Lípidos ectópicos, resistencia a la insulina y enfermedad cardiometabólica

REFERENCIAS
1. International Diabetes Federation. IDF diabetes atlas. 6th ed. Brussels: International Diabetes Federation, 2014 (http://www.idf.org/diabetesatlas).
2. Porte D Jr, Kahn SE. Beta-cell dysfunction and failure in type 2 diabetes: potential mechanisms. Diabetes 2001;50: Suppl 1:S160-S163.
3. Rothman DL, Magnusson I, Cline G, et al. Decreased muscle glucose transport/ phosphorylation is an early defect in the pathogenesis of non-insulin-dependent diabetes mellitus. Proc Natl Acad Sci U S A 1995; 92:983-7.
4. Shulman GI, Rothman DL, Jue T, Stein P, DeFronzo RA, Shulman RG. Quantitation of muscle glycogen synthesis in normal subjects and subjects with non–insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy. N Engl J Med 1990; 322:223-8.
5. Taylor R, Magnusson I, Rothman DL, et al. Direct assessment of liver glycogen storage by 13C nuclear magnetic resonance spectroscopy and regulation of glucose homeostasis after a mixed meal in normal subjects. J Clin Invest 1996; 97: 126-32.
6. Krssak M, Falk Petersen K, Dresner A, et al. Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study. Diabetologia 1999; 42:113-6. [Errata, Diabetologia 1999;42:386, 1269.]
7. Perseghin G, Scifo P, De Cobelli F, et al. Intramyocellular triglyceride content is a determinant of in vivo insulin resistance in humans: a 1H-13C nuclear magnetic resonance spectroscopy assessment in offspring of type 2 diabetic parents. Diabetes 1999; 48:1600-6.
8. Stefan N, Kantartzis K, Machann J, et al. Identification and characterization of metabolically benign obesity in humans. Arch Intern Med 2008; 168:1609-16.
9. Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle: its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1963;1: 785-9.
10. Roden M, Price TB, Perseghin G, et al. Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest 1996; 97:2859-65.
11. Dresner A, Laurent D, Marcucci M, et al. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest 1999; 103:253-9.
12. Petersen KF, Hendler R, Price T, et al. 13C/31P NMR studies on the mechanism of insulin resistance in obesity. Diabetes 1998;47: 381-6.
13. Cline GW, Petersen KF, Krssak M, et al. Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in type 2 diabetes. N Engl J Med 1999; 341:240-6.
14. Perseghin G, Price TB, Petersen KF, et al. Increased glucose transport–phosphorylation and muscle glycogen synthesis after exercise training in insulin-resistant subjects. N Engl J Med 1996; 335: 1357-62.
15. Griffin ME, Marcucci MJ, Cline GW, et al. Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes 1999; 48:1270-4.
16. Yu C, Chen Y, Cline GW, et al. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem 2002; 277:50230-6.
17. Kim JK, Fillmore JJ, Sunshine MJ, et al. PKC-theta knockout mice are protected from fat-induced insulin resistance. J Clin Invest 2004; 114:823-7.
18. Morino K, Neschen S, Bilz S, et al. Muscle-specific IRS-1 Ser→Ala transgenic mice are protected from fat-induced insulin resistance in skeletal muscle. Diabetes 2008; 57:2644-51.
19. Li Y, Soos TJ, Li X, et al. Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101). J Biol Chem 2004; 279:45304-7.
20. Itani SI, Ruderman NB, Schmieder F, Boden G. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes 2002; 51: 2005-11.
21. Szendroedi J, Yoshimura T, Phielix E, et al. Role of diacylglycerol activation of PKCθ in lipid-induced muscle insulin resistance in humans. Proc Natl Acad Sci U S A 2014; 111:9597-602.
22. Morino K, Petersen KF, Dufour S, et al. Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. J Clin Invest 2005;115: 3587-93.
23. Corbould A, Kim YB, Youngren JF, et al. Insulin resistance in the skeletal muscle of women with PCOS involves intrinsic and acquired defects in insulin signaling. Am J Physiol Endocrinol Metab 2005;288: E1047-E1054.
24. Itani SI, Pories WJ, Macdonald KG, Dohm GL. Increased protein kinase C theta in skeletal muscle of diabetic patients. Metabolism 2001; 50:553-7.
25. Samuel VT, Liu ZX, Qu X, et al. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem 2004; 279:32345-53.
26. Krssak M, Brehm A, Bernroider E, et al. Alterations in postprandial hepatic glycogen metabolism in type 2 diabetes. Diabetes 2004; 53:3048-56.
