Serum Alanine Aminotransferase is Associated with Serum Adiponectin, C-reactive Protein and Apolipoprotein B in Young Healthy Men

Abstract

Several studies have reported an association between markers of liver injury, including elevated concentrations of alanine aminotransferase (ALT) aspartate aminotransferase (AST), and prospective risk of type 2 diabetes. We therefore examined the relationship between ALT and AST on the one hand, and serum adiponectin and highly sensitive CRP on the other, both of which have been reported to be associated with prospective risk of type 2 diabetes; we also tested for variable components of metabolic syndrome in 198 male college students aged 18-20 years. ALT showed a positive relationship with percentage body fat (r = 0.19, p = 0.02), serum leptin (r = 0.21, p = 0.01), LDL cholesterol (r = 0.29, p = 0.0003), triglyceride (r = 0.28, p = 0.0004) and apolipoprotein B (r = 0.35, p < 0.0001) even after adjustment for body mass index (BMI). Although there was a significant relationship with serum insulin, adiponectin (inversely), homeostasis model assessment of insulin resistance, systolic and diastolic blood pressure, HDL cholesterol (inversely) and LDL particle diameter in simple regression analysis, significance disappeared after adjustment for BMI. In contrast, CRP (r = 0.16, p = 0.04) was associated with ALT after adjustment for BMI, although simple regression analysis revealed no association between the two. Relationships were smaller for AST, and significance disappeared after adjustment for BMI. Multiple regression analysis excluding lipid variables revealed significant and independent associations of ALT with adiponectin and percentage body fat. In a model including lipid variables, apolipoprotein B emerged as an independent predictor of ALT in addition to adiponectin and percentage body fat. These variables explained 29 % of ALT variability. In conclusion, serum ALT levels were associated with leptin and CRP as well as many components of the insulin resistance syndrome in young healthy men. Adiponectin, apolipoprotein B and percentage body fat emerged as significant and independent predictors of ALT. Since adiponectin and chronic subclinical inflammation have been reported to predict the development of type 2 diabetes and since abnormalities in apolipoprotein B metabolism occur in the early course of insulin resistance, these findings may be compatible with the association between liver markers and risk of diabetes.

