphism with cerebral vascular disease and diabetic nephropathy in Japanese men with type 2 diabetes. Clin Endocrinol. 2005;63:317–22.CrossRefGoogle Scholar
  226. 226.
    Armstrong M, Haldane F, Taylor RW, Humphriss D, Berrish T, Stewart MW, et al. Human insulin receptor substrate-1: variant sequences in familial non-insulin-dependent diabetes mellitus. Diabet Med. 1996;13:133–8.PubMedCrossRefGoogle Scholar
  227. 227.
    Jellema A, Zeegers MP, Feskens EJ, Dagnelie PC, Mensink RP. Gly972Arg variant in the insulin receptor substrate-1 gene and association with Type 2 diabetes: a meta-analysis of 27 studies. Diabetologia. 2003;46:990–5.PubMedCrossRefGoogle Scholar
  228. 228.
    Zacharova J, Chiasson JL. STOP-NIDDM Study Group. The common polymorphisms (single nucleotide polymorphism [SNP] +45 and SNP +276) of the adiponectin gene predict the conversion from impaired glucose tolerance to type 2 diabetes: the STOP-NIDDM trial. Diabetes. 2005;54:893–9.PubMedCrossRefGoogle Scholar
  229. 229.
    Bacci S, Menzaghi C, Ercolino T, Ma X, Rauseo A, Salvemini L, et al. The +276 G/T single nucleotide polymorphism of the adiponectin gene is associated with coronary artery disease in type 2 diabetic patients. Diab Care. 2004;27:2015–20.CrossRefGoogle Scholar
  230. 230.
    Ukkola O, Santaniemi M, Rankinen T, Leon AS, Skinner JS, Wilmore JH, et al. Adiponectin polymorphisms, adiposity and insulin metabolism: HERITAGE family study and Oulu diabetic study. Ann Med. 2005;37:141–50.PubMedCrossRefGoogle Scholar
  231. 231.
    Mori H, Ikegami H, Kawaguchi Y, Seino S, Yokoi N, Takeda J, et al. The Pro12®Ala substitution in PPAR-gamma is associated with resistance to development of diabetes in the general population: possible involvement in impairment of insulin secretion in individuals with type 2 diabetes. Diabetes. 2001;50:891–4.PubMedCrossRefGoogle Scholar
  232. 232.
    Doney AS, Fischer B, Leese G, Morris AD, Palmer CN. Cardiovascular risk in type 2 diabetes is associated with variation at the PPARG locus: a Go-DARTS study. Arterioscler Thromb Vasc Biol. 2004;24:2403–7.PubMedCrossRefGoogle Scholar
  233. 233.
    Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC, Nemesh J, et al. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet. 2000;26:76–80.PubMedCrossRefGoogle Scholar
  234. 234.
    Nistico L, Buzzetti R, Pritchard LE, Van der Auwera B, Giovannini C, Bosi E, et al. The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes Registry. Hum Mol Genet. 1996;5:1075–80.PubMedCrossRefGoogle Scholar
  235. 235.
    Van der Auwera BJ, Vandewalle CL, Schuit FC, Winnock F, De Leeuw IH, Van Imschoot S, et al. CTLA-4 gene polymorphism confers susceptibility to insulin-dependent diabetes mellitus (IDDM) independently from age and from other genetic or immune disease markers. The Belgian Diabetes Registry. Clin Exp Immunol. 1997;110:98–103.PubMedCrossRefGoogle Scholar
  236. 236.
    Redondo MJ, Fain PR, Eisenbarth GS. Genetics of type 1A diabetes. Recent Prog Horm Res. 2001;56:69–89.PubMedCrossRefGoogle Scholar
  237. 237.
    Erlich HA. HLA class II sequences and genetic susceptibility to insulin dependent diabetes mellitus. Baillières Clin Endocrinol Metab. 1991;5:395–411.PubMedCrossRefGoogle Scholar
  238. 238.
    Kennedy GC, German MS, Rutter WJ. The minisatellite in the diabetes susceptibility locus IDDM2 regulates insulin transcription. Nat Genet. 1995;9:293–8.PubMedCrossRefGoogle Scholar
  239. 239.
