Heart Failure Reviews

, Volume 21, Issue 1, pp 11–23 | Cite as

Insulin resistance: an additional risk factor in the pathogenesis of cardiovascular disease in type 2 diabetes

  • Tushar P. Patel
  • Komal Rawal
  • Ashim K. Bagchi
  • Gauri Akolkar
  • Nathalia Bernardes
  • Danielle da Silva Dias
  • Sarita Gupta
  • Pawan K. Singal


Sedentary life style and high calorie dietary habits are prominent leading cause of metabolic syndrome in modern world. Obesity plays a central role in occurrence of various diseases like hyperinsulinemia, hyperglycemia and hyperlipidemia, which lead to insulin resistance and metabolic derangements like cardiovascular diseases (CVDs) mediated by oxidative stress. The mortality rate due to CVDs is on the rise in developing countries. Insulin resistance (IR) leads to micro or macro angiopathy, peripheral arterial dysfunction, hampered blood flow, hypertension, as well as the cardiomyocyte and the endothelial cell dysfunctions, thus increasing risk factors for coronary artery blockage, stroke and heart failure suggesting that there is a strong association between IR and CVDs. The plausible linkages between these two pathophysiological conditions are altered levels of insulin signaling proteins such as IR-β, IRS-1, PI3K, Akt, Glut4 and PGC-1α that hamper insulin-mediated glucose uptake as well as other functions of insulin in the cardiomyocytes and the endothelial cells of the heart. Reduced AMPK, PFK-2 and elevated levels of NADP(H)-dependent oxidases produced by activated M1 macrophages of the adipose tissue and elevated levels of circulating angiotensin are also cause of CVD in diabetes mellitus condition. Insulin sensitizers, angiotensin blockers, superoxide scavengers are used as therapeutics in the amelioration of CVD. It evidently becomes important to unravel the mechanisms of the association between IR and CVDs in order to formulate novel efficient drugs to treat patients suffering from insulin resistance-mediated cardiovascular diseases. The possible associations between insulin resistance and cardiovascular diseases are reviewed here.


Insulin resistance CVD Dyslipidemia Metabolic syndrome Oxidative stress Inflammation 



Angiotensin-converting enzyme


Angiotensin receptor blockers


American Diabetes Association


Advanced glycation end-products


AMP-activated protein kinase


Angiotensin II type I receptor


CCAAT/enhancer binding protein


Cardiac autonomic neuropathy


C-reactive protein


Cardio vascular diseases


Diacyl glycerol


Diabetes mellitus


Endothelial nitric oxide synthase


Estrogen-related nuclear receptors




Fatty acid translocase




Free fatty acid


Glucose transporter 4


High-density lipoprotein


Heme oxygenase-1


Intracellular adhesion molecule-1




Insulin resistance


Insulin receptor β


Insulin receptor substrate-1


Janus kinase


Signal transducer and activator of transcription


Long-chain fatty acid


Low-density lipoprotein


Lipoprotein lipase


Mitogen-activated protein kinase


Macrophage chemo attractant protein-1


Mammalian target of rapamycin


Nicotinamide adenine dinucleotide phosphate


Non-esterified fatty acid


Nuclear factor of activated T cells


Nuclear factor kappa-light-chain-enhancer of activated B cells


Nitric oxide


NADPH oxidases


Nuclear respiratory factor 1


Oxidative phosphorylation


Plasminogen activator inhibitor-1


Phosphofructokinase 2


PPAR-γ coactivator 1α


Pleckstrin homology


Phosphatidylinositol 3-kinase


Protein kinase C


Protein kinase B


Peroxisome proliferator-activated receptors


Phosphatase and tensin homolog


Protein tyrosine phosphatase 1B


Reactive oxygen species


SH2-containing inositol 5′-phosphatase


Suppressors of cytokine signaling


Sterol regulatory element binding protein


Triacyl glycerol

Tfam A

Mitochondrial transcription factor A


Toll-like receptors


Tumor necrosis factor-α


Uncoupling protein


Visceral adipose tissue


Vascular endothelial growth factor


Very low-density lipoprotein



Prof. Sarita Gupta was a visiting scientist in Institute of Cardiovascular Sciences. Nathalia Bernardes and Danielle da Silva Dias were exchange students, under the Canada-Brazil Training program. Dr. Pawan Singal is the holder of the Dr. Naranjan S. Dhalla Chair in Cardiovascular Research supported by St. Boniface Hospital and Research Foundation.

