Digestive Diseases and Sciences

, Volume 56, Issue 12, pp 3655–3663 | Cite as

Nonalcoholic Fatty Liver Disease Markers Are Associated with Insulin Resistance in Type 1 Diabetes

  • Tomislav BulumEmail author
  • Branko Kolarić
  • Lea Duvnjak
  • Marko Duvnjak
Original Article



Nonalcoholic fatty liver disease (NAFLD) has been associated with the insulin resistance.


To explore the relationship between markers of NAFLD, namely concentrations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALK), γ-glutamyltransferase (GGT), ferritin and bilirubin and insulin resistance in type 1 diabetes.


Our study included 353 patients with type 1 diabetes. Insulin sensitivity was measured with estimated glucose disposal rate calculated using the equation: eGDR = 24.31 − (12.22 × WHR) − (3.29 × HT) − (0.57 × HbA1c); WHR = waist to hip ratio, HT = hypertension. Correlations and multiple logistic regressions analysis were performed to identify the relationships between NAFLD associated markers and eGDR, individual components of insulin resistance and risk of insulin resistance.


AST, ALT, AST-to-ALT ratio, ALK and ferritin significantly correlated with insulin resistance measured by eGDR (r = −0.13, −0.14, 0.13, −0.18, and −0.24, respectively; all P < 0.05), and with individual components of insulin resistance, most notably WHR. In a multiple logistic regression model adjusted according to age, sex, duration of diabetes and BMI, increased levels of AST, ALT and ALK resulted in an increased risk for the development of insulin resistance in our subjects (OR = 1.03, 1.02, and 1.01, respectively; all P < 0.05).


These findings indicate that higher levels of ALT, AST and ALK are additional markers of insulin resistance in type 1 diabetes and suggest that those subjects must be considered as potentially affected not only by a hepatic but also by a multisystemic disease through altered insulin sensitivity.


Nonalcoholic fatty liver disease Liver enzymes Type 1 diabetes Insulin resistance Estimated glucose disposal rate 


Conflict of interest

The authors disclose that they did not receive any financial support for the study. No proprietary interest is involved in the study.


