Morales VE

Language: Spanish
References: 122
Page: 173-188
PDF size: 217.06 Kb.

ABSTRACT

Himsworth in 1939 postulated that Diabetes Mellitus type 2 (DM2) was not only an insulin deficiency state but also a cellular insulin insensitivity disease. Thirty years later, DeFronzo and Reaven demonstrated that insulin resistance (IR) preceded and predisposed for DM2 and atherosclerotic-cardiovascular-disease (ACVD). Reaven was the first to point out the relationship between IR and with hyperglycemia, dyslipidosis, and hypertension as mediators for ACVD, creating the concept of Syndrome X (SX) in 1988. WHO and, thereafter, other medical societies and medical groups, mainly ATP-III, in 2002, based on the difficulty of diagnosing IR in a simple, reliable, and inexpensive way, proposed and published the Metabolic Syndrome (MS) concept, as a group of five variables, i.e., obesity, hyperglycemia, hypertriglyceridemia, low HDL, and hypertension, as an easy clinical approximation to suspect and treat an increased cardiometabolic risk. Nowadays, there are deep and extensive controversies on this issue; however, these controversies do not really exist since all discordant points of view are rather quantitative and not qualitative in nature. This article is aimed at differentiating and harmonizing the complementary concepts of SX and MS, at analyzing why MS is a good “clinical window” to look for IR and its underlying manifestations, and finally to accept that the MS concept complements, but does not substitute or antagonize, traditional scales used to asses cardiovascular risk, such as the Framingham scale.

REFERENCES

1. Reaven G: Role of insulin resistance in human disease. Diabetes 1988; 37: 1595-1607.

2. Miller CJ, Miller NE: Plasma high-density lipoprotein concentrations and the development of ischemic heart disease. Lancet 1975; 1: 16-19.

3. Carlson LA, Bottiger LE, Ahfeldt PE: Risk factors for myocardial infarction in the Stockholm prospective study: a 14 year follow-up focusing on the role of plasma triglycerides and cholesterol. Acta Med Scand 1979; 206: 351-360.

4. Fuller JH, Shipley MJ, Rose G, Jarret RJ, Keen H: Coronary-heart disease and impaired glucose tolerance: the Whitehall Study. Lancet 1980; 1: 1373-1376.

5. Castelli WP, Garrison RJ, Wilson PWF, Abbot RO, Kalonsdian S, Kannel WB: Incidence of coronary heart disease and lipoprotein cholesterol levels: the Framingham Study. JAMA 1986; 256: 2385-2387.

6. Executive summary of the third report of the National Cholesterol Education Program (NCEP). Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2002; 285: 2846-2897.

7. Reaven GM: The metabolic syndrome: requiescat in pace. Clinical Chem 2005; 51: 931-938.

8. Greenland P: Critical questions about the Metabolic Syndrome. Circulation 2005; 112: 3675-3676.

9. Burley S, Dobson C, Eisenberg D, Harrison S, Kuriyan J, Petzco G: How cells obtain energy from food. pp 91-109. Chapter 2. Cell chemistry and biosynthesis. En: Molecular Biology of the Cell. 2nd Ed, 2002. (Eds) Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. Taylor, Francis Group.

10. Isganaitis E, Lustig RH: Fast food, central nervous system, insulin resistance and obesity. Arterioscler Throm Vasc Biol 2005; 25: 2451-2462.

11. Angelopoulus N, Goula A, Tolis G: Current knowledge in the neurophysiologic modulation of obesity. Metabolism Clin Exp 2005; 54: 1202-1217.

12. Kojima M, Hosoda H, Date Y, Nakasato M, Matzuo H, Kangawa K: Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999; 402(6762): 656-660.

13. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM: Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372: 425-432.

14. Shalev U, Yap J, Shaham Y: Leptin attenuates food deprivation-induced relapse to heroin seeking. J Neurosci 2001; 21: RC129: 1-5.

15. Kawai K, Sugimoto K, Nakashima K, Miura H, Ninomiya Y: Leptin as a modulator of sweet taste sensitivities in mice. Proc Nat Acad Sci USA 2000; 97: 11044-11049.

16. Carr KD, Tsimberg Y, Berman Y, Yamamoto N: Evidence of increased dopamine receptor signaling in food-restricted rats. Neuroscience 2003; 119: 1157-1167.