Compliance with ethical standards

Conflict of interest



  1. 1.
    Ceriello A (2005) Postprandial hyperglycemia and diabetes complications is it time to treat? Diabetes 54(1):1–7PubMedCrossRefGoogle Scholar
  2. 2.
    Kannel WB, Hjortland M, Castelli WP (1974) Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol 34(1):29–34PubMedCrossRefGoogle Scholar
  3. 3.
    Garcia M, McNamara P, Gordon T, Kannel W (1972) Cardiovascular complications in diabetics. Adv Metab Disord 2(Suppl 2):493–499Google Scholar
  4. 4.
    Fowler MJ (2008) Microvascular and macrovascular complications of diabetes. Clin Diabetes 26(2):77–82CrossRefGoogle Scholar
  5. 5.
    Ceriello A (2003) New insights on oxidative stress and diabetic complications may lead to a “causal” antioxidant therapy. Diabetes Care 26(5):1589–1596PubMedCrossRefGoogle Scholar
  6. 6.
    Farahmand F, Lou H, Singal PK (2003) Oxidative stress in cardiovascular complications of diabetes. In: Pierce GN, Nagano M, Zahradka P, Dhalla NS (eds) Atherosclerosis, hypertension and diabetes. Kluwer Academic Publications, Boston, pp 427–437CrossRefGoogle Scholar
  7. 7.
    Gyurko R, Siqueira CC, Caldon N, Gao L, Kantarci A, Van Dyke TE (2006) Chronic hyperglycemia predisposes to exaggerated inflammatory response and leukocyte dysfunction in Akita mice. J Immunol 177(10):7250–7256PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Lum H, Roebuck KA (2001) Oxidant stress and endothelial cell dysfunction. Am J Physiol Cell Physiol 280(4):C719–C741PubMedGoogle Scholar
  9. 9.
    Versari D, Daghini E, Virdis A, Ghiadoni L, Taddei S (2009) Endothelial dysfunction as a target for prevention of cardiovascular disease. Diabetes Care 32(suppl 2):S314–S321PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Schram MT, Chaturvedi N, Schalkwijk C, Giorgino F, Ebeling P, Fuller JH, Stehouwer CD (2003) Vascular risk factors and markers of endothelial function as determinants of inflammatory markers in type 1 diabetes the EURODIAB Prospective complications study. Diabetes Care 26(7):2165–2173PubMedCrossRefGoogle Scholar
  11. 11.
    El-Osta A, Brasacchio D, Yao D, Pocai A, Jones PL, Roeder RG, Cooper ME, Brownlee M (2008) Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. J Exp Med 205(10):2409–2417PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Hink U, Li H, Mollnau H, Oelze M, Matheis E, Hartmann M, Skatchkov M, Thaiss F, Stahl RA, Warnholtz A (2001) Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res 88(2):e14–e22PubMedCrossRefGoogle Scholar
  13. 13.
    Watts G, Playford D (1998) Dyslipoproteinaemia and hyperoxidative stress in the pathogenesis of endothelial dysfunction in non-insulin dependent diabetes mellitus: an hypothesis. Atherosclerosis 141(1):17–30PubMedCrossRefGoogle Scholar
  14. 14.
    Renard CB, Kramer F, Johansson F, Lamharzi N, Tannock LR, von Herrath MG, Chait A, Bornfeldt KE (2004) Diabetes and diabetes-associated lipid abnormalities have distinct effects on initiation and progression of atherosclerotic lesions. J Clin Investig 114(5):659PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Poirier P, Giles TD, Bray GA, Hong Y, Stern JS, Pi-Sunyer FX, Eckel RH (2006) Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss an update of the 1997 American Heart Association Scientific statement on obesity and heart disease from the obesity committee of the council on nutrition, physical activity, and metabolism. Circulation 113(6):898–918PubMedCrossRefGoogle Scholar
  16. 16.
    Duncan BB, Schmidt MI, Pankow JS, Ballantyne CM, Couper D, Vigo A, Hoogeveen R, Folsom AR, Heiss G (2003) Low-grade systemic inflammation and the development of type 2 diabetes the atherosclerosis risk in communities study. Diabetes 52(7):1799–1805PubMedCrossRefGoogle Scholar
  17. 17.
