Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease

New England Journal of Medicine

Volumn 371, Issue 12, 2014, Pages 1131-1141

  Shulman, Gerald I ^a  

^a YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; FIBROBLAST GROWTH FACTOR 21; GLUCOSE; INSULIN;

BARIATRIC SURGERY; CARBOHYDRATE DIET; CARDIOMETABOLIC DISEASE; DISEASE ASSOCIATION; DISORDERS OF MITOCHONDRIAL FUNCTIONS; DRUG TARGETING; DYSLIPIDEMIA; ECTOPIC LIPID ACCUMULATION; ENERGY EXPENDITURE; FATTY ACID METABOLISM; GENETIC POLYMORPHISM; GLUCOSE METABOLISM; HEART DISEASE; HUMAN; HYPERGLYCEMIA; IMPAIRED GLUCOSE TOLERANCE; INFLAMMATION; INSULIN RESISTANCE; LIPID STORAGE; LIPOGENESIS; LIVER METABOLISM; MACROPHAGE FUNCTION; METABOLIC DISORDER; MUSCLE METABOLISM; NON INSULIN DEPENDENT DIABETES MELLITUS; NONALCOHOLIC FATTY LIVER; NONHUMAN; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; OBESITY; PANCREAS ISLET CELL FUNCTION; PATHOGENESIS; REVIEW; WEIGHT REDUCTION; ADIPOSE TISSUE; CHORISTOMA; LIPOLYSIS; METABOLISM; MITOCHONDRION; PHYSIOLOGY; SKELETAL MUSCLE;

ADIPOSE TISSUE; CHORISTOMA; DIABETES MELLITUS, TYPE 2; DYSLIPIDEMIAS; HUMANS; HYPERGLYCEMIA; INSULIN RESISTANCE; LIPOLYSIS; MAGNETIC RESONANCE SPECTROSCOPY; MITOCHONDRIA; MUSCLE, SKELETAL; OBESITY;

EID: 84907386500     PISSN: 00284793     EISSN: 15334406     Source Type: Journal    
DOI: 10.1056/NEJMra1011035     Document Type: Review

References (75)

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 insulinresistant 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. Agingassociated 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. Rabøl 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 livertargeted mitochondrial uncoupler. Cell Metab 2013;18:740-8.