Key words

ALT · adiponectin · leptin · CRP · apolipoprotein B

References

• 1 Matteoni C A, Younossi Z M, Gramlich T, Boparai N, Liu Y C, McCullough A J. Nonalcoholic fatty liver disease: a spectrum of Clinical and pathological severity.  Gastroenterology. 1999;  116 1413-1419
• 2 Charlton M, Kasparova P, Weston S, Lindor K, Maor-Kendler Y, Wiesner R H, Rosen C B, Batts K P. Frequency of nonalcoholic steatohepatitis as a cause of advanced liver disease.  Liver Transpl. 2001;  7 608-614
• 3 Clark J M, Brancati F L, Diehl A M. The prevalence and etiology of elevated aminotransferase levels in the United States.  Am J Gastroenterol. 2003;  98 960-967
• 4 Daniel S, Ben-Menachem T, Vasudevan G, Ma C K, Blumenkehl M. Prospective evaluation of unexplained chronic liver transaminase abnormalities in asymptomatic and symptomatic patients.  Am J Gastroenterol. 1999;  94 3010-3014
• 5 Chitturi S, Abeygunasekera S, Farrell G C, Holmes-Walker J, Hui J M, Fung C, Karim R, Lin R, Samarasinghe D, Liddle C, Weltman M, George J. NASH and insulin resistance: Insulin hypersecretion and specific association with the insulin resistance syndrome.  Hepatology. 2002;  35 373-379
• 6 Marchesini G, Brizi M, Morselli-Labate A M, Bianchi G, Bugianesi E, McCullough A J, Forlani G, Melchionda N. Association of nonalcoholic fatty liver disease with insulin resistance.  Am J Med. 1999;  107 450-455
• 7 Kaplan M L. Leptin, obesity, and liver disease.  Gastroenterology. 1998;  115 997-1001
• 8 Xu A, Wang Y, Keshaw H, Xu A, Wang Y, Keshaw H. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice.  J Clin Invest. 2003;  112 91-100
• 9 Petersen K F, Oral E A, Dufour S, Befroy D, Ariyan C, Yu C, Cline G W, DePaoli A M, Taylor S I, Gorden P, Shulman G I. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy.  J Clin Invest. 2002;  109 1345-1350
• 10 Perry I J, Wannamethee S G, Shape A G. Prospective study of serum gamma-glutamyltransferase and risk of NIDDM.  Diabetes Care. 1998;  21 732-737
• 11 Nakanishi N, Nishina K, Li W, Sato M, Suzuki K. Serum gamma-glutamyltransferase and development of impaired fasting glucose or type 2 diabetes in middle-aged Japanese men.  J Intern Med. 2003;  254 287-295
• 12 Lee D H, Jacobs D R Jr, Gross M, Kiefe C I, Roseman J, Lewis C E, Steffes M. Gamma-glutamyltransferase is a predictor of incident diabetes and hypertension: the Coronary Artery Risk Development in Young Adults (CARDIA) Study.  Clin Chem. 2003;  49 1358-1366
• 13 Lee D H, Ha M H, Kim J H, Christiani D C, Gross M D, Steffes M, Blomhoff R, Jacobs D R jr. Gamma-glutamyltransferase and diabetes-a 4 year follow-up study.  Diabetologia. 2003;  46 359-364
• 14 Vosarova B, Stefan N, Lindsay R S, Saremi A, Pratley R E, Bogardus C, Tataranni P A. High alanine aminotransferase is associated with decreased hepatic insulin sensitivity and predicts the development of type 2 diabetes.  Diabetes. 2002;  51 1889-1895
• 15 Ohlson L O, Larsson B, Bjorntorp P, Eriksson H, Svardsudd K, Welin L, Tibblin G, Wilhelmsen L. risk factor for type 2 (non-insulin dependent) diabetes mellitus: thirteen and half years of follow-up of the participants in a study of Swedish men born in 1913.  Diabetologia. 1988;  31 798-805
• 16 Hanley A JG, Williams K, Festa A, Wagenknecht L E, D’Agostino R B Jr, Kempf J, Zinman B, Haffner S M. Elevations in markers of liver injury and risk of type 2 diabetes. The Insulin Resistance Atherosclerosis Study.  Diabetes. 2004;  53 2623-2632
• 17 Sattar N, Scherbakova O, Ford I, O’Reilly D S, Stanley A, Forrest E, Macfarlane P W, Packard C J, Cobbe S M, Shepherd J. Elevated alanine aminotransferase predicts new-onset type 2 diabetes independently of classical risk factors, metabolic syndrome, and C-reactive protein in the west of Scotland Coronary Prevention Study.  Diabetes. 2004;  5311 2855-2860
• 18 Duncan B B, Schmidt M I, Pankow J S, Bang H, Couper D, Ballantyne C M, Hoogeveen R C, Heiss G. Adiponectin and the development of type 2 diabetes: the atherosclerosis risk in communities study.  Diabetes. 2004;  53 2473-2478
• 19 Nakanishi S, Yamane K, Kamei N, Okubo M, Kohno N. Elevated C-reactive protein is a risk factor for the development of type 2 diabetes in Japanese Americans.  Diabetes Care. 2003;  26 2754-2757
• 20 Kazumi T, Kawaguchi A, Hirano T, Yoshino G. C-reactive protein in young, apparently healthy men: Associations with serum leptin, QTc interval and HDL cholesterol.  Metabolism. 2003;  52 1113-1116
