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Hepatic steatosis and type 2 diabetes mellitus

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Abstract

Type 2 diabetes is strongly associated with nonalcoholic fatty liver disease (NAFLD), a spectrum of liver damage that ranges from relatively benign hepatic steatosis to potentially fatal cirrhosis. The severities of insulin resistance and liver damage parallel each other, with the greatest prevalence of cirrhosis occurring in cirrhotics. However, it is unknown whether one of these conditions causes the other, or if both are consequences of another process. Experimental evidence suggests that both insulin resistance and NAFLD result from a chronic inflammatory state. The mechanisms driving this chronic inflammation are unknown but might include the egress of products from intestinal bacteria into the portal blood, liver, and systemic circulation to trigger a sustained inflammatory cytokine response in genetically susceptible individuals. More research is needed to evaluate this hypothesis and to determine the benefits of treatments that interrupt this pathogenic cascade.

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References and Recommended Reading

  1. Harris MI, Elegal KM, Cowie CC, et al.: Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults. Diabetes Care 1998, 21:518–524.

    Article  PubMed  CAS  Google Scholar 

  2. Moss SE, Klein R, Klein BE: Cause-specific mortality in a population-based study of diabetes. Am J Public Health 1991, 81:1158–1162.

    PubMed  CAS  Google Scholar 

  3. Ludwig J, Viggiano RT, McGill DB: Nonalcoholic steatohepatitis. Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980, 55:342–348.

    Google Scholar 

  4. Matteoni C, Younossi ZM, McCullough A: Nonalcoholic fatty liver disease: a spectrum of clinical pathological severity. Gastroenterology 1999, 116:1413–1419.

    Article  PubMed  CAS  Google Scholar 

  5. Clarke JM, Brancati F, Diehl AM: Prevalence of nonalcoholic fatty liver disease in the general population of the United States. JAMA 2002, in press.

  6. Caldwell SH, Oelsner DH, Iezzoni JC, et al.: Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology 1999, 29:664–669.

    Article  PubMed  CAS  Google Scholar 

  7. Falck-Ytter Y, Younassi ZM, Marchesini G, McCullough AJ: Clinical features and natural history of nonalcoholic steatosis syndromes. Semin Liver Dis 2001, 21:71–76. Succinct but comprehensive summary of the clinical features of NAFLD.

    Article  Google Scholar 

  8. Bellentani S, Tiribelli C, Saccoccio G, et al., and the Dyonisos study group: Prevalence of chronic liver disease in the general population of northern Italy: the Dyonisos study. Hepatology 1994, 20:1442–1449.

    PubMed  CAS  Google Scholar 

  9. Nomura H, Kashiwagi S, Hayashi J, et al.: Prevalence of fatty liver in a general population of Okinawa, Japan. Jpn J Med 1988, 27:142–149.

    PubMed  CAS  Google Scholar 

  10. Gines P, Quintero E, Arroyo V, et al.: Compensated cirrhosis: natural history and prognostic factors. Hepatology 1987, 7:122–128.

    Article  PubMed  CAS  Google Scholar 

  11. Zelman S: The liver in obesity. Arch Intern Med 1958, 90:141–156.

    Google Scholar 

  12. Angulo P, Deach JC, Batts KP, Lindor KD: Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999, 30:1356–1362.

    Article  PubMed  CAS  Google Scholar 

  13. Ratziu V, Giral P, Charlotte F, et al.: Liver fibrosis in overweight patients. Gastroenterology 2000, 118:1117–1123.

    Article  PubMed  CAS  Google Scholar 

  14. Cortez-Pinto H, Camilo ME, Baptista A, et al.: Nonalcoholic fatty liver: another feature of the metabolic syndrome? Clin Nutr 1999, 18:353–358.

    Article  PubMed  CAS  Google Scholar 

  15. James O: Nonalcoholic steatohepatitis (NASH): a disease of emerging identity and importance. J Hepatol 1998, 20:495–501.

    Article  Google Scholar 

  16. Ikai E, Ishizaki M, Suzuki Y, et al.: Association between hepatic steatosis, insulin resistance and hyperinsulinemia as related to hypertension in alcohol consumers and obese people. J Hum Hypertens 1995, 101–105.

  17. Itoh S, Tsukada T, Motomura A, Ichinoe A: Five patients with nonalcoholic diabetic cirrhosis. Acta Hepto-Gastroenterol 1979, 26:90–97.

    CAS  Google Scholar 

  18. Nagore N, Scheuer P: The pathology of diabetic hepatitis. J Pathol 1988, 156:155–160.

    Article  PubMed  CAS  Google Scholar 

  19. Powell EE, Cooksley GE, Hanson R, et al.: The natural history of nonalcoholic steatohepatitis: a follow-up study of 42 patients follow for up to 21 years. Hepatology 1990, 11:74–80.