  1. 1.
    DeFronzo RA, Hendler R, Simonson D. Insulin resistance is a prominent feature of insulin-dependent diabetes. Diabetes. 1982;31:795–801.PubMedGoogle Scholar
  2. 2.
    Martin FIR, Hopper JL. The relationship of acute insulin sensitivity to the progression of vascular disease in long-term type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1987;24:1–9.Google Scholar
  3. 3.
    Yip J, Mattock MB, Morocutti A, Sethi M, Trevisan R, Viberti GC. Insulin resistance in insulin-dependent diabetic patients with microalbuminuria. Lancet. 1993;342:883–887.PubMedCrossRefGoogle Scholar
  4. 4.
    Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–419.PubMedCrossRefGoogle Scholar
  5. 5.
    Williams KV, Erbey JR, Becker D, Arsianian S, Orchard TJ. Can clinical factors estimate insulin resistance in type 1 diabetes? Diabetes. 2000;49:626–632.PubMedCrossRefGoogle Scholar
  6. 6.
    Kilpatrick ES, Rigby AS, Atkin SL. Insulin resistance, the metabolic syndrome, and complication risk in type 1 diabetes. Double diabetes in the diabetes control and complications trial. Diabetes Care. 2007;30:707–712.PubMedCrossRefGoogle Scholar
  7. 7.
    Davis TME, Bruce DG, Davis WA. Prevalence and prognostic implications of the metabolic syndrome in community-based patients with type 1 diabetes: The Fremantle Diabetes Study. Diab Res Clin Prac. 2007;78:412–417.CrossRefGoogle Scholar
  8. 8.
    Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365:1415–1428.PubMedCrossRefGoogle Scholar
  9. 9.
    Mulhall BP, Ong JP, Younossi ZM. Non-alcoholic fatty liver disease: an overview. J Gastroenterol Hepatol. 2002;17:1136–1143.PubMedCrossRefGoogle Scholar
  10. 10.
    Angulo P, Lindor KD. Non-alcoholic fatty liver disease. J Gastroenterol Hepatol. 2002;17:S186–S190.PubMedCrossRefGoogle Scholar
  11. 11.
    Ramesh S, Sanyal AJ. Evaluation and management of non-alcoholic steatohepatitis. J Hepatol. 2005;42:S2–12.PubMedCrossRefGoogle Scholar
  12. 12.
    Angulo P, Keach JC, Batts KP, Lindor KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology. 1999;30:1356–1362.PubMedCrossRefGoogle Scholar
  13. 13.
    Dichl AM, Goodman Z, Ishak KG. Alcohollike liver disease in nonalcoholics: a clinical and histologic comparison with alcohol-induced liver disease. Gastroenterology. 1988;95:1056–1062.Google Scholar
  14. 14.
    Pinto HC, Baptista A, Camilo ME, Valente A, Saragoca A, de Moura MC. Nonalcoholic steatohepatitis: clinicopathological comparison with alcoholic hepatitis in ambulatory and hospitalized patients. Dig Dis Sci. 1996;41:172–179.PubMedCrossRefGoogle Scholar
  15. 15.
    Bacon BR, Farahvash MJ, Janney CG, Neuschwander-Tetri BA. Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology. 1994;107:1103–1109.PubMedGoogle Scholar
  16. 16.
    Duckworth WC, Hamel FG, Peavy DE. Hepatic metabolism of insulin. Am J Med. 1988;85:71–76.PubMedCrossRefGoogle Scholar
  17. 17.
    Michael MD, Kulkarni RN, Postic C, et al. Loss of insulin signalling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol Cell. 2000;6:87–97.PubMedGoogle Scholar
  18. 18.
    Bugianesi E, Gastaldelli A, Vanni E, et al. Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms. Diabetologia. 2005;48:634–642.PubMedCrossRefGoogle Scholar
  19. 19.
    Chitturi S, Abeygunasekera S, Farrell GC, et al. Nonalcoholic steatohepatitis and insulin resistance: insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology. 2002;35:373–379.PubMedCrossRefGoogle Scholar
  20. 20.
    Cassader M, Gambino R, Musso G, et al. Postprandial triglyceride-rich lipoprotein metabolism and insulin sensitivity in nonalcoholic steatohepatitis patients. Lipids. 2001;36:1117–1124.PubMedCrossRefGoogle Scholar
  21. 21.
    Tiikkainen M, Tamminen M, Hakkinen AM, et al. Liver-fat accumulation and insulin resistance in obese women with previous gestational diabetes. Obes Res. 2002;10:859–867.PubMedCrossRefGoogle Scholar
  22. 22.
    Utzschneider KM, Kahn SE. The role of insulin resistance in nonalcoholic fatty liver disease. J Clin Endocrinol Metab. 2006;91:4753–4761.PubMedCrossRefGoogle Scholar
  23. 23.
    Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003;37:917–923.PubMedCrossRefGoogle Scholar
  24. 24.
    Angelico F, Del Ben M, Conti R, et al. Insulin resistance, the metabolic syndrome, and nonalcoholic fatty liver disease. J Clin Endocrinol Metab. 2005; 1578–1582.Google Scholar
  25. 25.
    Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care. 2001;24:683–689.PubMedCrossRefGoogle Scholar
  26. 26.
    Vozarova B, Stefan N, Lindsay RS, et al. High alanine aminotransferase is associated with decreased hepatic insulin sensitivity and predicts the development of type 2 diabetes. Diabetes. 2002;51:1889–1895.PubMedCrossRefGoogle Scholar
  27. 27.
    Rashid M, Roberts EA. Nonalcoholic steatohepatitis in children. J Pediatr Gastroenterol Nutr. 2000;30:48–53.PubMedCrossRefGoogle Scholar