17. Heymsfield SB, Greenberg AS, Fujioka K, Dixon RM, Kushner R, Hunt T, et al: Recombinant leptin for weigth loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 1999; 82: 568-1575.

18. Ahima RS, Flier JS: eptin. Ann Rev Physiol 2000; 2: 13-437.

19. Flier JS: Leptin and obesity. Banting Lecture. ADA Meeting San Diego USA, 2005.

20. Drucker DJ: Enhancing incretin action for the treatment of type-2 diabetes. Diabetes Care 2003; 26: 2929-2940.

21. Lambeir AM, Durinx X, Scharpe S, DeMessterm I: Dipeptidyl-Peptidase-IV from bench to bedside. An update on structural properties, functions, and clinical aspects of the enzyme DPP-IV. Critical Rev in Clin Lab Sci 2003; 40: 209-294.

22. Figlewics DP, Szot P, Chavez M, Woods SC, Veith RC: Intraventricular insulin increases dopaminergic transporter mRNA in rat VTA-substantia nigra. Brain Res 1994; 644: 331-334.

23. Sipols AJ, Stuber GD, Klein SN, Higgins MS, Figlewics DP: Insulin and raclopride combine to decrease short-term intake of sucrose solutions. Peptide 2000; 21: 1361-1367.

24. Figlewics DP: Adiposity signals and food reward: expanding the CNS roles of insulin and leptin. Am J Physiol Regul Integr Comp Physiol 2003; 284: R882-R892.

25. Sipols AJ, Bayer J, Bennet R, Figlewics DP: Intraventricular insulin decreases kappa opioid-mediated sucrose intake in rats. Peptides 2002; 23: 2181-2187.

26. Lusting RH, Preeyasombant C, Velazquez-Mieyer PA: Childhood obesity. En: Pescovitz OH, Eugster EA (eds): Pediatric endocrinology; mechanisms, manifestations and management. Philadelphia. Lippincott Williams & Wilkins 2003: 683-714.

27. Lustig RH: Autonomic dysfunction of the beta-cell and the pathogenesis of obesity. Rev Endocrinol Metab Dis 2003; 4: 23-32.

28. Prentice AM, Jebb SA: Fast foods, energy density and obesity: a possible mechanistic link. Obesity Reviews 2003: 4: 187-194.

29. Rolls BJ, Castellanos VH, Halford JC, Kilara A, Panyam D, Pelkman CL, et al: Volume of food consumed affects satiety in men. Am J Clin Nutr 1998; 67: 1170-1177.

30. Rolls BJ, Bell EA, Castellanos VH, Chow M, Pelkman CL, Thorwart ML: Energy density but not fat content of foods affected energy intake in obese and lean women. Am J Clin Nutr 1999; 69: 863-871.

31. Ebbeling CB, Sinclair KB, Pereira MA, Garcia-Lago E, Feldman HA, Ludwing DS: Compensation for energy intake from fase food among overweight and lean adolescents. JAMA 2004; 291: 2828-2833.

32. Sherwood NE, Jeffery RW, French SA, Hannan PJ, Murray DM: Predictors of weigth gain in the Pound of Prevention study. Int J Obes Relat Metab Disord 2000; 24: 395-403.

33. Harris RB, Mitchel TD, Hebert S: Leptin-induced changes in body composition in high fad-fed mice. Exp Biol Med 2003; 228: 24-32.

34. Boden G: Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 1996; 45: 3-10.

35. Stein DT, Stevenson BE, Chester MW, Basit M, Daniels MB, Turley SD, et al: The insulinotropic potency of fatty acids is influenced profoundly by their chain length and degree of saturation. J Clin Invest 1997; 100: 398-403.

36. Parker DR, Weiss ST, Troisi R, Cassano PA, Vokonas PS, Landsberg L: Relationship of dietary saturated fatty acids and body habitus to serum insulin concentrations: the normative aging study. Am J Clin Nutr 1993; 58: 129-136.

37. Mayer EJ, Newman B, Quesenberry CP, Selby JV: Usual dietary fat intake and insulin concentrations in healthy women twins. Diabetes Care 1993; 16: 1456-1469.

38. Dobbins RL, Szczepaniak LS, Myhill J, Tamura Y, Uchino H, Giacca A, et al: The composition of dietary fat directly influences glucose-stimulated insulin secretion in rats. Diabetes 2002; 51: 1825-1833.

