Impact of Glucocorticoid Excess on Glucose Tolerance: Clinical and Preclinical Evidence

Abstract

Glucocorticoids (GCs) are steroid hormones that exert important physiological actions on metabolism. Given that GCs also exert potent immunosuppressive and anti-inflammatory actions, synthetic GCs such as prednisolone and dexamethasone were developed for the treatment of autoimmune- and inflammatory-related diseases. The synthetic GCs are undoubtedly efficient in terms of their therapeutic effects, but are accompanied by significant adverse effects on metabolism, specifically glucose metabolism. Glucose intolerance and reductions in insulin sensitivity are among the major concerns related to GC metabolic side effects, which may ultimately progress to type 2 diabetes mellitus. A number of pre-clinical and clinical studies have aimed to understand the repercussions of GCs on glucose metabolism and the possible mechanisms of GC action. This review intends to summarize the main alterations that occur in liver, skeletal muscle, adipose tissue, and pancreatic islets in the context of GC-induced glucose intolerance. For this, both experimental (animals) and clinical studies were selected and, whenever possible, the main cellular mechanisms involved in such GC-side effects were discussed.

Keywords: dexamethasone; glucose homeostasis; glucose tolerance; insulin sensitivity; insulin signaling; outcomes; peripheral tissues; prednisolone; side-effects.

Figure 1

Adverse actions of glucocorticoids (GCs) on peripheral tissues involved in the control of glucose homeostasis. Excess or prolonged GC treatment may disrupt glucose homeostasis by interfering with several metabolic-related tissues. In visceral adipose tissue, GCs elevate LPL activity, leading to fat accumulation at this fat site; while at the same time exhibiting increased HSL activity, resulting in increased lipid (FFA and glycerol) release, supplying for hepatic triacylglycerol synthesis, fat accumulation and gluconeogenesis, and also in intramuscular fat accumulation. These steroids may also affect insulin signaling in adipose tissue. GCs impair insulin-stimulated glucose uptake in skeletal muscles and induce muscle wasting, which, in turn, provides gluconeogenesis substrates. In the liver, GCs have a negative effect on rate-limiting enzymes controlled by insulin. Finally, * GC in excess may also lead to an insulin hypersecretion that may not be sufficient to match with the disposition index, which means relative increase in islet function or ** cause insulinopenia depending on previous individual’s susceptibility (read Section 5 for more details). Continuous line means direct effect, while dotted lines means indirect action. FFA, free fatty acids; G6Pase, glucose-6-phospatase; HSL, hormone-sensitive lipase; LPL, lipoprotein lipase; PEPCK, phophoenolpyruvate carboxykinase; TG, triacylglycerol. Modified from Rafacho et al. [30].

Figure 2

Cellular mechanisms involved with the glucocorticoid (GC) side effects. The main cellular components or pathways altered in metabolic-related cells from experimental models subjected to GC administration. Please, find abbreviations in the list of abbreviations.