Low Serum Sex Hormone-Binding Globulin Associated with Insulin Resistance in Men with Nonalcoholic Fatty Liver Disease

Abstract

The presence of nonalcoholic fatty liver disease (NAFLD) is a strong risk predictor for type 2 diabetes (T2D). A reduction in sex hormone-binding globulin (SHBG) is associated with NAFLD. Low SHBG is also associated with insulin resistance (IR). However, very limited data are available for the association of SHBG and IR in patients with NAFLD. The study aims to clarify the association between SHBG and IR in patients with NAFLD. In this cross-sectional study, 334 men with NAFLD were recruited. SHBG, total testosterone, free testosterone, total cholesterol, triglyceride, insulin, and glucose concentrations were measured. Homeostatic model assessment (HOMA)-IR and HOMA-β were calculated. Spearman’s correlations and multiple linear regressions were used to analyze the association between SHBG and IR. Men with moderate-severe NAFLD had higher waist circumference, BMI, total cholesterol, triglyceride, insulin, HOMA-IR, HOMA-β, and free testosterone, but lower SHBG than the mild NAFLD. The moderate-severe NAFLD group exhibited higher HOMA-IR (2.38±1.35 vs. 4.16±2.84, p<0.001) and lower SHBG (25.89±11.89 vs. 30.13±12.97 nmol/l, p<0.001) than the other group. SHBG value was negatively correlated with insulin, and HOMA-IR, but was not significantly correlated with glucose and testosterone. The multiple linear regression analysis showed that SHBG was significantly associated with insulin (β=− 0.241, p<0.001), and HOMA-IR (β=− 0.229, p<0.001), even adjusting for potential confounders. In conclusion, low serum SHBG is associated with IR in men with NAFLD.