39. Zierath JR, Houseknecht KL, Gnudi L, Kahn BB: High fat feeding impairs insulin-stimulated GLUT-4 recruitment via an early signaling defect. Diabetes 1997; 46: 215-223.

40. El-Haschimi K, Pierroz DD, Hileman SM, Bjorbaek C, Flier JS: Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. J Clin Invest 2000; 105: 1827-1832.

41. Lin L, Martin R, Schaffhauser AO, York DA: Accute changes in the response to peripheral leptin with alteration in the diet composition. Am J Physiol Regil Integr Comp Physiol 2001; 280: R504-R509.

42. Hu FB, Stamfer MJ, Manson JE, Grodstein F, Colditz GA, Speizer FE, et al: Trends in the incidence of coronary heart disease and changes in diet and life style in women. N Engl J Med 2000; 343: 530-537.

43. Ludwig DS: The glycemic index: physiological mechanisms relating to obesity, diabetes, and cardiovascular disease. JAMA 2002; 287: 2414-2423.

44. Ludwig DS, Majzoub, Al-Zaharani A, Dallal GE, Blanco I, Roberts SB: High glycemic index foods, overeating, and obesity. Pediatrics 1999; 103: E261-E266.

45. Ludwig DS: Dietary glycemic index and obesity. J Nutr 2000; 130: 280S-283S.

46. Pereira MA, Swain J, Goldfine AB, Rifai N, Ludwig DS: Effects of a low-glycemic load diet on resting energy expediture and heart disease risk factors during weigth loss. JAMA 2004; 292: 2482-2490.

47. Salmeron j, Manson JE, Stampfer MJ, Colditz GA, Wing AL, Willet WC: Dietary fiber, glycemic load, and risk of non-insulin-dependent diabetes mellitus in women. JAMA 1997; 277: 472-477.

48. Gross LS, Li L, Ford ES, Liu S: Increased consumption of refined carbohydrates and the epidemic of type 2 diabetes in the United States: an ecologic assessment. Am J Clin Nutr 2004; 79: 774-779.

49. Anderson JW, Story LJ, Zettwoch NC, Gustafson NJ, Jefferson BS: Metabolic effects of fructuose supplementation in diabetic individuals. Diabetes Care 1989; 12: 337-344.

50. Jurgens H, Haass W, Castaneda TR, Schurmann A, Koebnick C, Dombrowski F et al: Consuming fructose sweetened beverages increases body adiposity in mice. Obes Res 2005; 13: 1146-1156.

51. Havel PJ: Dietary fructose: implications for dysregulation of energy homeostasis and lipid-carbohydrate metabolism. Nutrition Reviews 2005; 63: 133-157.

52. Moyer AE, Rodin J: Fructose and behavior: does fructose influence food intake and macronutrients selection? Am J Clin Nutr 1993; 58(Suppl 5): 810S-814S.

53. Teff KL, Elliott SS, Tshop M, Kieffer TJ, Rader D, Heiman M, et al: Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women. J Clin Endocr Metab 2004; 89: 2963-2972.

54. Wirfalt E, Hedblad B, Gullberg B, Mattisson I, Andren C, Rosander U, et al: Food patterns and components of Metabolic Syndrome in men and women: a cross-sectional study within the Malmo Diet and Cancer cohort. Am J Epidemiol 2001; 154: 1150-1159.

55. Pereira MA, Ludwig DS: Dietary fiber and body-weight regulation: observations and mechanisms. Pediatr Clin North Am 2001; 48: 969-980.

56. Davies KM, Heaney RP, Recker RR, Lappe JM,Barger-Lux MJ, Rafferty K, et al: Calcium intake and body weight. J Clin Endocrinol Metab 2000; 85: 4635-4638.

57. Pereira MA, Jacobs DR, Van Horn L, Slattery ML, Kartashov AI, Ludwig DS: Dairy consumption, obesity, and the insulin resistance syndrome in young adults: the CARDIA study. JAMA 2002; 287: 2081-2089.

58. Zemel MB, Thompson W, Milstead A, Morris K, Campbell P: Calcium and dairy acceleration of weigth and fat loss during energy restriction in obese adults. Obes Res 2004; 12: 582-590.

59. Himsworth HP: The mechanism of diabetes mellitus, I. Lancet 1939: 2: 1-6.

60. Himsworth HP: The mechanism of diabetes mellitus, II: the control of the blood sugar level. Lancet 1939: 2: 65-68.

61. Himsworth HP: The mechanism of diabetes mellitus, II: the control of the blood sugar level (cont). Lancet 1939: 2: 118-122.