    Turner R, Holman R, Matthews D, Bassett P, Coster R, Stratton I, Cull C, Peto R, Frighi V, Kennedy I (1993) Hypertension in diabetes study (Hds). 1. Prevalence of hypertension in newly presenting type-2 diabetic-patients and the association with risk-factors for cardiovascular and diabetic complications. J Hypertens 11(3):309–317CrossRefGoogle Scholar
  18. 18.
    ADA (1993) Treatment of hypertension in diabetes. Diabetes Care 16:1394–1401CrossRefGoogle Scholar
  19. 19.
    Goto A, Arah OA, Goto M, Terauchi Y, Noda M (2013) Severe hypoglycaemia and cardiovascular disease: systematic review and meta-analysis with bias analysis. BMJ 347:F4533PubMedCrossRefGoogle Scholar
  20. 20.
    Sommerfield AJ, Wilkinson IB, Webb DJ, Frier BM (2007) Vessel wall stiffness in type 1 diabetes and the central hemodynamic effects of acute hypoglycemia. Am J Physiol Endocrinol Metab 293(5):E1274–E1279PubMedCrossRefGoogle Scholar
  21. 21.
    Frier BM, Schernthaner G, Heller SR (2011) Hypoglycemia and cardiovascular risks. Diabetes Care 34(Supplement 2):S132–S137PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Desouza CV, Bolli GB, Fonseca V (2010) Hypoglycemia, diabetes, and cardiovascular events. Diabetes Care 33(6):1389–1394PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Spallone V, Ziegler D, Freeman R, Bernardi L, Frontoni S, Pop-Busui R, Stevens M, Kempler P, Hilsted J, Tesfaye S (2011) Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev 27(7):639–653PubMedCrossRefGoogle Scholar
  24. 24.
    Witte D, Tesfaye S, Chaturvedi N, Eaton S, Kempler P, Fuller J, Group EPCS (2005) Risk factors for cardiac autonomic neuropathy in type 1 diabetes mellitus. Diabetologia 48(1):164–171PubMedCrossRefGoogle Scholar
  25. 25.
    Astrup AS, Tarnow L, Rossing P, Hansen BV, Hilsted J, Parving H-H (2006) Cardiac autonomic neuropathy predicts cardiovascular morbidity and mortality in type 1 diabetic patients with diabetic nephropathy. Diabetes Care 29(2):334–339PubMedCrossRefGoogle Scholar
  26. 26.
    DeFronzo RA, Tripathy D (2009) Skeletal muscle insulin resistance is the primary defect in type 2 diabetes. Diabetes Care 32(suppl 2):S157–S163PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Groop L, Bonadonna R, Del Prato S, Ratheiser K, Zyck K, DeFronzo R (1989) Effect of insulin on oxidative and non-oxidative pathways of glucose and FFA metabolism in NIDDM. Evidence for multiple sites of insulin resistance. J Clin Invest 84:205–213PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Morino K, Petersen KF, Shulman GI (2006) Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes 55(Supplement 2):S9–S15PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Langin D, Dicker A, Tavernier G, Hoffstedt J, Mairal A, Rydén M, Arner E, Sicard A, Jenkins CM, Viguerie N (2005) Adipocyte lipases and defect of lipolysis in human obesity. Diabetes 54(11):3190–3197PubMedCrossRefGoogle Scholar
  30. 30.
    Kern PA (1997) Potential role of TNFα and lipoprotein lipase as candidate genes for obesity. J Nutr 127(9):1917S–1922SPubMedGoogle Scholar
  31. 31.
    Bugianesi E, McCullough AJ, Marchesini G (2005) Insulin resistance: a metabolic pathway to chronic liver disease. Hepatology 42(5):987–1000PubMedCrossRefGoogle Scholar
  32. 32.
    Dröge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82(1):47–95PubMedCrossRefGoogle Scholar
  33. 33.
    Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414(6865):813–820PubMedCrossRefGoogle Scholar
  34. 34.
    Greene DA, Stevens MJ, Obrosova I, Feldman EL (1999) Glucose-induced oxidative stress and programmed cell death in diabetic neuropathy. Eur J Pharmacol 375(1):217–223PubMedCrossRefGoogle Scholar
  35. 35.
    Wolff SP, Dean R (1987) Glucose autoxidation and protein modification. The potential role of ‘autoxidative glycosylation’ in diabetes. Biochem J 245:243–250PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Yan S, Stern D, Schmidt A (1997) What’s the RAGE? The receptor for advanced glycation end products (RAGE) and the dark side of glucose. Eur J Clin Invest 27(3):179–181PubMedCrossRefGoogle Scholar