Key words

insulin resistance - HOMA-IR - SHBG - NAFLD

• References

• 1 Rinella ME. Nonalcoholic fatty liver disease: a systematic review. JAMA 2015; 313: 2263-2273
• 2 Tian GX, Sun Y, Pang CJ, Tan AH, Gao Y, Zhang HY, Yang XB, Li ZX, Mo ZN. Oestradiol is a protective factor for non-alcoholic fatty liver disease in healthy men. Obes Rev 2012; 13: 381-387
• 3 Anstee QM, Targher G, Day CP. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol 2013; 10: 330-344
• 4 Stefan N, Fritsche A, Schick F, Häring H-U. Phenotypes of prediabetes and stratification of cardiometabolic risk. Lancet Diabetes Endocrinol 2016; 4: 789-798
• 5 Adams LA, Waters OR, Knuiman MW, Elliott RR, Olynyk JK. NAFLD as a risk factor for the development of diabetes and the metabolic syndrome: an eleven-year follow-up study. Am J Gastroenterol 2009; 104: 861-867
• 6 Sung KC, Wild SH, Byrne CD. Resolution of fatty liver and risk of incident diabetes. J Clin Endocrinol Metab 2013; 98: 3637-3643
• 7 Stefan N, Schick F, Haring HU. Sex hormone-binding globulin and risk of type 2 diabetes. N Engl J Med 2009; 361: 2675-2676 authors’ reply 2677–2678
• 8 Ding EL, Song Y, Manson JE, Hunter DJ, Lee CC, Rifai N, Buring JE, Gaziano JM, Liu S. Sex hormone-binding globulin and risk of type 2 diabetes in women and men. N Engl J Med 2009; 361: 1152-1163
• 9 Hua X, Sun Y, Zhong Y, Feng W, Huang H, Wang W, Zhang T, Hu Y. Low serum sex hormone-binding globulin is associated with nonalcoholic fatty liver disease in type 2 diabetic patients. Clin Endocrinol (Oxf) 2014; 80: 877-883
• 10 Shin JY, Kim SK, Lee MY, Kim HS, Ye BI, Shin YG, Baik SK, Chung CH. Serum sex hormone-binding globulin levels are independently associated with nonalcoholic fatty liver disease in people with type 2 diabetes. Diabetes Res Clin Pract 2011; 94: 156-162
• 11 Li C, Ford ES, Li B, Giles WH, Liu S. Association of testosterone and sex hormone-binding globulin with metabolic syndrome and insulin resistance in men. Diabetes Care 2010; 33: 1618-1624
• 12 Gao Y, Wang M, Zhang H, Tan A, Yang X, Qin X, Hu Y, Zhang Y, Liao M, Mo Z. Are metabolic syndrome and its components associated with lower urinary tract symptoms? Results from a Chinese male population survey. Urology 2012; 79: 194-201
• 13 Liu Z, Ye F, Zhang H, Gao Y, Tan A, Zhang S, Xiao Q, Zhang B, Huang L, Ye B, Qin X, Wu C, Lu Z, Zhang Y, Liao M, Yang X, Mo Z. The association between the levels of serum ferritin and sex hormones in a large scale of chinese male population. PLoS One 2013; 8: e75908
• 14 Adams LA, Angulo P. Treatment of non-alcoholic fatty liver disease. Postgrad Med J 2006; 82: 315-322
• 15 Wang X, Liu Z, Wang K, Wang Z, Sun X, Zhong L, Deng G, Song G, Sun B, Peng Z, Liu W. Additive effects of the risk alleles of PNPLA3 and TM6SF2 on non-alcoholic fatty liver disease (NAFLD) in a Chinese Population. Front Genet 2016; 7: 140
• 16 Xie Y, Wang M, Zhang Y, Zhang S, Tan A, Gao Y, Liang Z, Shi D, Huang Z, Zhang H, Yang X, Lu Z, Wu C, Liao M, Sun Y, Qin X, Hu Y, Li L, Peng T, Li Z, Yang X, Mo Z. Serum uric acid and non-alcoholic fatty liver disease in non-diabetic Chinese men. PLoS One 2013; 8: e67152
• 17 Zhang Y, Gao Y, Tan A, Yang X, Zhang H, Zhang S, Wu C, Lu Z, Wang M, Liao M, Qin X, Li L, Hu Y, Mo Z. Endogenous sex hormones and C-reactive protein in healthy Chinese men. Clin Endocrinol (Oxf) 2013; 78: 60-66
• 18 Vavlk JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab 1999; 84: 7
• 19 Privitera G, Spadaro L, Alagona C, Calanna S, Piro S, Rabuazzo AM, Purrello F. Hepatic insulin resistance in NAFLD: relationship with markers of atherosclerosis and metabolic syndrome components. Acta Diabetol 2016; 53: 449-459
• 20 Motamed N, Rabiee B, Hemasi GR, Ajdarkosh H, Khonsari MR, Maadi M, Keyvani H, Zamani F. Body roundness index and waist-to-height ratio are strongly associated with non-alcoholic fatty liver disease: a population-based study. Hepat Mon 2016; 16: e39575
• 21 Sung KC, Jeong WS, Wild SH, Byrne CD. Combined influence of insulin resistance, overweight/obesity, and fatty liver as risk factors for type 2 diabetes. Diabetes Care 2012; 35: 717-722
• 22 Li X, Pang X, Zhang Q, Qu Q, Hou Z, Liu Z, Lv L, Na G, Zhang W, Sun C, Li Y. Long-Term single and joint effects of excessive daytime napping on the HOMA-IR index and glycosylated hemoglobin: a prospective cohort study. Medicine (Baltimore) 2016; 95: e2734
• 23 Son JW, Park CY, Kim S, Lee HK, Lee YS. Insulin resistance as primary pathogenesis in newly diagnosed DNTDPiKSG. Changing Clinical Characteristics according to Insulin Resistance and Insulin Secretion in Newly Diagnosed Type 2 Diabetic Patients in Korea. Diabetes Metab J 2015; 39: 387-394
• 24 Liu JJ, Chen YY, Mo ZN, Tian GX, Tan AH, Gao Y, Yang XB, Zhang HY, Li ZX. Relationship between serum osteocalcin levels and non-alcoholic fatty liver disease in adult males, South China. Int J Mol Sci 2013; 14: 19782-19791
• 25 Bonnet F, Velayoudom Cephise FL, Gautier A, Dubois S, Massart C, Camara A, Larifla L, Balkau B, Ducluzeau PH. Role of sex steroids, intrahepatic fat and liver enzymes in the association between SHBG and metabolic features. Clin Endocrinol (Oxf) 2013; 79: 517-522
• 26 Peter A, Kantartzis K, Machann J, Schick F, Staiger H, Machicao F, Schleicher E, Fritsche A. Haring HU, Stefan N. Relationships of circulating sex hormone-binding globulin with metabolic traits in humans. Diabetes 2010; 59: 3167-3173
• 27 Ding EL, Song Y, Malik VS, Liu S. Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA 2006; 295: 1288-1299
• 28 Goto A, Morita A, Goto M, Sasaki S, Miyachi M, Aiba N, Terauchi Y, Noda M, Watanabe S. Associations of sex hormone-binding globulin and testosterone with diabetes among men and women (the Saku Diabetes study): a case control study. Cardiovasc Diabetol 2012; 11: 130