    Bell GI, Horita S, Karam JH. A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus. Diabetes. 1984;33:176–83.PubMedCrossRefGoogle Scholar
  240. 240.
    Steinle NI, Kazlauskaite R, Imumorin IG, Hsueh WC, Pollin TI, O’Connell JR, et al. Variation in the lamin A/C gene: associations with metabolic syndrome. Arterioscler Thromb Vasc Biol. 2004;24:1708–13.PubMedCrossRefGoogle Scholar
  241. 241.
    Murase Y, Yagi K, Katsuda Y, Asano A, Koizumi J, Mabuchi H. An LMNA variant is associated with dyslipidemia and insulin resistance in the Japanese. Metabolism. 2002;51:1017–21.PubMedCrossRefGoogle Scholar
  242. 242.
    Caux F, Dubosclard E, Lascols O, Buendia B, Chazouilleres O, Cohen A, et al. A new clinical condition linked to a novel mutation in lamins A and C with generalized lipoatrophy, insulin-resistant diabetes, disseminated leukomelanodermic papules, liver steatosis, and cardiomyopathy. J Clin Endocrinol Metab. 2003;88:1006–13.PubMedCrossRefGoogle Scholar
  243. 243.
    Ukkola O, Rankinen T, Lakka T, Leon AS, Skinner JS, Wilmore JH, et al. Protein tyrosine phosphatase 1B variant associated with fat distribution and insulin metabolism. Obes Res. 2005;13:829–34.PubMedCrossRefGoogle Scholar
  244. 244.
    Spencer-Jones NJ, Wang X, Snieder H, Spector TD, Carter ND, O’Dell SD. Protein tyrosine phosphatase-1B gene PTPN1: selection of tagging single nucleotide polymorphisms and association with body fat, insulin sensitivity, and the metabolic syndrome in a normal female population. Diabetes. 2005;54:3296–304.PubMedCrossRefGoogle Scholar
  245. 245.
    Palmer ND, Bento JL, Mychaleckyj JC, Langefeld CD, Campbell JK, Norris JM, Haffner SM, Bergman RN, Bowden DW; insulin resistance atherosclerosis study (IRAS) family study. Association of protein tyrosine phosphatase 1B gene polymorphisms with measures of glucose homeostasis in Hispanic Americans: the insulin resistance atherosclerosis study (IRAS) family study. Diabetes. 2004;53:3013–19Google Scholar
  246. 246.
    Manraj M, Francke S, Hebe A, Ramjuttun US, Froguel P. Genetic and environmental nature of the insulin resistance syndrome in Indo-Mauritian subjects with premature coronary heart disease: contribution of beta3-adrenoreceptor gene polymorphism and beta blockers on triglyceride and HDL concentrations. Diabetologia. 2001;44:115–22.PubMedCrossRefGoogle Scholar
  247. 247.
    Strazzullo P, Iacone R, Siani A, Cappuccio FP, Russo O, Barba G, et al. Relationship of the Trp64Arg polymorphism of the beta3-adrenoceptor gene to central adiposity and high blood pressure: interaction with age. Cross-sectional and longitudinal findings of the Olivetti Prospective Heart Study. J Hypertens. 2001;19:399–406.PubMedCrossRefGoogle Scholar
  248. 248.
    Bracale R, Pasanisi F, Labruna G, Finelli C, Nardelli C, Buono P, et al. Metabolic syndrome and ADRB3 gene polymorphism in severely obese patients from South Italy. Eur J Clin Nutr. 2007;61(10):1213–9.PubMedCrossRefGoogle Scholar
  249. 249.
    Robitaille J, Brouillette C, Houde A, Lemieux S, Perusse L, Tchernof A, et al. Association between the PPARalpha-L162V polymorphism and components of the metabolic syndrome. J Hum Genet. 2004;49:482–9.PubMedCrossRefGoogle Scholar
  250. 250.