  37. 37.
    Stojiljkovic MP, Lopes HF, Zhang D, Morrow JD, Goodfriend TL, Egan BM (2002) Increasing plasma fatty acids elevates F2-isoprostanes in humans: implications for the cardiovascular risk factor cluster. J Hypertens 20(6):1215–1221PubMedCrossRefGoogle Scholar
  38. 38.
    S-i Yamagishi, Edelstein D, X-l Du, Kaneda Y, Guzmán M, Brownlee M (2001) Leptin induces mitochondrial superoxide production and monocyte chemoattractant protein-1 expression in aortic endothelial cells by increasing fatty acid oxidation via protein kinase A. J Biol Chem 276(27):25096–25100CrossRefGoogle Scholar
  39. 39.
    Paz K, Hemi R, LeRoith D, Karasik A, Elhanany E, Kanety H, Zick Y (1997) A Molecular Basis for Insulin Resistance elevated serine/threonine phosphorylation of irs-1 and irs-2 inhibits their binding to the juxtamembrane region of the insulin receptor and impairs their ability to undergo insulin-induced tyrosine phosphorylation. J Biol Chem 272(47):29911–29918PubMedCrossRefGoogle Scholar
  40. 40.
    Potashnik R, Bloch-Damti A, Bashan N, Rudich A (2003) IRS1 degradation and increased serine phosphorylation cannot predict the degree of metabolic insulin resistance induced by oxidative stress. Diabetologia 46(5):639–648PubMedGoogle Scholar
  41. 41.
    Ogihara T, Asano T, Katagiri H, Sakoda H, Anai M, Shojima N, Ono H, Fujishiro M, Kushiyama A, Fukushima Y (2004) Oxidative stress induces insulin resistance by activating the nuclear factor-κB pathway and disrupting normal subcellular distribution of phosphatidylinositol 3-kinase. Diabetologia 47(5):794–805PubMedCrossRefGoogle Scholar
  42. 42.
    Khamaisi M, Potashnik R, Tirosh A, Demshchak E, Rudich A, Trischler H, Wessel K, Bashan N (1997) Lipoic acid reduces glycemia and increases muscle GLUT4 content in streptozotocin-diabetic rats. Metabolism 46(7):763–768PubMedCrossRefGoogle Scholar
  43. 43.
    Pessler D, Rudich A, Bashan N (2001) Oxidative stress impairs nuclear proteins binding to the insulin responsive element in the GLUT4 promoter. Diabetologia 44(12):2156–2164PubMedCrossRefGoogle Scholar
  44. 44.
    Castelló A, Rodríguez-Manzaneque JC, Camps M, Perez-Castillo A, Testar X, Palacin M, Santos A, Zorzano A (1994) Perinatal hypothyroidism impairs the normal transition of GLUT4 and GLUT1 glucose transporters from fetal to neonatal levels in heart and brown adipose tissue. Evidence for tissue-specific regulation of GLUT4 expression by thyroid hormone. J Biol Chem 269(8):5905–5912PubMedGoogle Scholar
  45. 45.
    Randle PJ, Kerbey AL, Espinal J (1988) Mechanisms decreasing glucose oxidation in diabetes and starvation: role of lipid fuels and hormones. Diabetes Metab Rev 4(7):623–638PubMedCrossRefGoogle Scholar
  46. 46.
    Shulman GI (2000) Cellular mechanisms of insulin resistance. J Clin Investig 106(2):171PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Stalder M, Pometta D, Suenram A (1981) Relationship between plasma insulin levels and high density lipoprotein cholesterol levels in healthy men. Diabetologia 21(6):544–548PubMedGoogle Scholar
  48. 48.
    Sadur UN, Yost TJ, Eckel RH (1984) Insulin responsiveness of adipose tissue lipoprotein lipase is delayed but preserved in obesity*. J Clin Endocrinol Metab 59(6):1176–1182PubMedCrossRefGoogle Scholar
  49. 49.
    Golay A, Zech L, Shi M-Z, Chiou Y-A, Reaven G, Chen Y-D (1987) High density lipoprotein (HDL) metabolism in noninsulin-dependent diabetes mellitus: measurement of HDL turnover using tritiated HDL*. J Clin Endocrinol Metab 65(3):512–518PubMedCrossRefGoogle Scholar
  50. 50.
    Eriksson P, Nilsson L, Karpe F, Hamsten A (1998) Very-low-density lipoprotein response element in the promoter region of the human plasminogen activator inhibitor-1 gene implicated in the impaired fibrinolysis of hypertriglyceridemia. Arterioscler Thromb Vasc Biol 18(1):20–26PubMedCrossRefGoogle Scholar