    Article  PubMed  Google Scholar 

  20. Bacon B, Faravash MJ, Janney CG, et al.: Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology 1994, 107:1103–1106.

    PubMed  CAS  Google Scholar 

  21. Falchuk KR, Fiske SC, Haggit RC, et al.: Pericentral hepatic fibrosis and intracellular hyalin in diabetes mellitus. Gastroenterology 1980, 78:535–540.

    PubMed  CAS  Google Scholar 

  22. Chitturi S, Farrell GC: Etiopathogenesis of nonalcoholic steatohepatitis. Semin Liver Dis 2001, 21:27–41.

    Article  PubMed  CAS  Google Scholar 

  23. Stone BG, Van Thiele DH: Diabetes mellitus and the liver. Semin Liver Dis 1985, 5:8–28.

    PubMed  CAS  Google Scholar 

  24. Batman PA, Scheuer PJ: Diabetic hepatitis preceding the onset of glucose intolerance. Histopathology 1985, 9:237–243.

    Article  PubMed  CAS  Google Scholar 

  25. Marchesini G, Brizi M, Morselli-Labate AM, et al.: Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med 1999, 107:450–455. Identifies insulin resistance in very early stages of NAFLD, suggesting a role for the former in the pathogenesis of the latter.

    Article  PubMed  CAS  Google Scholar 

  26. Lee JH, Rhee PL, Lee JK, et al.: Role of hyperinsulinemia and glucose intolerance in the pathogenesis fatty liver disease. Korean J Intern Med 1998, 13:12–14.

    PubMed  CAS  Google Scholar 

  27. Leonardo A: Fatty liver and nonalcoholic steatohepatitis: where do we stand and where are we going? J Dig Dis 1999, 17:80–89.

    Article  Google Scholar 

  28. Fong D, Lindor KD: Metabolic and nutritional considerations in nonalcoholic steatohepatitis. Hepatology 2000, 32:3–10.

    Article  PubMed  CAS  Google Scholar 

  29. Koteish A, Diehl AM: Animal models of steatosis. Semin Liver Dis 2001, 21:89–104. Comprehensive review about various animal models of hepatic steatosis.

    Article  PubMed  CAS  Google Scholar 

  30. Pelleymounter MA, Cullen MF, Baker MB, et al.: Effects of the obese gene product on body weight regulation in ob/ob mice. Science 1995, 269:540–543.

    Article  PubMed  CAS  Google Scholar 

  31. Lin HZ, Yang SQ, Kujhada F, et al.: Metformin reverses nonalcoholic fatty liver disease in obese leptin-deficient mice. Nat Med 2000, 6:998–1003.

    Article  PubMed  CAS  Google Scholar 

  32. Shimano H, Horton JD, Hammer RE, et al.: Overproduction of cholesterol and fatty acids causes massive liver enlargement in transgenic mice expressing truncated SREBP-1a. J Clin Invest 1996, 98:1575–1584.

    PubMed  CAS  Google Scholar 

  33. Shimomura I, Hammer RE, Richardson JA, et al.: Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev 1998, 12:3182–3194.

    PubMed  CAS  Google Scholar 

  34. Shimomura I, Hammer RE, Ikemoto S, et al.: Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 1999, 401:73–76.

    Article  PubMed  CAS  Google Scholar 

  35. Reitman ML, Mason MM, Moitra J, et al.: Transgenic mice lacking white fat: models for understanding human lipoatrophic diabetes. Ann N Y Acad Sci 1999, 10:289–296.

    Article  Google Scholar 

  36. Yang SQ, Lin HZ, Lane MD, et al.: Obesity increases sensitivity to endotoxin liver injury: implications for pathogenesis of steatohepatitis. Proc Natl Acad Sci U S A 1997, 94:2557–2562.

    Article  PubMed  CAS  Google Scholar 

  37. Chavin K, Yang SQ, Lin HZ, et al.: Obesity induces expression of uncoupling protein-2 in hepatocytes and promotes liver ATP depletion. J Biol Chem 1999, 274:5692–5700.

    Article  PubMed  CAS  Google Scholar 

  38. Day CP, James O: Steatohepatitis: a tale of two "hits"? Gastroenterology 1998, 114:842–845. Outlines the "multiple-hit" hypothesis for NAFLD progression.

    Article  PubMed  CAS  Google Scholar 

  39. Diehl AM: Cytokine regulation of liver injury and repair. Immunol Rev 2000, 174:160–171.

    Article  PubMed  CAS  Google Scholar 

  40. Cope K, Risby T, Diehl AM: Increased gastrointestinal ethanol production in obese mice: implications for fatty liver disease pathogenesis. Gastroenterology 2000, 119:1340–1347.

