Fresh insights into glucocorticoid-induced diabetes mellitus and new therapeutic directions

Abstract

Glucocorticoid hormones were discovered to have use as potent anti-inflammatory and immunosuppressive therapeutics in the 1940s and their continued use and development have successfully revolutionized the management of acute and chronic inflammatory diseases. However, long-term use of glucocorticoids is severely hampered by undesirable metabolic complications, including the development of type 2 diabetes mellitus. These effects occur due to glucocorticoid receptor activation within multiple tissues, which results in inter-organ crosstalk that increases hepatic glucose production and inhibits peripheral glucose uptake. Despite the high prevalence of glucocorticoid-induced hyperglycaemia associated with their routine clinical use, treatment protocols for optimal management of the metabolic adverse effects are lacking or underutilized. The type, dose and potency of the glucocorticoid administered dictates the choice of hypoglycaemic intervention (non-insulin or insulin therapy) that should be provided to patients. The longstanding quest to identify dissociated glucocorticoid receptor agonists to separate the hyperglycaemic complications of glucocorticoids from their therapeutically beneficial anti-inflammatory effects is ongoing, with selective glucocorticoid receptor modulators in clinical testing. Promising areas of preclinical research include new mechanisms to disrupt glucocorticoid signalling in a tissue-selective manner and the identification of novel targets that can selectively dissociate the effects of glucocorticoids. These research arms share the ultimate goal of achieving the anti-inflammatory actions of glucocorticoids without the metabolic consequences.

Abstract

Glucocorticoid therapies are widely used to treat acute and chronic inflammatory diseases, yet these drugs induce adverse metabolic effects. This Review highlights new insights into mechanisms of glucocorticoid-induced diabetes mellitus and discusses current and future therapeutic options.

Key points

• Glucocorticoid drugs are widely prescribed to treat inflammatory diseases and to prevent organ transplant rejection yet they promote hyperglycaemia and diabetes mellitus.

• Glucocorticoid-induced hyperglycaemia manifests directly via glucocorticoid signalling in metabolic organs and tissues (liver, adipose tissue, muscle, bone and pancreatic β-cells) and indirectly via inter-organ hormone and metabolite flux.

• No single consensus exists with respect to optimal screening frequency for glucocorticoid-induced hyperglycaemia due to context-dependent factors, although analysis of postprandial glucose (not fasting glucose) is recommended.

• Hypoglycaemic agents (such as insulin sensitizers and insulin) can provide satisfactory glucose control but need to be tailored for differences in the dose and type of glucocorticoid used.

• Developing selective glucocorticoid modulators that dissociate the diabetogenic from the anti-inflammatory effects of glucocorticoids continues to be challenging; however, new pharmacological targets that prevent diabetogenic effects are on the horizon.