| Previous studies have shown that low serum testosterone levels are strongly related to the development of type 2 diabetes mellitus(T2DM)in men.However,the associations between serum testosterone level and T2DM in women were rarely studied.The transformation of testosterone is affected by several reductases.Abnormal testosterone level may lead to dysregulation of glucose and fatty acid metabolism.The underlying mechanism has not been fully elucidated.ObjectiveWe aimed to investigate the associations of serum testosterone with impaired fasting glucose(IFG)and T2DM and calculate the proportion explained by obesity status on the relationship.Then,the correlations of steroid-5a-reductase type 1(SRD5A1)single nucleotide polymorphisms(SNP)with IFG and T2DM and the interactive effects of testosterone and genotypes on glycometabolism were further analyzed.MethodsThe participants were selected from the Henan Rural Cohort(Registration Number:ChiCTR-OOC-15006699).925 individuals aged 18 to 79 with T2DM were selected.All cases withT2DM were matched with normal fasting glucose subjects and IFG subjects based on gender and age(±3 years)in the same general population.Finally,2767 participants were recruited,including 1059 men and 1708 women.Information on the general characteristics of participants’ demography,lifestyles,and family history of disease was obtained by well-trained investigators through face-to-face interviews using a structured questionnaire.Anthropometric variables were measured.Venous blood samples for biochemical analysis were drawn after fasting for at least 8 hours to collect basic information about the biochemical indicators.Serum testosterone was quantified by liquid chromatography-tandem mass spectrometry and categorized into low,medium and high levels according to the control group in women and men separately.Genomic DNA was extracted from the whole blood and genotyped for the SRD5A1 rs 1691053 SNP.Multivariable logistic regression and linear regression were performed to estimate the relationships of testosterone and SRD5A1 rs 1691053 alleles and genotypes with IFG,T2DM and glycometabolism indexes.Waist circumference(WC)was used as a mediator to estimate the mediation effect.Generalized linear models were used to investigate the interactive effects of serum testosterone and SRD5A1 rs1691053 gene polymorphism on glycometabolism indexes in men.Results1.After adjusting for multiple variables,compared with individuals with low serum testosterone level,the odds ratio(OR)(95%confidence interval(CI))of IFG and T2DM for men with high level were 0.58(0.39～0.860)and 0.52(0.34～0.82).Then,the OR(95%CI)of T2DM for women with medium and high level were 2.24(1.65～3.02)和 3.72(2.49～5.55).Serum testosterone levels were positively associated with T2DM in women(per 1 unit natural log transformed,OR(95%CI):1.64(1.41～1.90)).After adjusting for multiple variables,in men,a higher testosterone level tended to be associated with a lower fasting plasma glucose(FPG)level and a weaker glycosylated hemoglobin A1c(HbA1c)but a stronger homeostasis model assessment 2 of β-cell function(HOMA2-β%).Opposite findings were observed in women.In women,serum testosterone level was positively associated with FPG,HbAlc,insulin(INS)and homeostasis model assessment 2 of insulin resistance(HOMA2-IR)but negatively associated with HOMA2-β%.2.The mediating effect(β(95%CI))of WC between serum testosterone and IFG in men was-0.08(-0.16～-0.02),which suggested a full mediation effect and a 100%proportion of the mediating effect(PE).The mediating effect(β(95%CI))of WC between serum testosterone and T2DM in men was-0.21(-0.35～-0.10),which suggested a partial mediation effect and a 41.31%PE.The mediating effect(β(95%CI))of WC between serum testosterone and IFG in women was 0.01(0.01～0.03),which suggested a full mediation effect and a 100%PE.The mediating effect(β(95%CI))of WC between serum testosterone and T2DM in women was 0.04(0.01-0.08),which suggested a partial mediation effect and a 9.54%PE.3.Compared to men with the wild genotype TT,after multivariable adjustment,the OR(95%CI)of IFG for homozygous CC genotypes in men was 2.55(1.08-6.04).Besides,neither men nor women with other mutant alleles or genotypes were significantly associated with IFG or T2DM.Furthermore,significant associations of SRD5A1 rs 1691053 polymorphisms with adverse indices of glycometabolism were observed in men,including elevated FPG,HbA1c,HOMA2-IR and decreased HOMA2-β%.Interestingly,the opposite association for HOMA2-IR in women were observed.4.The multiplication interactive associations of testosterone and SRD5A1 rs 1691053 SNP on FPG、HbAlc and HOMA2-β%were found and mutations were more likely to lead unfavorable metabolic phenotypes.Conclusions1.Serum testosterone levels in men were negatively associated with IFG and T2DM.Serum testosterone levels in women were only positively associated with T2DM.2.WC played a full mediating role in the relationship between testosterone and IFG for men and women.However,WC played a partial mediating role in the relationship between testosterone and T2DM in men and women,accounting for 41.31%and 9.54%,respectively.3.The SRD5A1 rs 1691053 gene polymorphism in men was independently associated with IFG.4.The interaction between a genetic polymorphism from SRD5A1 and serum testosterone involved FPG,HbA1c and islet β-cell function was identified in men. |
