Glucocorticoid excess may have adverse effects on glucose tolerance by various mechanisms. They may not only induce defective pancreatic insulin secretion, but also increase insulin resistance and food intake while translocating glucose transporters from the plasma membrane. About 20% of patients with Cushing's disease, characterized by chronic hypercortisolism, will develop frank diabetes mellitus and virtually all the remainder have some milder impairment of glucose metabolism, while the prevalence of diabetes mellitus during chronic glucocorticoid therapy is not known exactly. Normalization of (endogenous and exogenous) cortisol levels by surgery and/or medical therapy may be an important first step to improve glucose tolerance. Although diabetes and/or impaired glucose tolerance generally improve with normalization of cortisol levels, the metabolic syndrome, diabetes and cardiovascular risk often persist in a substantial number of subjects despite the normalization of glucocorticoid levels. This suggests that some individuals have developed a 'metabolic memory' or 'legacy effect' after (chronic) hypercortisolism. Whether this is due to a number of glucocorticoid-induced epigenetic changes is not clear at the moment.