    Article  PubMed  CAS  Google Scholar 

  41. Nair S, Cope K, Risby T, Diehl AM: Obesity and female gender increase breath ethanol concentration: potential implications for the pathogenesis of nonalcoholic steatohepatitis. Am J Gastroenterol 2001, 96:1200–1204.

    Article  PubMed  CAS  Google Scholar 

  42. Mezey E, Imbembo AL, Potter JJ, et al.: Endogenous ethanol production and hepatic disease following jejunoileal bypass for morbid obesity. Am J Clin Nutr 1975, 28:1277–1283.

    PubMed  CAS  Google Scholar 

  43. Halverson JD, Wise L, Wazna MF, et al.: Jejunoileal bypass for morbid obesity: a critical appraisal. Am J Med 1978, 64:461–467.

    Article  PubMed  CAS  Google Scholar 

  44. Thiele GM, Tuma DJ, Miller JA, et al.: Monoclonal and polyclonal antibodies recognizing acetaldehyde protein adducts. Biochem Pharmacol 1998, 56:1515–1523.

    Article  PubMed  CAS  Google Scholar 

  45. Kern PA, Saghizaheh M, Ong JM, et al.: The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J Clin Invest 1995, 95:2111–2119.

    Article  PubMed  CAS  Google Scholar 

  46. Sakkinen PA, Wahl P, Cushman M, et al.: Clustering of procoagulation, inflammation and fibrinolysis variables with metabolic factors in insulin resistance. Am J Epidemiol 2000, 152:897–907.

    Article  PubMed  CAS  Google Scholar 

  47. Marceau P, Iron S, Hould FS, et al.: Liver pathology and the metabolic syndrome X in severe obesity. J Clin Endocrinol Metab 1999, 84:1513–1517.

    Article  PubMed  CAS  Google Scholar 

  48. Hotamisligil GS, Peraldi SP, Budavari A, et al.: IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNFalpha-and obesity-induced insulin resistance. Science 1996, 271:665–668.

    Article  PubMed  CAS  Google Scholar 

  49. Solomon SS, Mishra SK, Cwik C, et al.: Pioglitazone and metformin reverse insulin resistance induced by tumor necrosis factor-alpha in liver cells. Horm Metab Res 1997, 29:379–382.

    Article  PubMed  CAS  Google Scholar 

  50. Kakuma T, Lee Y, Higa M, Wang Z-W, et al.: Leptin, troglitazone, and the expression of sterol regulatory element binding proteins in liver and pancreatic islets. Proc Natl Acad Sci U S A 2000, 97:8536–8541.

    Article  PubMed  CAS  Google Scholar 

  51. Kwong SC, Brubacher J: Phenformin and lactic acidosis: a case report and review. J Emerg Med 1998, 16:881–886.

    Article  PubMed  CAS  Google Scholar 

  52. Stang M, Wysowski DK, Butler-Jones D: Incidence of lactic acidosis in metformin users. Diabetes Care 1999, 22:925–927.

    Article  PubMed  CAS  Google Scholar 

  53. HHS Secretary Thompson to Announce Results of Diabetes Prevention Program [press release]. Bethesda, MD: National Institutes of Health; August 2001.

  54. Scheen AJ: Thiazolidinediones and liver toxicity. Diabetes Metab 2001, 27:305–313.

    PubMed  CAS  Google Scholar 

  55. Miller ERJ, Erlinger TP, Young DR, et al.: Lifestyle changes that reduce blood pressure. Implementation in clinical practice. J Clin Hypertens 1999, 1:191–198.

    Google Scholar 

  56. Palmer M, Schaffner F: Effect of weight reduction on hepatic abnormalities in overweight patients. Gastroenterology 1990, 99:1408–1411.

    PubMed  CAS  Google Scholar 

  57. Poulsom R: Morphological changes of organs after sucrose or fructose feeding. Prog Biochem Pharmacol 1986, 21:104–134.

    PubMed  CAS  Google Scholar 

  58. Newberne PM: Effect of two synthetic antioxidants, vitamin E and ascorbic acid, on the choline-deficient rat. J Nutr 1969, 97:219–231.

    PubMed  CAS  Google Scholar 

  59. Lavine JE: Vitamin E treatment of non-alcoholic steatohepatitis in children: a pilot study. J Pediatr 2000, 136:734–738.

    Article  PubMed  CAS  Google Scholar 

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Clark, J.M., Diehl, A.M. Hepatic steatosis and type 2 diabetes mellitus. Curr Diab Rep 2, 210–215 (2002). https://doi.org/10.1007/s11892-002-0085-3

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