In conclusion, testosterone deficiency promotes obesity, especially visceral obesity, IR, MetS and T2-DM, which in turn contribute to a further reduction of testosterone levels, determined by (1) IR-mediated and pro-inflammatory cytokine-mediated decrease of SHBG levels, ultimately resulting in negative feedback on the HPT axis; (2) direct inhibitory effect of increased leptin levels on Leydig cells; and (3) indirect inhibition due to HPT axis suppression induced not only by estradiol excess but also by inflammatory mediators, leptin resistance and IR. The gene discussed is SHBG; the disease is diabetes mellitus.