62. Himsworth HP: The syndrome of diabetes mellitus and its causes. Lancet 1949: 1: 465-473.

63. Shen SW, Reaven GM, Farquhar JW: Comparison of impedance to insulin mediated glucose uptake in normal and diabetic subjects. J Clin Invest 1970; 49: 2151-2160.

64. DeFronzo RA, Tobin JD, Andres R: Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979; 237: E214-E223.

65. Ginsberg H, Kimmerling G, Olefsky JM, Reaven GM: Demonstration of insulin resistance in untreated adult onset diabetic subjects with fasting hyperglycemia. J Clin Invest 1975; 55: 454-461.

66. Reaven GM: Insulin resistance in noninsulin-dependent diabetes mellitus: does it exist and it can be measured? Am J Med 1983; 74(Suppl IA): 3-17.

67. Warran JH, Martin BC, Krowlewsky AS, Soeldner JS, Kahn CR: Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the off-spring of the diabetic parents. Ann Intern Med 1990; 113: 909-915.

68. Lillioja S, Mott DM, Spraul M, Ferraro R, Foley JE, Ravussin E, et al: Insulin resistance and insulin secretory dysfunction as precursors of non-insulin dependent diabetes mellitus. N Engl J Med 1993; 329: 1988-1992.

69. Miller CJ, Miller NE: Plasma high-density lipoprotein concentration and the development of ischaemic heart disease. Lancet 1975; 1: 16-19.

70. Carlson LA, Bottiger LE, Ahfeldt PE: Risk factors for myocardial infarction in the Stockholm prospective study: a 14 year follow-up focusing on the role of plasma triglycerides and cholesterol. Acta Med Scand 1979; 206: 351-360.

71. Fuller JH, Shipley MJ, Rose G, Jarret RJ, Keen H: Coronary-heart disease and impaired glucose tolerance: the Whitehall Study. Lancet 1980; 1: 1373-1376.

72. Castelli WP, Garrison RJ, Wilson PWF, Abbott RO, Kalonsdian S, Kannel WB: Incidence of coronary heart disease and lipoprotein cholesterol levels: the Framingham Study. JAMA 1986; 256: 2385-2387.

73. Hanley AJG, Karter AJ, Williams K, Festa A, Dagostino RD, Wagenknetch LE, et al: Prediction of type 2 diabetes mellitus with alternative definitions of the metabolic syndrome. The Insulin Resistance Atherosclerosis Study. Circulation 2005; 112: 3713-3721.

74. Reaven GM: Obesity, insulin resistance, and cardiovascular disease. Recent Prog Horm Res 2004; 59: 207-223.

75. Ninomiya JK, Lítalien G, Criqui MH, White JL, Gamst A, Chen R: Association of the metabolic syndrome with history of myocardial infarction and stroke in the Third Health and Nutrition Examination Survey. Circulation 2004; 109: 42-46.

76. Wessel TR, Arant CB, Olson MB, Johnson BD, Reis SE, Sharaf BI, et al: Relationship of physical fitness vs body mass index with coronary artery disease and cardiovascular disease in women. JAMA 2004; 292: 1179-1187.

77. Sullivan PW, Morrato EH, Ghushchyan V, Wyatt HR, Hill JO: Obesity, inactivity, and prevalence of diabetes-related cardiovascular comorbidities in the US. 2000-2002. Diabetes Care 2005; 28: 1599-1603.

78. Dekker JM, Girman C, Rhodes T, Nijpels G, Stehowner CDA, Bouter LM: Metabolic syndrome and 10-year cardiovascular disease risk in the Hoorn Study. Circulation 2005; 112: 666-673.

79. Wilson PWJ, Dagostino RB, Parise H, Sullivan L, Meigs JB: Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Circulation 2005; 112: 3066-3072.

80. Kahn R, Buse J, Ferrannini E, Stern M: The metabolic syndrome: time for a critical appraisal. Diabetes Care 2005; 28: 2289-2304.

81. Reaven G: The metabolic syndrome or the insulin resistance syndrome? Different names, different concepts, and different goals. Endocrinol Metab Clin N Am 2004; 33: 283-303.

82. Walli R, Herfort O, Michl GM, Demant T, Jager H, Dieterle C, et al: Treatment with protease inhibitors associated with peripheral insulin resistance and impaired oral glucose tolerance in HIV-I-infected patients. AIDS. 1998; 12: F167-F173.