  28. 28.
    Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology. 1990;12:1106–1110.PubMedCrossRefGoogle Scholar
  29. 29.
    Amarapurka DN, Amarapurkar AD, Patel ND, et al. Nonalcoholic steatohepatitis (NASH) with diabetes: predictors of liver fibrosis. Ann Hepatol. 2006;5:30–33.PubMedGoogle Scholar
  30. 30.
    Mofrad P, Contos MJ, Haque M, et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology. 2003;37:1286–1292.PubMedCrossRefGoogle Scholar
  31. 31.
    Lee JY, Kim KM, Lee SG, et al. Prevalence of risk factors of non-alcoholic fatty liver disease in potential living donors in Korea: a review of 589 consecutive liver biopsies in a single center. J Hepatol. 2007;47:239–244.PubMedCrossRefGoogle Scholar
  32. 32.
    Marchesini G, Brizi M, Morselli-Labate AM, et al. Association of non-alcoholic fatty liver disease to insulin resistance. Am J Med. 1999;107:450–455.PubMedCrossRefGoogle Scholar
  33. 33.
    Marchesini G, Brizi M, Bianchi G, et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes. 2001;50:1844–1850.PubMedCrossRefGoogle Scholar
  34. 34.
    Shimada M, Kawahara H, Ozaki K, et al. Usefulness of a combined evaluation of the serum adiponectin level, HOMA-IR, and serum type IV collagen 7S level to predict the early stage of nonalcoholic steatohepatits. Am J Gastroenterol. 2007;102:1931–1938.PubMedCrossRefGoogle Scholar
  35. 35.
    Nakanishi N, Nishina K, Li W, Sato M, Suzuki K, Tatara K. Serum gamma-glutamyltransferase and development of impaired fasting glucose or type 2 diabetes in middle-aged Japanese men. J Intern Med. 2003; 95–287.Google Scholar
  36. 36.
    Hanley AJ, Williams K, Festa A, et al. Elevations in markers of liver injury and risk of type 2 diabetes: the Insulin Resistance Atherosclerosis Study. Diabetes. 2004;53:2623–2632.PubMedCrossRefGoogle Scholar
  37. 37.
    Dixon JB, Bhathal PS, O’Brien PE. Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology. 2001;121:91–100.PubMedCrossRefGoogle Scholar
  38. 38.
    Fraser A, Harris R, Sattar N, Ebrahim S, Smith GD, Lawlor DA. Alanine aminotransferase, γ-glutamyltransferase, and incident diabetes. Diabetes Care. 2009;32:741–749.PubMedCrossRefGoogle Scholar
  39. 39.
    Fracanzani AL, Valenti L, Bugianesi E, et al. Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: a role for insulin resistance and diabetes. Hepatology. 2008;48:792–798.PubMedCrossRefGoogle Scholar
  40. 40.
    Ekstedt M, Franzen LE, Mathiesen UL, et al. Long term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006;44:865–873.PubMedCrossRefGoogle Scholar
  41. 41.
    Targher G, Bertolini L, Poli F, et al. Nonalcoholic fatty liver disease and risk of future cardiovascular events among type 2 diabetic patients. Diabetes. 2005;54:3541–3546.PubMedCrossRefGoogle Scholar
  42. 42.
    Browning JD, Szczepaniak LS, Dobbins R, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40:1387–1395.PubMedCrossRefGoogle Scholar
  43. 43.
    Reaven GM. Role of insulin resistance in human disease. Diabetes. 1988;37:1595–1607.PubMedCrossRefGoogle Scholar
  44. 44.
    Kelly DE, McKolanis TM, Hegazi RAF, Kuller LH, Kalhan SC. Fatty liver in type 2 diabetes: relation to regional adiposity, fatty acids, and insulin resistance. Am J Physiol Endocrinol Metab. 2003;285:E906–E916.Google Scholar
  45. 45.
    Seppala-Lindroos A, Vehkavaara S, Hakkinen AM, et al. Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J Clin Endocrinol Metab. 2002;87:3023–3028.PubMedCrossRefGoogle Scholar
  46. 46.
    O’Brien RM, Granner DK. Regulation of gene expression by insulin. Biochem J. 1991;278:609–619.PubMedGoogle Scholar
  47. 47.
    Fernandez-Real JM, Ricart-Engel W, Arroyo E, et al. Serum ferritin as a component of the insulin resistance syndrome. Diabetes Care. 1998;21:62–68.PubMedCrossRefGoogle Scholar
  48. 48.
    Marchesini G, Brizi M, Bianchi G, Tomassetti S, Zoli M, Melchionda N. Metformin in non-alcoholic steatohepatitis. Lancet. 2001;358:893–894.PubMedCrossRefGoogle Scholar
  49. 49.
    Promrat K, Lutchman G, Uwaifo GI, et al. A pilot study of pioglitazone treatment for non-alcoholic steatohepatitis. Hepatology. 2004;39:188–196.PubMedCrossRefGoogle Scholar
  50. 50.
    Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol. 2003;98:960–967.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Tomislav Bulum
    • 1
    Email author
  • Branko Kolarić
    • 2
    • 3
  • Lea Duvnjak
    • 1
    • 4
  • Marko Duvnjak
    • 4
    • 5
  1. 1.Vuk Vrhovac Clinic for Diabetes, Endocrinology and Metabolic DiseasesUniversity Hospital MerkurZagrebCroatia
  2. 2.Medical SchoolUniversity of RijekaRijekaCroatia
  3. 3.Zagreb County Institute of Public HealthVelika Gorica, ZagrebCroatia
  4. 4.Medical SchoolUniversity of ZagrebZagrebCroatia
  5. 5.Division of Gastroenterology and HepatologyUniversity Hospital Centre “Sestre milosrdnice”ZagrebCroatia

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