  51. 51.
    Nishikawa T, Edelstein D, Du XL, S-i Yamagishi, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes H-P (2000) Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404(6779):787–790PubMedCrossRefGoogle Scholar
  52. 52.
    Pyörälä K (1979) Relationship of glucose tolerance and plasma insulin to the incidence of coronary heart disease: results from two population studies in Finland. Diabetes Care 2(2):131–141PubMedCrossRefGoogle Scholar
  53. 53.
    Després J-P, Lamarche B, Mauriège P, Cantin B, Dagenais GR, Moorjani S, Lupien P-J (1996) Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 334(15):952–958PubMedCrossRefGoogle Scholar
  54. 54.
    Suzuki M, Shinozaki K, Kanazawa A, Hara Y, Hattori Y, Tsushima M, Harano Y (1996) Insulin resistance as an independent risk factor for carotid wall thickening. Hypertension 28(4):593–598PubMedCrossRefGoogle Scholar
  55. 55.
    Shen D-C, Shieh S-M, Fuh M-T, Wu D-A, Chen Y-D, Reaven G (1988) Resistance to insulin-stimulated-glucose uptake in patients with hypertension*. J Clin Endocrinol Metab 66(3):580–583PubMedCrossRefGoogle Scholar
  56. 56.
    Reaven GM, Chang H (1991) Relationship between blood pressure, plasma insulin ana triglyceride concentration, and insulin action in spontaneous hypertensive and Wistar-Kyoto rats. Am J Hypertens 4(1 Pt 1):34–38PubMedGoogle Scholar
  57. 57.
    Sechi LA, Melis A, Tedde R (1992) Insulin hypersecretion: a distinctive feature between essential and secondary hypertension. Metabolism 41(11):1261–1266PubMedCrossRefGoogle Scholar
  58. 58.
    Reaven G (1996) Hypertension and associated metabolic abnormalities—the role of insulin resistance and the sympathoadrenal system. N Engl J Med 334:374–381PubMedCrossRefGoogle Scholar
  59. 59.
    Mitchell TH, Nolan B, Henry M, Cronin C, Baker H, Greely G (1997) Microalbuminuria in patients with non-insulin-dependent diabetes mellitus relates to nocturnal systolic blood pressure. Am J Med 102(6):531–535PubMedCrossRefGoogle Scholar
  60. 60.
    Laine H, Yki-Jarvinen H, Kirvela O, Tolvanen T, Raitakari M, Solin O, Haaparanta M, Knuuti J, Nuutila P (1998) Insulin resistance of glucose uptake in skeletal muscle cannot be ameliorated by enhancing endothelium-dependent blood flow in obesity. J Clin Investig 101(5):1156PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Ginsberg HN (2000) Insulin resistance and cardiovascular disease. J Clin Investig 106(4):453PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Seidell JC, Pérusse L, Després J-P, Bouchard C (2001) Waist and hip circumferences have independent and opposite effects on cardiovascular disease risk factors: the Quebec Family Study. Am J Clin Nutr 74(3):315–321PubMedGoogle Scholar
  63. 63.
    Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH (1997) Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 336(14):973–979PubMedCrossRefGoogle Scholar
  64. 64.
    Brown NJ, Kim K-S, Chen Y-Q, Blevins LS, Nadeau JH, Meranze SG, Vaughan DE (2000) Synergistic effect of adrenal steroids and angiotensin II on plasminogen activator inhibitor-1 production 1. J Clin Endocrinol Metab 85(1):336–344PubMedGoogle Scholar
  65. 65.
    Sowers JR, Sowers PS, Peuler JD (1994) Role of insulin resistance and hyperinsulinemia in development of hypertension and atherosclerosis. J Lab Clin Med 123(5):647–652PubMedGoogle Scholar
  66. 66.
    Chen Y-Q, Su M, Walia RR, Hao Q, Covington JW, Vaughan DE (1998) Sp1 sites mediate activation of the plasminogen activator inhibitor-1 promoter by glucose in vascular smooth muscle cells. J Biol Chem 273(14):8225–8231PubMedCrossRefGoogle Scholar
  67. 67.
    Westerbacka J, Vehkavaara S, Bergholm R, Wilkinson I, Cockcroft J, Yki-Järvinen H (1999) Marked resistance of the ability of insulin to decrease arterial stiffness characterizes human obesity. Diabetes 48(4):821–827PubMedCrossRefGoogle Scholar