    Tai ES, Collins D, Robins SJ, O’Connor Jr JJ, Bloomfield HE, Ordovas JM, et al. The L162V polymorphism at the peroxisome proliferator activated receptor alpha locus modulates the risk of cardiovascular events associated with insulin resistance and diabetes mellitus: the Veterans Affairs HDL Intervention Trial (VA-HIT). Atherosclerosis. 2006;187:153–60.PubMedCrossRefGoogle Scholar
  251. 251.
    Frederiksen L, Brodbaek K, Fenger M, Jorgensen T, Borch-Johnsen K, Madsbad S, et al. Comment: studies of the Pro12Ala polymorphism of the PPAR-gamma gene in the Danish MONICA cohort: homozygosity of the Ala allele confers a decreased risk of the insulin resistance syndrome. J Clin Endocrinol Metab. 2002;87:3989–92.PubMedCrossRefGoogle Scholar
  252. 252.
    Li S, Chen W, Srinivasan SR, Boerwinkle E, Berenson GS. The Bogalusa Heart Study The peroxisome proliferator-activated receptor-gamma2 gene polymorphism (Pro12Ala) beneficially influences insulin resistance and its tracking from childhood to adulthood: the Bogalusa Heart Study. Diabetes. 2003;52:1265–9.PubMedCrossRefGoogle Scholar
  253. 253.
    Meirhaeghe A, Cottel D, Amouyel P, Dallongeville J. Association between peroxisome proliferator-activated receptor gamma haplotypes and the metabolic syndrome in French men and women. Diabetes. 2005;54:3043–8.PubMedCrossRefGoogle Scholar
  254. 254.
    Kahara T, Takamura T, Hayakawa T, Nagai Y, Yamaguchi H, Katsuki T, et al. PPARgamma gene polymorphism is associated with exercise-mediated changes of insulin resistance in healthy men. Metabolism. 2003;52:209–12.PubMedCrossRefGoogle Scholar
  255. 255.
    Rhee EJ, Oh KW, Lee WY, Kim SY, Oh ES, Baek KH, et al. Effects of two common polymorphisms of peroxisome proliferator-activated receptor-gamma gene on metabolic syndrome. Arch Med Res. 2006;37:86–94.PubMedCrossRefGoogle Scholar
  256. 256.
    Sookoian S, Garcia SI, Porto PI, Dieuzeide G, Gonzalez CD, Pirola CJ. Peroxisome proliferator-activated receptor gamma and its coactivator-1 alpha may be associated with features of the metabolic syndrome in adolescents. J Mol Endocrinol. 2005;35:373–80.PubMedCrossRefGoogle Scholar
  257. 257.
    Grarup N, Albrechtsen A, Ek J, Borch-Johnsen K, Jorgensen T, Schmitz O, et al. Variation in the peroxisome proliferator-activated receptor delta gene in relation to common metabolic traits in 7,495 middle-aged white people. Diabetologia. 2007;50:1201–8.PubMedCrossRefGoogle Scholar
  258. 258.
    Dallongeville J, Helbecque N, Cottel D, Amouyel P, Meirhaeghe A. The Gly16–>Arg16 and Gln27–>Glu27 polymorphisms of beta2-adrenergic receptor are associated with metabolic syndrome in men. J Clin Endocrinol Metab. 2003;88:4862–6.PubMedCrossRefGoogle Scholar
  259. 259.
    Vohl MC, Houde A, Lebel S, Hould FS, Marceau P. Effects of the peroxisome proliferator-activated receptor-gamma co-activator-1 Gly482Ser variant on features of the metabolic syndrome. Mol Genet Metab. 2005;86:300–6.PubMedCrossRefGoogle Scholar
  260. 260.
    Ambye L, Rasmussen S, Fenger M, Jorgensen T, Borch-Johnsen K, Madsbad S, et al. Studies of the Gly482Ser polymorphism of the peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) gene in Danish subjects with the metabolic syndrome. Diab Res Clin Pract. 2005;67:175–9.CrossRefGoogle Scholar
  261. 261.
    Boullu-Sanchis S, Lepretre F, Hedelin G, Donnet JP, Schaffer P, Froguel P, et al. Type 2 diabetes mellitus: association study of five candidate genes in an Indian population of Guadeloupe, genetic contribution of FABP2 polymorphism. Diab Metab. 1999;25:150–6.Google Scholar
  262. 262.
