The association of sex hormone-binding globulin (SHBG) with non-alcoholic fatty liver disease in type 2 diabetic patients

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a predictor of metabolic syndrome (MetS), type 2 diabetes, and cardiovascular disease (CVD) and is considered as a hepatic phenotype of MetS. Low sex hormone-binding globulin (SHBG) level has been reported to be significantly associated with insulin resistance (IR), MetS, type 2 diabetes and CVD. Furthermore, several polymorphisms in the SHBG gene have been associated with plasma SHBG level, IR and type 2 diabetes. In this study, we investigated the associations of serum SHBG level with NAFLD, and further evaluated the associations of SHBG polymorphisms with SHBG level and NAFLD in type 2 diabetes.We enrolled 279 type 2 diabetic patients (age 57.0±9.3 years, men 55.2%) and measured their clinical and chemical metabolic parameters. The severity of NAFLD was measured using liver ultrasound. Sex hormones (SHBG, total and free testosterone, and estradiol) levels and the SHBG polymorphisms were measured.The SHBG levels were lower in men, patients with MetS, and patients with overt NAFLD compared to those of women, patients without MetS, and patients without NAFLD (p < 0.01). The SHBG levels were significantly decreased in proportion to the severity of fatty liver disease. The rs6259 locus had a minor-allele frequency of 21.8%, but the rs6257 and the rs1799941 loci had minor-allele frequencies of 0%. However, the presence of a variant allele of rs6259 yielded no difference in SHBG level and was not significantly associated with overt NAFLD. After adjustments for age and gender, the SHBG level was negatively correlated with hypertension, MetS, body mass index (BMI), waist circumference, overt NAFLD, triglycerides, alanine aminotransferase (ALT), γ-glutamyltransferase (γGT), fasting insulin, HOMA-IR and C-reactive protein (CRP) levels. The SHBG level was positively correlated with testosterone and estradiol levels (p < 0.05). The odds ratio (OR) predicting the presence of overt NAFLD after adjusting for age was significantly decreased with increasing levels of SHBG in both men and women. The ORs with increasing level of SHBG in both men and women remained significant even after adjustments for BMI, waist circumference, hypertension, MetS, triglycerides, γGT, ALT, CRP, HOMA-IR, testosterone, and estradiol. To confirm this in vitro, TNF-α treatment decreased the mRNA and protein expression of SHBG in HepG2 cells.Collectively, these data indicate that low serum SHBG level in both men and women were closely associated with overt NAFLD in type 2 diabetic patients. This suggests that SHBG level might be used as a supplementary marker for the assessment of NAFLD severity in type 2 diabetes