• 21 Kazumi T, Kawaguchi A, Hozumi T, Ishida Y, Yoshino G. Serum HDL cholesterol values are associated with apoB-containing lipoprotein metabolism and triglyceride-body fat interrelation in young Japanese men.  Atherosclerosis. 1997;  130 93-100
• 22 Friedwald W T, Levy R I, Fredrickson D S. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.  Clin Chem. 1972;  18 499-502
• 23 Nichols A V, Krauss R M, Musliner T A. Nondenaturing polyacrylamide gradients gel electrophoresis. In: Segrest JP, Albert JJ, (eds) Methods in Enzymology, Volume 128, Plasma Lipoproteins, Part A, Preparation, Structure and Molecular Biology. Fla Academic Press 1986 128: 417-431
• 24 Matthews D R, Hosker J P, Rudenski A S, Naylor B A, Treacher D F, Turner R C. Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man.  Diabetologia. 1985;  28 412-419
• 25 Haffner S M, Miettinen H, Stern M P. The homeostasis model in the San Antonio Heart Study.  Diabetes Care. 1997;  20 1087-1092
• 26 Emoto M, Nishizawa Y, Maekawa K. et al . Homeostasis model assessment as a clinical index of insulin resistance in type 2 diabetic patients treated with sulfonylureas.  Diabetes Care. 1999;  22 818-822
• 27 Hermans M P, Levy J C, Morris R J, Turner R C. Comparison of insulin sensitivity tests across a range of glucose tolerance from normal to diabetes.  Diabetologia. 1999;  42 678-687
• 28 Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity.  Biochem Biophys Res Comm.. 1999;  257 79-83
• 29 Ledue T B, Weiner D L, Sipe J D, Poulin S E, Collins M F, Rifai N. Analytical evaluation of particle-enhanced immunonephrometric assays for C-reactive protein, serum amyloid A and mannose-binding protein in human serum.  Ann Clin Biochem. 1998;  35 745-753
• 30 Cook D G, Mendall M A, Whincup P H, Carey I M, Ballam L, Morris J E, Miller G J, Strachan D P. C-reactive protein concentration in children: relationship to adiposity and other cardiovascular risk factors.  Atherosclerosis. 2000;  149 139-150
• 31 Lopez-Bermejo A, Botas P, Funahashi T, Delgado E, Kihara S, Ricart W, Fernandez-Real J M. Adiponectin, hepatocellular dysfunction and insulin sensitivity.  Clin Endocrinol,. 2004;  60 256-263
• 32 Kazumi T, Kawaguchi A, Hirano T, Yoshino G. Serum adiponectin is associated with high-density lipoprotein cholesterol, triglycerides, and low-density lipoprotein particle size in young healthy men.  Metabolism. 2004;  53 589-593
• 33 Lewis G F, Steiner G. Acute effects of insulin in the control of VLDL production in humans. Implications for the insulin-resistant state.  Diabetes Care. 1996;  19 390-393
• 34 Cummings M H, Watts G F, Umpleby A M, Hennessy T R, Naoumova R, Slavin B M, Thompson G R, Sonksen P H. Increased hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 in NIDDM.  Diabetologia. 1995;  38 959-967
• 35 Pont F, Duvillard L, Florentin E, Gambert P, Verges B. Early kinetic abnormalities of apoB-containing lipoproteins in insulin-resistant women with abdominal obesity.  Arterioscler Thromb Vasc Biol.. 2002;  22 1726-1732
• 36 Festa A, D’Agostino R Jr, Howard G, Mykkanen L, Tracy R P, Haffner S M. Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS).  Circulation. 2000;  102 42-47
• 37 Pickup J C, Chusney G D, Thomas S M. et al . Plasma interleukin-6, tumor necrosis factor and blood cytokine production in type 2 diabetes.  Life Sci. 2000;  67 291-300
• 38 Lemieux I, Poscot A, Prud’homme D. et al . Elevated C-reactive protein. Another component of the atherothrombotic profile of abdominal obesity.  Arterioscler Thromb Vasc Biol. 2001;  21 961-967
• 39 James O FW, Day C P. Non-alcoholic steatohepatitis (NASH): a disease of emerging identity and importance.  J Hepatol. 1998;  29 495-501
• 40 Dixon J B, Bathal P S, O’Brien P E. Nonalcoholic fatty liver disease: Predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese.  Gastroenterology. 2001;  121 91-100
• 41 Sorbi D, McGill D B, Thistle J L, Therneau T M, Henry J, Lindor K D. An assessment of the role of liver biopsies in asymptomatic patients with chronic liver test abnormalities.  Am J Gastroenterol. 2000;  95 3206-3210
• 42 Marchesini G, Brizi M, Bianchi G, Tomassetti S, Zoli M, Melchionda N. Metformin in non-alcoholic steatohepatitis.  Lancet.. 2001;  358 893-894
• 43 Caldwell S H, Hespenheide E E, Redick J A, Iezzoni J C, Battle E H, Sheppard B L. A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis.  Am J Gastroenterol. 2001;  96 519-525