Glucose Metabolism Abnormalities in Cushing Syndrome: From Molecular Basis to Clinical Management

Abstract

An impaired glucose metabolism, which often leads to the onset of diabetes mellitus (DM), is a common complication of chronic exposure to exogenous and endogenous glucocorticoid (GC) excess and plays an important part in contributing to morbidity and mortality in patients with Cushing syndrome (CS). This article reviews the pathogenesis, epidemiology, diagnosis, and management of changes in glucose metabolism associated with hypercortisolism, addressing both the pathophysiological aspects and the clinical and therapeutic implications. Chronic hypercortisolism may have pleiotropic effects on all major peripheral tissues governing glucose homeostasis. Adding further complexity, both genomic and nongenomic mechanisms are directly induced by GCs in a context-specific and cell-/organ-dependent manner. In this paper, the discussion focuses on established and potential pathologic molecular mechanisms that are induced by chronically excessive circulating levels of GCs and affect glucose homeostasis in various tissues. The management of patients with CS and DM includes treating their hyperglycemia and correcting their GC excess. The effects on glycemic control of various medical therapies for CS are reviewed in this paper. The association between DM and subclinical CS and the role of screening for CS in diabetic patients are also discussed.

Dynamic modulation of glucose utilisation by glucocorticoid rhythms in health and disease

“…Our results also suggest OGTTs should be interpreted carefully in patients with diabetes secondary to glucocorticoid therapy or with endogenous cortisol disorders, with special attention to the transient post-OGTT dynamics. This is important in view of the fact that an OGTT may not be performed when a patient’s fasting glucose is normal, thus leading to an underestimation of the prevalence of diabetes in hypercortisolism ( 15 ). Our model is also a step towards an integrated theoretical framework that accounts for the circadian dynamics of insulin and glucose utilisation.…”

“…GLUTs are also involved in glucose sensing in pancreatic beta cells, with the caveat that the GLUT isoforms present in these insulin-secreting cells possess a different glucose sensitivity threshold than those in fat and muscle cells ( 28-31 ). Furthermore, CORT regulates glucose uptake by antagonising the insulin-mediated translocation of GLUTs in fat and muscle ( 32-35 ), by modulating insulin secretion in pancreatic beta cells ( 36-39 ), and by stimulating liver gluconeogenesis and glycogenolysis ( 4, 15 ). Importantly, our model considers the distribution of GLUT isoforms with different glucose affinities for glucose transport across cell membranes (Supplementary Material).…”

“…In addition, chronic conditions such as coronary artery disease, fibromyalgia, rheumatoid arthritis, and mood disorders such as Major Depressive Disorder (MDD) and Post Traumatic Stress Disorder (PTSD) have also been associated with abnormally high CORT levels and metabolic disruptions ( 5-13 ). Interestingly, while diabetes in people with normal CORT levels is characterised by increased fasting glucose, a static metric by all means, secondary diabetes in hypercortisolemic patients can be better characterised by impaired glucose tolerance, a medical test that is intrinsically dynamic ( 14, 15 ). However, a theoretical framework to help understand the complex regulation that fluctuating stress hormones exert on glucose homeostasis is lacking.…”

Monocyte Count to HDL-Cholesterol Ratio May Be a Novel Cardiometabolic Marker in Patients With Functional Adrenal Tumors

“…Park et al reported that patients with au-tonomous cortisol secretion presented obesity, glucose intolerance, arterial hypertension, and, increased CIMT compared with patients with nonfunctional adrenal adenoma (21). A grater prevalence of diabetes, insulin resistance, dyslipidemia, and increased inflammation was observed in patients with Cushing's syndrome (24,25). Low-grade inflammation participates in an increased cardiovascular risk in patients with Cushing's syndrome (24).…”

Does glucocorticoid exposure explain the association between metabolic dysfunction and tendinopathy?

“…Glucocorticoid excess affects all major peripheral tissues involved in glucose regulation (20,66). Furthermore, significant overlap exists between these pathways and those leading to visceral adiposity and dyslipidemia.…”