  68. 68.
    Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD (1996) Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Investig 97(11):2601PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Després J-P (2006) Abdominal obesity: the most prevalent cause of the metabolic syndrome and related cardiometabolic risk. Eur Heart J Suppl 8(suppl B):B4–B12CrossRefGoogle Scholar
  70. 70.
    Steinberger J, Daniels SR (2003) Obesity, insulin resistance, diabetes, and cardiovascular risk in children an American Heart Association scientific statement from the atherosclerosis, hypertension, and obesity in the Young Committee (Council on Cardiovascular Disease in the Young) and the Diabetes Committee (Council on Nutrition, Physical Activity, and Metabolism). Circulation 107(10):1448–1453PubMedCrossRefGoogle Scholar
  71. 71.
    Van Gaal LF, Mertens IL, Christophe E (2006) Mechanisms linking obesity with cardiovascular disease. Nature 444(7121):875–880PubMedCrossRefGoogle Scholar
  72. 72.
    Turer AT, Hill JA, Elmquist JK, Scherer PE (2012) Adipose tissue biology and cardiomyopathy translational implications. Circ Res 111(12):1565–1577PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Ramkhelawon B, Hennessy EJ, Ménager M, Ray TD, Sheedy FJ, Hutchison S, Wanschel A, Oldebeken S, Geoffrion M, Spiro W (2014) Netrin-1 promotes adipose tissue macrophage retention and insulin resistance in obesity. Nat Med 20(4):377–384PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Sell H, Habich C, Eckel J (2012) Adaptive immunity in obesity and insulin resistance. Nat Rev Endocrinol 8(12):709–716PubMedCrossRefGoogle Scholar
  75. 75.
    De Marchi E, Faldassari B, Bononi A, Wieckowski M, Pinton P (2013) Oxidative stress in cardiovascular diseases and obesity: role of p66Shc and protein kinase C. Oxid Med Cell Longev 2013:564961. doi: 10.1155/2013/564961 PubMedPubMedCentralGoogle Scholar
  76. 76.
    Borén J, Taskinen MR, Olofsson SO, Levin M (2013) Ectopic lipid storage and insulin resistance: a harmful relationship. J Intern Med 274(1):25–40PubMedCrossRefGoogle Scholar
  77. 77.
    Yang R, Barouch LA (2007) Leptin signaling and obesity cardiovascular consequences. Circ Res 101(6):545–559PubMedCrossRefGoogle Scholar
  78. 78.
    Lumeng CN, Bodzin JL, Saltiel AR (2007) Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Investig 117(1):175PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Ruan H, Hacohen N, Golub TR, Van Parijs L, Lodish HF (2002) Tumor necrosis factor-α suppresses adipocyte-specific genes and activates expression of preadipocyte genes in 3T3-L1 adipocytes nuclear factor-κB activation by TNF-α is obligatory. Diabetes 51(5):1319–1336PubMedCrossRefGoogle Scholar
  80. 80.
    Permana PA, Menge C, Reaven PD (2006) Macrophage-secreted factors induce adipocyte inflammation and insulin resistance. Biochem Biophys Res Commun 341(2):507–514PubMedCrossRefGoogle Scholar
  81. 81.
    Schächinger V, Britten MB, Zeiher AM (2000) Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 101(16):1899–1906PubMedCrossRefGoogle Scholar
  82. 82.
    Bugiardini R, Manfrini O, Pizzi C, Fontana F, Morgagni G (2004) Endothelial function predicts future development of coronary artery disease a study of women with chest pain and normal coronary angiograms. Circulation 109(21):2518–2523PubMedCrossRefGoogle Scholar
  83. 83.
    Han S, Liang C-P, DeVries-Seimon T, Ranalletta M, Welch CL, Collins-Fletcher K, Accili D, Tabas I, Tall AR (2006) Macrophage insulin receptor deficiency increases ER stress-induced apoptosis and necrotic core formation in advanced atherosclerotic lesions. Cell Metab 3(4):257–266PubMedCrossRefGoogle Scholar
  84. 84.
    Kuboki K, Jiang ZY, Takahara N, Ha SW, Igarashi M, Yamauchi T, Feener EP, Herbert TP, Rhodes CJ, King GL (2000) Regulation of endothelial constitutive nitric oxide synthase gene expression in endothelial cells and in vivo a specific vascular action of insulin. Circulation 101(6):676–681PubMedCrossRefGoogle Scholar