83. American Diabetes Association: Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 2004; 27: 596-600.

84. Craft S, Watson G: Insulin and neurodegenerative disease: shared and specific mechanisms. Lancet Neurol 2004; 3: 169-178.

85. Mohanty P, Hamouda W, Garg R, Aljada A, Ghanim H, Dandona P: Glucose challenge stimulates reactive oxygen species (ROS) generation by leucocytes. J Clin Endocrinol Metab 2000; 85: 2970-2973.

86. Mohanty P, Ghanim H, Hamouda W, Aljada A, Garg R, Dandona P: Both lipid and protein intakes stimulate increased generation of reactive oxygen species by polymorphonuclear leucocytes and mononuclear cells. Am J Clin Nutr 2002; 75: 767-772.

87. Dandona P, Mohanty P, Hamouda W, Ghanim H, Aljada A, Garg R, Kumar V: Inhibitory effect of a two day fast on reactive oxygen species (ROS) generation by leucocytes and plasma ortho-tyrosine and meta-tyrosine concentrations. J Clin Endocrinol Metab 2001; 86: 2899-2902.

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

89. Kern PA, Saghizedeh M, Ong, Bosh RJ, Deem R, Simsolo RB: The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weigth loss, and relationship with lipoprotein lipase. J Clin Invest 1995; 95: 2111-2119.

90. Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM: IRS1- mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alfa and obesity-induced insulin resistance. Science 1996; 271; 665-668.

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

92. Ryden M, Dicker A, van Harmelen V, Hauner H, Brunnberg M, Perbeck L: Mapping of early signaling events in tumor necrosis factor alfa-metiated lipolysis in human fat cells. J Biol Chem 2002; 277; 1085-1091.

93. Souza SC, Palmer HJ, Kang YH, Yamamoto MT, Muliro KV, Paulson KE: TNF-alfa induction of lipolysis is mediated through activation of the extracellular signal related kinase pathway in 3T3-L1 adipocytes. J Cell Biochem 2003; 89: 1077-1086.

94. Kim KY, Kim JK, Jeon JH, Yoon SR, Choi I, Tang Y: C-Jun N-terminal kinase is involved in the suppression of adiponectin expression by TNF-alfa in 3T3-L1 adipocytes. Biochem Biophys Res Commun 2005; 327: 460-467.

95. Curat CA, Miranville A, Sengenes C, Diehl M, Tonus C, Busse R: From blood monocytes to adipose tissue-resident macrophages: induction of diapedesis by human mature adipocytes. Diabetes 2004; 53: 1285-1292.

96. Dhindsa S, Triphaty D, Mohanty P, Ghanim H, Syed T, Aljada A, Dandona P: Differential effects of glucose and alcohol on reactive oxygen species generation and intranuclear nuclear-factor kappaB in mononuclear cells. Metabolism 2004; 53: 330-334.

97. Aljada A, Ghanim H, Mohanty P, Tufail S, Bandyopathyay A, Dandona P: Glucose intake induces an increase in AP-1 and Erg-1 binding activities and tissue factor and matrix metalloproteinase expression in mononuclear cells and plasma tissue factor an matrix metalloproteinase concentrations. Am J Clin Nutr 2004; 80: 51-57.

98. Aljada A, Mohanty P, Ghanim H, Abdo T, Tripathy D, Chaudhuri A, Dandona P: Increase in intranuclear factor kappaB and decrease in inhibitor kappaB in mononuclear cells after a mixed meal: evidence for a proinflammatory effect. Am J Clin Nutr 2004; 79: 682-690.

99. Woronics JD, Gao X, Cao Z, Rhote M, Goeddel DV: IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK. Science 1997; 278: 866-869.

100. Wang S, Leonard SS, Castranova V, Vallyathan V, Shi X: The role of superoxide radicals in TNF-alpha induced NF-kappaB activation. Ann Clin Lab Sci 1999; 29: 192-199.

101. Bays H, Mandarino L, DeFronzo A: Mechanisms of endocrine disease. Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: Peroxisomal proliferated-activated receptor agonists provide a rational therapeutic approach. J Clin Endocrinol Metab 2004; 89: 463-478.

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

103. Xu H, Barnes GT, Yang Q, Tang G, Yang D, Chou CJ: Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003; 112: 1821-1830.

