Endocrine Abstracts

The liver produces and secretes sex hormone–binding globulin (SHBG), which transports sex steroids and regulates their access to tissues. Body mass index is a major determinant SHBG concentration in the blood of men and women. Low plasma SHBG levels are associated with obesity and predict the development of type 2 diabetes and cardiovascular disease. The reason why obese individuals have low circulating SHBG has been attributed to hyperinsulinemia, but no mechanistic evidence has ever been described. Over the past decade we and others have contributed to gathering evidences that demonstrate that insulin does not regulate SHBG production. We have used in vitro (HepG2 cells) and in vivo (human SHBG transgenic mice) approaches to show that hyperinsulinemia does not reduce SHBG production. We have elucidated the molecular mechanisms by which carbohydrates and proinflammatory cytokines (i.e. tumor necrosis factor alpha and interleukin 1 beta) reduce SHBG production. Importantly we and others have corroborated these results in humans. All these evidences point to the downregulation of SHBG mediated by carbohydrates and proinflammatory cytokines as one explanation for the low levels of total sexual steroids that exist in chronic inflammatory diseases such as obesity and type 2 diabetes.