  85. 85.
    Hamsten A, Wiman B, de Faire U, Blombäck M (1985) Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 313(25):1557–1563PubMedCrossRefGoogle Scholar
  86. 86.
    Wiman B, Andersson T, Hallqvist J, Reuterwall C, Ahlbom A (2000) Plasma levels of tissue plasminogen activator/plasminogen activator inhibitor-1 complex and von Willebrand factor are significant risk markers for recurrent myocardial infarction in the Stockholm Heart Epidemiology Program (SHEEP) study. Arterioscler Thromb Vasc Biol 20(8):2019–2023PubMedCrossRefGoogle Scholar
  87. 87.
    Calles-Escandon J, Mirza SA, Sobel BE, Schneider DJ (1998) Induction of hyperinsulinemia combined with hyperglycemia and hypertriglyceridemia increases plasminogen activator inhibitor 1 in blood in normal human subjects. Diabetes 47(2):290–293PubMedCrossRefGoogle Scholar
  88. 88.
    Bertrand L, Horman S, Beauloye C, Vanoverschelde J-L (2008) Insulin signalling in the heart. Cardiovasc Res 79(2):238–248PubMedCrossRefGoogle Scholar
  89. 89.
    Randle P, Garland P, Hales C, Newsholme E (1963) The glucose fatty-acid cycle its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 281(7285):785–789CrossRefGoogle Scholar
  90. 90.
    Proud C (2007) Signalling to translation: how signal transduction pathways control the protein synthetic machinery. Biochem J 403:217–234PubMedCrossRefGoogle Scholar
  91. 91.
    Heineke J, Molkentin JD (2006) Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol 7(8):589–600PubMedCrossRefGoogle Scholar
  92. 92.
    Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM (1999) Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 399(6736):601–605PubMedCrossRefGoogle Scholar
  93. 93.
    McFarlane SI, Banerji M, Sowers JR (2001) Insulin resistance and cardiovascular disease. J Clin Endocrinol Metab 86(2):713–718PubMedGoogle Scholar
  94. 94.
    Mehta PK, Griendling KK (2007) Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. Am J Physiol Cell Physiol 292(1):C82–C97PubMedCrossRefGoogle Scholar
  95. 95.
    Lowell BB, Shulman GI (2005) Mitochondrial dysfunction and type 2 diabetes. Science 307(5708):384–387PubMedCrossRefGoogle Scholar
  96. 96.
    Kim YJ, Park T (2008) Genes are differentially expressed in the epididymal fat of rats rendered obese by a high-fat diet. Nutr Res 28(6):414–422PubMedCrossRefGoogle Scholar
  97. 97.
    Dong F, Li Q, Sreejayan N, Nunn JM, Ren J (2007) Metallothionein prevents high-fat diet-induced cardiac contractile dysfunction role of peroxisome proliferator-activated receptor γ coactivator 1α and mitochondrial biogenesis. Diabetes 56(9):2201–2212PubMedCrossRefGoogle Scholar
  98. 98.
    Garcia-Roves P, Huss JM, Han D-H, Hancock CR, Iglesias-Gutierrez E, Chen M, Holloszy JO (2007) Raising plasma fatty acid concentration induces increased biogenesis of mitochondria in skeletal muscle. Proc Natl Acad Sci 104(25):10709–10713PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Hancock CR, Han D-H, Chen M, Terada S, Yasuda T, Wright DC, Holloszy JO (2008) High-fat diets cause insulin resistance despite an increase in muscle mitochondria. Proc Natl Acad Sci 105(22):7815–7820PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI (2004) Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 350(7):664–671PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Huo L, Scarpulla RC (2001) Mitochondrial DNA instability and peri-implantation lethality associated with targeted disruption of nuclear respiratory factor 1 in mice. Mol Cell Biol 21(2):644–654PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Patti ME, Butte AJ, Crunkhorn S, Cusi K, Berria R, Kashyap S, Miyazaki Y, Kohane I, Costello M, Saccone R (2003) Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: potential role of PGC1 and NRF1. Proc Natl Acad Sci 100(14):8466–8471PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Mootha VK, Lindgren CM, Eriksson K-F, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstråle M, Laurila E (2003) PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34(3):267–273PubMedCrossRefGoogle Scholar
