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.

Fig. 1. The pathophysiology of glucocorticoid-induced hyperglycaemia and insulin resistance involves multi-organ crosstalk.

Glucocorticoids increase appetite and promote the intake of high-calorie (high-fat and/or high-sugar) ‘comfort food’, which indirectly promotes obesity and diabetes mellitus. Glucocorticoids upregulate the transcriptional and functional activity of neuropeptide Y (NPY)–agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus and promote leptin resistance. Skeletal muscle atrophy results from glucocorticoid-mediated protein degradation and decreased protein synthesis in myocytes, and glucocorticoids also decrease glucose uptake into these cells. In the liver, glucocorticoids act directly to upregulate enzymes involved in gluconeogenesis and promote hepatic insulin resistance, which together accelerate the development of hyperglycaemia. Furthermore, glucocorticoids synergize with insulin to stimulate non-esterified fatty acid (NEFA) uptake by hepatocytes and triglyceride synthesis in the liver, which causes hepatic steatosis. In adipose tissue, glucocorticoids increase adipogenesis, de novo lipogenesis and triglyceride synthesis as well as lipid uptake and storage. Concurrently, glucocorticoids facilitate lipolysis, which promotes the futile cycling of lipids. Glucocorticoids also decrease glucose uptake into adipocytes. Acute exposure of pancreatic β-cells to glucocorticoids can stimulate insulin secretion and β-cell hyperplasia to counterbalance glucocorticoid-induced insulin resistance and to maintain plasma levels of glucose within the physiological range. However, long-term exposure to glucocorticoids can interfere with insulin biosynthesis and secretion and induce β-cell apoptosis. Osteocalcin is secreted by osteoblasts and circulating osteocalcin from bone promotes insulin secretion by β-cells. Glucocorticoids suppress the expression of osteocalcin, thereby indirectly inhibiting insulin secretion. The increase in circulating levels of amino acids from muscle breakdown and NEFAs and glycerol from adipose tissue lipolysis provide substrates to the liver for gluconeogenesis. High plasma levels of NEFAs also accumulate ectopically in skeletal muscle, liver and β-cells, which further exacerbates insulin resistance. Thick solid arrows indicate effects; thin solid arrows indicate a transition in time; dashed arrows indicate secreted factors.

Fig. 2. Novel pharmacological targets to combat glucocorticoid-induced hyperglycaemia and insulin resistance.

In the absence of ligand, glucocorticoid receptor resides in the cytoplasm bound to chaperone proteins, including heat shock protein 90 (HSP90) and p23. Histone deacetylase 6 (HDAC6) deacetylates HSP90, thereby enabling its interaction with the co-chaperone p23, which in turn promotes the proper folding of the glucocorticoid receptor. Inhibition of HDAC6 prevents the interaction of HSP90 with p23, inhibiting glucocorticoid receptor translocation. In the presence of glucocorticoids, the glucocorticoid receptor binds to glucocorticoid-response elements (GREs) in genes related to metabolism in target tissues to exert their metabolic effects. Liver X receptor-β (LXRβ), basic helix–loop–helix transcription factor E47 and the glucocorticoid receptor arginine and glutamate-rich protein 1 (ARGLU1) are required for the full recruitment of the glucocorticoid receptor to target genes involved in gluconeogenesis. Loss of any of these factors protects against glucocorticoid-induced hyperglycaemia. Elevated ceramide levels in the portal circulation and the liver, occurring as a result of increased gene and protein expression of serine palmitoyltransferase (SPT) induced by glucocorticoids, promote hepatic gluconeogenesis. Likewise, increased serotonin synthesis (from glucocorticoid-induced TPH1 and AADC) and serotonin receptor expression promote gluconeogenesis and steatosis in liver and lipolysis in adipose tissue. LXRβ also promotes glucocorticoid-induced lipolysis increasing the flux of non-esterified fatty acids and glycerol into the liver, which exacerbates hepatic steatosis. Small-molecule inhibitors (HDAC6, SPT, PKCζ, TPH1 and AADC) or antagonists (LXRβ and serotonin receptor) have been shown to protect against glucocorticoid-induced hyperglycaemia and insulin resistance in mouse models. Thick solid arrows indicate effects; dashed arrows indicate secreted factors.