Glucocorticoids are very efficacious and frequently prescribed anti-inflammatory drugs. However, glucocorticoid treatment is associated with frequent occurrence of multiple side effects, including adverse metabolic effects. Indeed, glucocorticoid treatment may induce diabetes in a large proportion of subjects using these agents. The odds ratio for new-onset diabetes in glucocorticoid-treated patients ranges from 1.5-2.5. Several mechanisms contribute to their diabetogenic effects. Glucocorticoids are well-known to induce insulin resistance at the level of liver, skeletal muscle and adipose tissue, resulting in increased endogenous glucose production, decreased glucose disposal, impaired insulin-mediated suppression of lipolysis, respectively. In addition, due to adipose tissue en liver insulin resistance, dyslipidaemia develops. More recently, glucocorticoids were also shown to impair pancreatic islet-cell dysfunction by impairing insulin- and enhancing glucagon secretion. Due to the specific pattern of glucocorticoid-induced hyperglycaemia, i.e. normal or only mildly increased fasting plasma glucose and strongly elevated postprandial glucose levels, therapeutic efforts should specifically target the postprandial period. Short-acting insulin analogues and glucagon-like peptide-(GLP)1 receptor agonists seem a logical choice in this regard, however, there is currently, no evidence to substantiate this opinion due to lack of appropriate studies in clinical populations.
Due to their strong anti-inflammatory and immunosuppressive effects, glucocorticoids are the cornerstone in the treatment of numerous inflammatory conditions since their introduction in clinical practice in 1950. The scientists involved in the discovery and clinical introduction of cortisone, i.e. Tadeusz Reichstein, Calvin Kendall and Philip Showalter Hench shared the Nobel Prize for their work in that same year. Glucocorticoid use is still very common, with an estimated 10 million annual prescriptions for oral glucocorticoids in the US alone.
However, glucocorticoids have a broad spectrum of side effects, most notably adverse metabolic effects including the development of central obesity, insulin resistance, dyslipidaemia and hypertension. Collectively, these abnormalities increase the risk of diabetes and cardiovascular disease . Recent developments of novel glucocorticoid compounds that possess immunosuppressive properties devoid of dysmetabolic actions has revived research into the scope and mechanisms of steroid diabetes.
Estimation of diabetes risk
The glucocorticoid-associated risk to develop diabetes is difficult to estimate for a number of reasons. First, patients are often treated with different glucocorticoid formulations, during widely differing time periods and importantly, at different dosing regimen. Also, patient populations have a large variety of susceptibility to develop hyperglycaemia in part due to the varying indication for GC treatment, different comorbidities and genetic factors. Finally, since most studies measured only fasting glucose levels, steroid diabetes may go underreported in current literature. In a case control-study, a 36% [OR 1.36; 95%CI 1.10-1.69] increase in risk to develop diabetes was reported . In older population (aged>65 years), higher risks were observed [OR 2.31; 95%CI 2.11-2.54] . In patients using oral glucocorticoids a dose-dependent increase in the risk to develop diabetes requiring therapy was described, with an OR 1.36 [95%CI 1.10-1.69] and OR 5.82 [95%CI 2.74-12.35] for lower (defined as < 10 mg prednisolone equivalent)- and higher (defined as > 25 mg prednisolone equivalent) dosages of glucocorticoid therapy respectively . In glucocorticoid-treated rheumatoid arthritis patients  and primary renal disease patients , diabetes prevalence ranging between 20-40% has been reported, although in the non-glucocorticoid treated groups, diabetes prevalence was usually also high due to the adverse effect of systemic inflammation on glucose tolerance.
Mechanisms of steroid diabetes
Classically, the effects of glucocorticoids have been attributed to their induction of insulin resistance at the level of liver, skeletal muscle and adipose tissue. Indeed, high-dose glucocorticoid treatment impaired insulin-mediated suppression of endogenous glucose production, insulin-stimulated glucose disposal and insulin-induced suppression of adipose tissue lipolysis  . The latter mechanism may additionally exacerbate glucose intolerance since elevated levels of fatty acids may further impair skeletal muscle and liver insulin sensitivity. These changes in insulin sensitivity occur within days of treatment initiation and are independent of well-known changes in body weight and body fat distribution. In addition to insulin resistance at the level of these metabolically active organs, it was recently shown that glucocorticoids also induce vascular insulin resistance. As such, high-dose glucocorticoid treatment impaired insulin-stimulated capillary recruitment, thereby contributing to the concomitant reduction in glucose disposal, postprandial hyperglycaemia and increments in blood pressure.