  104. 104.
    Russell LK, Mansfield CM, Lehman JJ, Kovacs A, Courtois M, Saffitz JE, Medeiros DM, Valencik ML, McDonald JA, Kelly DP (2004) 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 94(4):525–533PubMedCrossRefGoogle Scholar
  105. 105.
    Lehman JJ, Barger PM, Kovacs A, Saffitz JE, Medeiros DM, Kelly DP (2000) Peroxisome proliferator–activated receptor γ coactivator-1 promotes cardiac mitochondrial biogenesis. J Clin Investig 106(7):847PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Huss JM, Kelly DP (2004) Nuclear receptor signaling and cardiac energetics. Circ Res 95(6):568–578PubMedCrossRefGoogle Scholar
  107. 107.
    Kelly DP, Scarpulla RC (2004) Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev 18(4):357–368PubMedCrossRefGoogle Scholar
  108. 108.
    Garnier A, Fortin D, Delomenie C, Momken I, Veksler V, Ventura-Clapier R (2003) Depressed mitochondrial transcription factors and oxidative capacity in rat failing cardiac and skeletal muscles. J Physiol 551(2):491–501PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Ritz P, Berrut G (2005) Mitochondrial function, energy expenditure, aging and insulin resistance. Diabetes Metab 31:5S67–65S73PubMedCrossRefGoogle Scholar
  110. 110.
    Savage DB, Petersen KF, Shulman GI (2005) Mechanisms of insulin resistance in humans and possible links with inflammation. Hypertension 45(5):828–833PubMedCrossRefGoogle Scholar
  111. 111.
    J-a Kim, Wei Y, Sowers JR (2008) Role of mitochondrial dysfunction in insulin resistance. Circ Res 102(4):401–414CrossRefGoogle Scholar
  112. 112.
    Zick Y (2005) Ser/Thr phosphorylation of IRS proteins: a molecular basis for insulin resistance. Sci STKE 2005(268):pe4. doi: 10.1126/stke.2682005pe4 Google Scholar
  113. 113.
    Mather KJ, Lteif A, Steinberg HO, Baron AD (2004) Interactions between endothelin and nitric oxide in the regulation of vascular tone in obesity and diabetes. Diabetes 53(8):2060–2066PubMedCrossRefGoogle Scholar
  114. 114.
    Ting HH, Timimi FK, Boles KS, Creager SJ, Ganz P, Creager MA (1996) Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus. J Clin Investig 97(1):22PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Chen H, Montagnani M, Funahashi T, Shimomura I, Quon MJ (2003) Adiponectin stimulates production of nitric oxide in vascular endothelial cells. J Biol Chem 278(45):45021–45026PubMedCrossRefGoogle Scholar
  116. 116.
    Whaley-Connell A, Govindarajan G, Habibi J, Hayden MR, Cooper SA, Wei Y, Ma L, Qazi M, Link D, Karuparthi PR (2007) Angiotensin II-mediated oxidative stress promotes myocardial tissue remodeling in the transgenic (mRen2) 27 Ren2 rat. Am J Physiol Endocrinol Metab 293(1):E355–E363PubMedCrossRefGoogle Scholar
  117. 117.
    Koh KK, Quon MJ, Han SH, Chung W-J, Ahn JY, Seo Y-H, Choi IS, Shin EK (2005) Additive beneficial effects of fenofibrate combined with atorvastatin in the treatment of combined hyperlipidemia. J Am Coll Cardiol 45(10):1649–1653PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Tushar P. Patel
    • 1
  • Komal Rawal
    • 1
  • Ashim K. Bagchi
    • 2
  • Gauri Akolkar
    • 2
  • Nathalia Bernardes
    • 2
  • Danielle da Silva Dias
    • 2
  • Sarita Gupta
    • 1
  • Pawan K. Singal
    • 2
  1. 1.Molecular Endocrinology and Stem Cell Research Lab, Department of Biochemistry, Faculty of ScienceThe Maharaja Sayajirao University of BarodaVadodaraIndia
  2. 2.Department of Physiology and Pathophysiology, Faculty of Health Sciences, St. Boniface Research Centre, Institute of Cardiovascular SciencesUniversity of ManitobaWinnipegCanada

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