SHBG and obesity due to melanocortin 4 receptor deficiency: Observational studies identified lower levels of SHBG as a risk factor for insulin resistance and incident DM, and in-vitro studies demonstrated G-protein-linked receptor-mediated effects of SHBG on intracellular processes related to insulin resistance.58 Multiple confounding factors (e.g. obesity, hyperinsulinemia) are associated with lower SHBG and risk for DM2; however, recent genetic studies suggest an independent role for sex steroids and SHBG in the etiology of DM2.59