27. Magnusson I, Rothman DL, Katz LD, Shulman RG, Shulman GI. Increased rate of gluconeogenesis in type II diabetes mellitus: a 13C nuclear magnetic resonance study. J Clin Invest 1992; 90:1323-7.
28. Choi CS, Savage DB, Abu-Elheiga L, et al. Continuous fat oxidation in acetyl-CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity. Proc Natl Acad Sci U S A 2007; 104:16480-5.
29. Matsuzaka T, Shimano H, Yahagi N, et al. Crucial role of a long-chain fatty acid elongase, Elovl6, in obesity-induced insulin resistance. Nat Med 2007; 13:1193-202.
30. Savage DB, Choi CS, Samuel VT, et al. Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2. J Clin Invest 2006; 116:817-24.
31. Varela GM, Antwi DA, Dhir R, et al. Inhibition of ADRP prevents diet-induced insulin resistance. Am J Physiol Gastrointest Liver Physiol  2008; 295:G621-G628.
32. Zhang D, Liu Z-X, Choi CS, et al. Mitochondrial dysfunction due to long-chain Acyl-CoA dehydrogenase deficiency causes hepatic steatosis and hepatic insulin resistance. Proc Natl Acad Sci U S A 2007; 104:17075-80.
33. Kumashiro N, Erion DM, Zhang D, et al. Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease. Proc Natl Acad Sci U S A 2011; 108:16381-5.
34. Magkos F, Su X, Bradley D, et al. Intrahepatic diacylglycerol content is associated with hepatic insulin resistance in obese subjects. Gastroenterology 2012; 142(7):1444.e2-1446.e2.
35. Raddatz K, Turner N, Frangioudakis G, et al. Time-dependent effects of Prkce deletion on glucose homeostasis and hepatic lipid metabolism on dietary lipid oversupply in mice. Diabetologia 2011;54: 1447-56.
36. Petersen KF, Oral EA, Dufour S, et al. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest 2002; 109:1345-50.
37. Lee HY, Choi CS, Birkenfeld AL, et al.Targeted expression of catalase to mitochondria prevents age-associated reductions in mitochondrial function and insulin resistance. Cell Metab 2010; 12:668-74.
38. Petersen KF, Befroy D, Dufour S, et al. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 2003; 300:1140-2.
39. Morino K, Petersen KF, Sono S, et al. Regulation of mitochondrial biogenesis by lipoprotein lipase in muscle of insulin resistant offspring of parents with type 2 diabetes. Diabetes 2012; 61:877-87.
40. 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.
41. Kim JK, Gavrilova O, Chen Y, Reitman ML, Shulman GI. Mechanism of insulin resistance in A-ZIP/F-1 fatless mice. J Biol Chem 2000; 275:8456-60.
42. Kim JK, Fillmore JJ, Chen Y, et al. Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. Proc Natl Acad Sci U S A 2001;98:7522-7.
43. Ferreira LD, Pulawa LK, Jensen DR, Eckel RH. Overexpressing human lipoprotein lipase in mouse skeletal muscle is associated with insulin resistance. Diabetes 2001; 50:1064-8. [Erratum, Diabetes 2001; 50:1512.]
44. Amaro A, Fabbrini E, Kars M, et al. Dissociation between intrahepatic triglyceride content and insulin resistance in familial hypobetalipoproteinemia. Gastroenterology 2010; 139:149-53.
45. Cantley JL, Yoshimura T, Camporez JP, et al. CGI-58 knockdown sequesters diacylglycerols in lipid droplets/ER-preventing diacylglycerol-mediated hepatic insulin resistance. Proc Natl Acad Sci U S A 2013; 110:1869-74.
46. Farese RV Jr, Zechner R, Newgard CB, Walther TC. The problem of establishing relationships between hepatic steatosis and hepatic insulin resistance. Cell Metab 2012; 15:570-3.
47. Amati F, Dubé JJ, Alvarez-Carnero E, et al. Skeletal muscle triglycerides, diacylglycerols, and ceramides in insulin resistance: another paradox in endurancetrained athletes? Diabetes 2011; 60: 2588-97.
48. Boumezbeur F, Mason GF, de Graaf RA, et al. Altered brain mitochondrial metabolism in healthy aging as assessed by in vivo magnetic resonance spectroscopy. J Cereb Blood Flow Metab 2010; 30: 211-21.
49. Zong H, Ren JM, Young LH, et al. AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc Natl Acad Sci U S A 2002; 99:15983-7.
50. Reznick RM, Zong H, Li J, et al. Aging associated reductions in AMP-activated protein kinase activity and mitochondrial biogenesis. Cell Metab 2007; 5:151-6.