    Guettier JM, Georgopoulos A, Tsai MY, Radha V, Shanthirani S, Deepa R, et al. Polymorphisms in the fatty acid-binding protein 2 and apolipoprotein C-III genes are associated with the metabolic syndrome and dyslipidemia in a South Indian population. J Clin Endocrinol Metab. 2005;90:1705–11.PubMedCrossRefGoogle Scholar
  263. 263.
    Pollex RL, Hanley AJ, Zinman B, Harris SB, Khan HM, Hegele RA. Metabolic syndrome in aboriginal Canadians: prevalence and genetic associations. Atherosclerosis. 2006;184:121–9.PubMedCrossRefGoogle Scholar
  264. 264.
    Vimaleswaran KS, Radha V, Mohan V. Thr54 allele carriers of the Ala54Thr variant of FABP2 gene have associations with metabolic syndrome and hyper-triglyceridemia in urban South Indians. Metabolism. 2006;55:1222–6.PubMedCrossRefGoogle Scholar
  265. 265.
    Erkkila AT, Lindi V, Lehto S, Pyorala K, Laakso M, Uusitupa MI. Variation in the fatty acid binding protein 2 gene is not associated with markers of metabolic syndrome in patients with coronary heart disease. Nutr Metab Cardiovasc Dis. 2002;12:53–9.PubMedGoogle Scholar
  266. 266.
    Ohashi K, Ouchi N, Kihara S, Funahashi T, Nakamura T, Sumitsuji S, et al. Adiponectin I164T mutation is associated with the metabolic syndrome and coronary artery disease. J Am Coll Cardiol. 2004;43:1195–200.PubMedCrossRefGoogle Scholar
  267. 267.
    Marzi C, Huth C, Kolz M, Grallert H, Meisinger C, Wichmann HE, et al. Variants of the transcription factor 7-like 2 gene (TCF7L2) are strongly associated with type 2 diabetes but not with the metabolic syndrome in the MONICA/KORA surveys. Horm Metab Res. 2007;39:46–52.PubMedCrossRefGoogle Scholar
  268. 268.
    Melzer D, Murray A, Hurst AJ, Weedon MN, Bandinelli S, Corsi AM, et al. Effects of the diabetes linked TCF7L2 polymorphism in a representative older population. BMC Med. 2006;4:34.PubMedCrossRefGoogle Scholar
  269. 269.
    Bing C, Ambye L, Fenger M, Jorgensen T, Borch-Johnsen K, Madsbad S, et al. Large-scale studies of the Leu72Met polymorphism of the ghrelin gene in relation to the metabolic syndrome and associated quantitative traits. Diabet Med. 2005;22:1157–60.PubMedCrossRefGoogle Scholar
  270. 270.
    Carlsson E, Groop L, Ridderstrale M. Role of the FOXC2–512C>T polymorphism in type 2 diabetes: possible association with the dysmetabolic syndrome. Int J Obes Lond. 2005;29:268–74.PubMedCrossRefGoogle Scholar
  271. 271.
    Weissglas-Volkov D, Huertas-Vazquez A, Suviolahti E, Lee J, Plaisier C, Canizales-Quinteros S, et al. Common hepatic nuclear factor-4alpha variants are associated with high serum lipid levels and the metabolic syndrome. Diabetes. 2006;55:1970–7.PubMedCrossRefGoogle Scholar
  272. 272.
    Miller M, Rhyne J, Chen H, Beach V, Ericson R, Luthra K, et al. APOC3 promoter polymorphisms C-482T and T-455C are associated with the metabolic syndrome. Arch Med Res. 2007;38:444–51.PubMedCrossRefGoogle Scholar
  273. 273.
    Koh KK, Han SH. Quon MJ.Inflammatory markers and the metabolic syndrome: insights from therapeutic interventions. J Am Coll Cardiol. 2005;46:1978–85.PubMedCrossRefGoogle Scholar
  274. 274.