104. Suganami T, Nishida J, Ogawa Y: A paracrine loop between adipocytes and macrophages aggravates Inflammatory changes. Role of free fatty acids and tumor necrosis factor alfa. Arterioscler Thromb Vasc Biol 2005; 25: 2062-2068.

105. Boden G: Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 1997; 46: 2111-2119.

106. Shi L, Kishore R, McMUllen MR, Nagy LE: Lipopolysaccharide stimulation of ERK1-2 increases TNF alfa production via Erg-1. Am J Physiol (Cell Physiol) 2002; 282: C1205-C1211.

107. Comalada M, Xaus J, Valledor AF, Lopez-Lopez C, Pennington DJ, Celada A: PKC epsilon is involved in JNK Activation that mediates LPS-induced TNF-alfa, which induces apoptosis in macrophages. Am J Physiol Cell Physiol 2003; 285: C1235-C1245.

108. Tripathy D, Mohanty P, Dhinsda S, Syed T, Ghanim H, Aljada A, Dandona P: Elevation of free fatty acids induces inflammation and impairs vascular reactivity in healthy subjects. Diabetes 2003; 52: 2882-2887.

109. Lee JY, Plakidas A, Lee WH, Heikkinen A, Chanmugan P, Bray G: Differential modulation of Toll-like-receptors by fatty acids: preferential inhibition by n-3 polyunsaturated fatty acids. J Lipid Res 2003; 44: 479-486.

110. Harberd N, Artavanis-Tsakonas S, Berridge MJ, Bourne H, Cantley L, Downward J: Signaling through enzyme-linked cell-surface receptors. pp 871-892. Chapter 15. Cell Communication. En: Molecular biology of the cell. 2nd edition 2002. Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. (Eds) GS Taylor, Francis Group.

111. Dandona P, Aljada A, Chaudhuri A, Mohanty P, Garg R: Metabolic syndrome. A comprehensive perspective, based on interactions between obesity, diabetes, and inflammation. Circulation 2005; 111: 1448-1454.

112. Sen-Benerjee S, Mir S, Lin Z, Hamik A, Atkins GB, Das H: Kruppel-like factor 2 as a novel mediator of statin effects in endothelial cells. Circulation 2005; 112: 720-726.

113. Dimmeler S, Fleming I, Fisslthale B, Hermann C, Busse R, Zeiher AM: Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 1999; 399: 601-605.

114. Cho H, Mu J, Kim JK, Thorvalsden JL, Chu Q, Crenshaw EB III: Insulin resistance and diabetes mellitus-like syndrome in mice lacking the protein kinase Akt-2 (PKB). Science 2001; 292: 1728-1731.

115. Scognaniglio R, Negut C, DeKreutzenberg SV, Tiengo A, Avogadro A: Postprandial myocardial perfusion in healthy subjects and in type 2 diabetic patients. Circulation 2005; 112: 179-184.

116. Ceriello A, Assaloni R, DaRos R, Maier A, Piconi L, Quagliario L: Effect of atorvastatin and irbesartan, alone and in combination, on postprandial endothelial dysfunction, oxidative stress, and inflammation in type 2 diabetic patients. Circulation 2005; 111: 2518-2524.

117. Lteif AA, Han K, Mather KJ: Obesity, insulin resistance and the metabolic syndrome. Determinants of endothelial dysfunction in whites and blacks. Circulation 2005; 112: 32-38.

118. Lerman A, Zeiher AM: Endothelial function. Cardiac events. Circulation 2005; 111: 363-368.

119. Alexánderson E: Cuantificación de la perfusión miocárdica y la angioTAC coronaria: una nueva forma de evaluar la disfunción endotelial en el SM a través de la prueba “de frío”. Presentación oral. XXIV Congreso Nal de Cardiología-XX Congreso Interamericano de Cardiología. Cancún, México, 2005.

120. Goldschmidt-Clermont PJ, Creager MA, Lorsordo DW, Lam GKW, Wassef M, Dzau VJ: Atherosclerosis 2005: Recent discoveries and novel hypotheses. Circulation 2005; 112: 3348-3353.

121. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al: Diagnosis and Management of the Metabolic Syndrome: An American Heart Association-National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005; 112: 2735-2752.

122. 122 Grundy SM: Metabolic Syndrome Scientific Statement by the American Heart Association and the National Heart, Lung, and Blood Institute. Editorial. Atheroscler Thromb Vasc Biol 2005; 25: 2243-2244.