提示: 手机请竖屏浏览!

异位脂肪在胰岛素抵抗、血脂异常和心血管代谢疾病中的作用
Ectopic Fat in Insulin Resistance, Dyslipidemia, and Cardiometabolic Disease


Gerald I. Shulman ... 心脑血管疾病 糖尿病 • 2014.09.18
相关阅读
• 无明显心血管危险因素的动脉粥样硬化

目前全世界有超过3.33亿人患2型糖尿病,该疾病是引起终末期肾病、非创伤性肢体缺损和就业成人失明的主要原因,估计每年在全球产生的医疗费用超过5,000亿美元1。此外,全球范围内的2型糖尿病患病率预计将在接下来20年内增加75%以上,其中增幅最明显的是亚洲和印度次大陆1。尽管β细胞功能受损是从正常血糖发展到高血糖的最终原因,但胰岛素抵抗早于β细胞功能障碍出现,并且在2型糖尿病的发病机制中起到重要作用2,3。碳水化合物摄入体内后,葡萄糖主要以糖原形式储存于肌肉和肝脏内,这些器官内胰岛素敏感性的变化可导致空腹和餐后高血糖4,5

本综述重点讨论近期应用磁共振波谱法(MRS)开展的研究,这些研究表明肌肉和肝脏胰岛素抵抗的发病机制中涉及异位脂质累积,并且阐明肌肉特异性胰岛素抵抗在促进肝内脂肪生成增加、非酒精性脂肪肝病和致动脉粥样硬化性血脂异常方面发挥的作用。然后,我提出从异位脂质诱发的胰岛素抵抗发展到糖耐量减低和2型糖尿病的过程中,炎症与巨噬细胞诱导的脂解之间有潜在关联。





作者信息

Gerald I. Shulman, M.D., Ph.D.
From the Howard Hughes Medical Institute and the Departments of Internal Medicine and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT. Address reprint requests to Dr. Shulman at gerald.shulman@yale.edu.

 

参考文献

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;92:983-987

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;322:223-228

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;97:126-132

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;42:113-116[Erratum, 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;48:1600-1606

8. Stefan N, Kantartzis K, Machann J, et al. Identification and characterization of metabolically benign obesity in humans. Arch Intern Med 2008;168:1609-1616

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;1:785-789

10. Roden M, Price TB, Perseghin G, et al. Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest 1996;97:2859-2865

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;103:253-259

12. Petersen KF, Hendler R, Price T, et al. 13C/31P NMR studies on the mechanism of insulin resistance in obesity. Diabetes 1998;47:381-386

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;341:240-246

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;335:1357-1362

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;48:1270-1274

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;277:50230-50236

17. Kim JK, Fillmore JJ, Sunshine MJ, et al. PKC-theta knockout mice are protected from fat-induced insulin resistance. J Clin Invest 2004;114:823-827

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;57:2644-2651

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;279:45304-45307

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;51:2005-2011

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;111:9597-9602

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;115:3587-3593

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;50:553-557

25. Samuel VT, Liu ZX, Qu X, et al. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem 2004;279:32345-32353

26. Krssak M, Brehm A, Bernroider E, et al. Alterations in postprandial hepatic glycogen metabolism in type 2 diabetes. Diabetes 2004;53:3048-3056

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;90:1323-1327

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;104:16480-16485

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;13:1193-1202

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;116:817-824

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;104:17075-17080

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;108:16381-16385

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;54:1447-1456

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;109:1345-1350

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;12:668-674

38. Petersen KF, Befroy D, Dufour S, et al. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 2003;300:1140-1142

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;61:877-887

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;350:664-671

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;275:8456-8460

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;98:7522-7527

43. Ferreira LD, Pulawa LK, Jensen DR, Eckel RH. Overexpressing human lipoprotein lipase in mouse skeletal muscle is associated with insulin resistance. Diabetes 2001;50:1064-1068[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;139:149-153

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;110:1869-1874

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;15:570-573

47. Amati F, Dube JJ, Alvarez-Carnero E, et al. Skeletal muscle triglycerides, diacylglycerols, and ceramides in insulin resistance: another paradox in endurance-trained athletes? Diabetes 2011;60:2588-2597

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;30:211-221

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;99:15983-15987

50. Reznick RM, Zong H, Li J, et al. Aging-associated reductions in AMP-activated protein kinase activity and mitochondrial biogenesis. Cell Metab 2007;5:151-156

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;56:1376-1381

52. Sleigh A, Raymond-Barker P, Thackray K, et al. Mitochondrial dysfunction in patients with primary congenital insulin resistance. J Clin Invest 2011;121:2457-2461

53. Choi CS, Fillmore JJ, Kim JK, et al. Overexpression of uncoupling protein 3 in skeletal muscle protects against fat-induced 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;51:2944-2950

55. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002;346:1221-1231

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;54:603-608

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;103:18273-18277

58. Petersen KF, Dufour S, Hariri A, et al. Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N Engl J Med 2010;362:1082-1089

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;36:774-782

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;54:1650-1660

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;154:1021-1028

62. Romeo S, Kozlitina J, Xing C, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008;40:1461-1465

63. Cortes 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;9:165-176

64. Gandotra S, Le Dour C, Bottomley W, et al. Perilipin deficiency and autosomal dominant partial lipodystrophy. N Engl J Med 2011;364:740-748

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;54:2506-2514

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;109:8236-8240

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;355:2297-2307

69. Perseghin G, Ghosh S, Gerow K, Shulman GI. Metabolic defects in lean nondiabetic offspring of NIDDM parents: a cross-sectional study. Diabetes 1997;46:1001-1009

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;104:12587-12594

71. Rabol 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;108:13705-13709

72. Perry RJ, Zhang X-M, Zhang D, et al. Leptin reverses diabetes by suppression of the hypothalamic-pituitary-adrenal axis. Nat Med 2014;20:759-763

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;106:12121-12126

74. Camporez JP, Jornayvaz FR, Petersen MC, et al. Cellular mechanisms by which FGF21 improves insulin sensitivity in male mice. Endocrinology 2013;154:3099-3109

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;18:740-748

服务条款 | 隐私政策 | 联系我们