    Hegele RA. Familial partial lipodystrophy: a monogenic form of the insulin resistance syndrome. Mol Genet Metab. 2000;71:539–44.PubMedCrossRefGoogle Scholar
  275. 275.
    Caux F, Dubosclard E, Lascols O, Buendia B, Chazouilleres O, Cohen A, et al. A new clinical condition linked to a novel mutation in lamins A and C with generalized lipoatrophy, insulin-resistant diabetes, disseminated leukomelanodermic papules, liver steatosis, and cardiomyopathy. J Clin Endocrinol Metab. 2003;88:1006–13.PubMedCrossRefGoogle Scholar
  276. 276.
    Haque WA, Oral EA, Dietz K, Bowcock AM, Agarwal AK, Garg A. Risk factors for diabetes in familial partial lipodystrophy, Dunnigan variety. Diab Care. 2003;26:1350–5.CrossRefGoogle Scholar
  277. 277.
    Cao H, Hegele RA. Nuclear lamin A/C R482Q mutation in canadian kindreds with Dunnigan-type familial partial lipodystrophy. Hum Mol Genet. 2000;9:109–12.PubMedCrossRefGoogle Scholar
  278. 278.
    Hegele RA, Cao H, Frankowski C, Mathews ST, Leff T. PPARG F388L, a transactivation-deficient mutant, in familial partial lipodystrophy. Diabetes. 2002;51:3586–90.PubMedCrossRefGoogle Scholar
  279. 279.
    Hegele RA, Pollex RL. Genetic and physiological insights into the metabolic syndrome. Am J Physiol Regul Integr Comp Physiol. 2005;289:R663–9.PubMedCrossRefGoogle Scholar
  280. 280.
    Hegele RA, Joy TR, Al-Attar S, Rutt BK. Lipodystrophies: windows on adipose biology and metabolism. J Lipid Res. 2007;48(7):1433–44.PubMedCrossRefGoogle Scholar
  281. 281.
    Savage DB, Tan GD, Acerini CL, Jebb SA, Agostini M, Gurnell M, et al. Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-gamma. Diabetes. 2003;52:910–7.PubMedCrossRefGoogle Scholar
  282. 282.
    Agostini M, Schoenmakers E, Mitchell C, Szatmari I, Savage D, Smith A, et al. Non-DNA binding, dominant-negative, human PPARgamma mutations cause lipodystrophic insulin resistance. Cell Metab. 2006;4:303–11.PubMedCrossRefGoogle Scholar
  283. 283.
    Kotzka J, Muller-Wieland D. Sterol regulatory element-binding protein (SREBP)-1: gene regulatory target for insulin resistance? Expert Opin Ther Targets. 2004;8:141–9.PubMedCrossRefGoogle Scholar
  284. 284.
    Koo SH, Satoh H, Herzig S, Lee CH, Hedrick S, Kulkarni R, et al. Montminy M.PGC-1 promotes insulin resistance in liver through PPAR-alpha-dependent induction of TRB-3. Nat Med. 2004;10:530–4.PubMedCrossRefGoogle Scholar
  285. 285.
    Shulman AI, Mangelsdorf DJ. Retinoid x receptor heterodimers in the metabolic syndrome. N Engl J Med. 2005;353:604–15.PubMedCrossRefGoogle Scholar
  286. 286.
    Berger JP, Akiyama TE, Meinke PT. PPARs: therapeutic targets for metabolic disease. Trends Pharmacol Sci. 2005;26:244–51.PubMedCrossRefGoogle Scholar
  287. 287.
    Han SH, Quon MJ, Koh KK. Beneficial vascular and metabolic effects of peroxisome proliferator-activated receptor-alpha activators. Hypertension. 2005;46:1086–92.PubMedCrossRefGoogle Scholar
  288. 288.
    Chinetti-Gbaguidi G, Fruchart JC, Staels B. Role of the PPAR family of nuclear receptors in the regulation of metabolic and cardiovascular homeostasis: new approaches to therapy. Curr Opin Pharmacol. 2005;5:177–83.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.The Molecular Cardiology and Neuromuscular InstituteHighland ParkUSA

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