Abstract
Until recently, the prevalence of endogenous Cushing syndrome has been considered to be low. However, improved diagnostic strategies and increased awareness have broadened our understanding of hypercortisolism and its role in the pathophysiology of type 2 diabetes, obesity, hypertension, and cardiovascular disease. Recent studies from Europe, South America, and the U.S. have demonstrated that a significant percentage of individuals with difficult-to-control type 2 diabetes, despite treatment with multiple glucose-lowering agents, have hypercortisolism as a causative factor in their poorly managed diabetes. In this review, we examine the pathophysiologic mechanisms via which excess cortisol contributes to the impairment in glucose homeostasis and recommend that hypercortisolism be added to the Ominous Octet to form the Noxious Nine as the pathophysiologic foundation for the development of type 2 diabetes. ARTICLE HIGHLIGHTS: Hypercortisolism as a causative factor in the development of type 2 diabetes has received scant attention. Studies from Europe, South America, and the U.S. have demonstrated that a significant percentage of individuals with poorly managed type 2 diabetes, despite treatment with multiple glucose-lowering agents, have endogenous hypersecretion of cortisol as a causative factor for their hyperglycemia. In vivo and in vitro studies in animals and humans have demonstrated that excess exposure to glucocorticoids can promote insulin resistance in muscle, liver, and adipocytes and impair insulin secretion. We propose a reverberating cycle in which hypercortisolism disrupts the normal circadian rhythm causing insulin resistance and hyperinsulinemia, which in turn further disrupts the hypothalamic-pituitary-adrenal axis.