51. Befroy DE, Petersen KF, Dufour S, et al. Impaired mitochondrial substrate oxidation in muscle of insulin-resistant offspring of type 2 diabetic patients. Diabetes 2007; 56:1376-81.
52. Sleigh A, Raymond-Barker P, Thackray K, et al. Mitochondrial dysfunction in patients with primary congenital insulin resistance. J Clin Invest 2011; 121:2457-61.
53. Choi CS, Fillmore JJ, Kim JK, et al. Overexpression of uncoupling protein 3 in skeletal muscle protects against fatinduced insulin resistance. J Clin Invest 2007; 117:1995-2003.
54. Kelley DE, He J, Menshikova EV, Ritov VB. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 2002; 51:2944-50.
55. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002; 346:1221-31.
56. Petersen KF, Dufour S, Befroy D, Lehrke M, Hendler RE, Shulman GI. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes 2005; 54:603-8.
57. Petersen KF, Dufour S, Feng J, et al. Increased prevalence of insulin resistance and nonalcoholic fatty liver disease in Asian-Indian men. Proc Natl Acad Sci U S A 2006; 103:18273-7.
58. Petersen KF, Dufour S, Hariri A, et al. Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N Engl J Med 2010; 362:1082-9.
59. Peter A, Kantartzis K, Machicao F, et al. Visceral obesity modulates the impact of apolipoprotein C3 gene variants on liver fat content. Int J Obes (Lond) 2012; 36:774-82.
60. Lee HY, Birkenfeld AL, Jornayvaz FR, et al. Apolipoprotein CIII overexpressing mice are predisposed to diet-induced hepatic steatosis and hepatic insulin resistance. Hepatology 2011; 54:1650-60.
61. Camporez JP, Jornayvaz FR, Lee HY, et al. Cellular mechanism by which estradiol protects female ovariectomized mice from high-fat diet-induced hepatic and muscle insulin resistance. Endocrinology 2013; 154:1021-8.
62. Romeo S, Kozlitina J, Xing C, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008; 40:1461-5.
63. Cortés VA, Curtis DE, Sukumaran S, et al. Molecular mechanisms of hepatic steatosis and insulin resistance in the AGPAT2-deficient mouse model of congenital generalized lipodystrophy. Cell Metab 2009; 9:165-76.
64. Gandotra S, Le Dour C, Bottomley W, et al. Perilipin deficiency and autosomal dominant partial lipodystrophy. N Engl J Med 2011; 364:740-8.
65. Lim EL, Hollingsworth KG, Aribisala BS, Chen MJ, Mathers JC, Taylor R. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia 2011; 54:2506-14.
66. Petersen KF, Dufour S, Morino K, Yoo PS, Cline GW, Shulman GI. Reversal of muscle insulin resistance by weight reduction in young, lean, insulin-resistant offspring of parents with type 2 diabetes. Proc Natl Acad Sci U S A 2012; 109:8236-40.
67. Mayerson AB, Hundal RS, Dufour S, et al. The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes 2002; 51:797-802.
68. Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006; 355:2297-307.
69. Perseghin G, Ghosh S, Gerow K, Shulman GI. Metabolic defects in lean nondiabetic offspring of NIDDM parents: a cross-sectional study. Diabetes 1997; 46:1001-9.
70. Petersen KF, Dufour S, Savage DB, et al. The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome. Proc Natl Acad Sci U S A 2007; 104:12587-94.
71. Rab.l R, Petersen KF, Dufour S, Flannery C, Shulman GI. Reversal of muscle insulin resistance with exercise reduces postprandial hepatic de novo lipogenesis in insulin resistant individuals. Proc Natl Acad Sci U S A 2011; 108:13705-9.
72. Perry RJ, Zhang X-M, Zhang D, et al. Leptin reverses diabetes by suppression of the hypothalamic–pituitary–adrenal axis. Nat Med 2014; 20:759-63.
73. Samuel VT, Beddow SA, Iwasaki T, et al. Fasting hyperglycemia is not associated with increased expression of PEPCK or G6Pc in patients with type 2 diabetes. Proc Natl Acad Sci U S A 2009; 106:12121-6.
74. Camporez JP, Jornayvaz FR, Petersen MC, et al. Cellular mechanisms by which FGF21 improves insulin sensitivity in male mice. Endocrinology 2013; 154:3099-109.
75. Perry RJ, Kim T, Zhang XM, et al. Reversal of hypertriglyceridemia, fatty liver disease, and insulin resistance by a liver targeted mitochondrial uncoupler. Cell Metab 2013; 18:740-8.