Pancreatic islet-cell dysfunction
In recent years, the contribution of impaired pancreatic islet-cell function to glucocorticoid-induced hyperglycaemia has been demonstrated. As such, glucocorticoids were shown to impair beta-cell function. In vitro, glucocorticoids inhibit insulin secretion by targeting various proteins involved in the insulin secretory process. In addition, glucocorticoids promote beta-cell apoptosis by, amongst others, the induction endoplasmic reticulum stress. In vivo, glucocorticoids reduce insulin secretion, however, following more prolonged exposure, the impairment in beta-cell function may be masked to some extent by hyperinsulinaemia as partial compensation by beta-cells for peripheral insulin resistance . Interestingly, glucocorticoid treatment was shown to reduce the insulinotropic effects of incretin hormones . These gut-derived hormones are normally secreted by intestinal cells in response to a meal and act on pancreatic beta cells to stimulate insulin secretion (and production) in a glucose-dependent manner. In addition to effects on beta-cell function, glucocorticoids also affect alpha-cell function by raising fasting and postprandial glucagon levels, thus contributing to hyperglycaemia through stimulation of hepatic glucose production. Figure 1 summarizes the effects of glucocorticoids on glucose metabolism. Due to the above-listed combined effects on insulin sensitivity and islet-cell function, combined with the specific PK/PD properties, glucocorticoids typically raise plasma glucose levels in the afternoon and evening, while fasting glucose levels remain near normal in healthy individuals, chronic obstructive pulmonary disease (COPD) patients and rheumatoid arthritis patients.
Metabolic adverse effects of low glucocorticoid dosages
It is important to note that many studies investigating the effects of glucocorticoids have used high dosages. However, in clinical practice, patients often use low-dosages as maintenance therapy, which is usually considered safe with respect to metabolic side effects. However, it was recently shown that low dose glucocorticoid treatment (prednisolone 7.5 mg equivalent daily) increased postprandial glucose levels . In addition, the same low dosage impaired insulin-stimulated suppression of hepatic glucose production and adipose tissue lipolysis . Thus, particularly in the postprandial, hyperinsulinemic state, glucocorticoids already at a low dose impair glucose metabolism and increase the risk to develop diabetes.
Steroid diabetes: from mechanism to treatment
Current treatment recommendations of steroid diabetes are based on expert opinions due to the absence of (large-sized) randomised clinical studies. Thus, official treatment guidelines are lacking. In a small group of healthy volunteers, metformin and the thiazolidinedione pioglitazone were unable to mitigate the effects of glucocorticoids on glucose tolerance. Another small study in healthy individuals did show beneficial effects of the thiazolidinedione troglitazone on glucocorticoid-induced hyperglycemia. Due to liver toxicity, however, troglitazone is no longer available for treatment in humans. In addition, since thiazolidinediones promote heart failure, edema and fractures, the combination with glucocorticoid therapy seems unfavourable. At present, given the predominant postmeal rise in glucose due to glucocorticoids, short-acting prandial insulin is recommended, although no head-to-head comparisons with other hypoglycemic agents were hitherto studied in relevant populations.
More recently, given their beneficial effects on islet-cell function, their ability to specifically reduce postprandial glucose excursions and their beneficial effects on cardiovascular risk factors, incretin-based therapies have been studied in steroid diabetes. One case report demonstrated good efficacy of the GLP-1 receptor agonist exenatide in a patient with Cushing’s disease, whereas in another case report steroid diabetes was effectively treated in a number of patients with exenatide or liraglutide. Moreover, in a proof-of-principle study in healthy volunteers, exenatide infusion prevented islet-cell dysfunction and hyperglycemia induced by short-term glucocorticoid treatment . Further randomized studies are needed to assess the effects of incretin-based therapies on steroid diabetes in relevant patient groups.
Future perspectives: new glucocorticoids on the horizon
At present, novel glucocorticoid receptor agonists are being developed that aim to display less metabolic adverse effects, with intact anti-inflammatory efficacy. These compounds are based on the more recent observation that the anti-inflammatory actions of glucocorticoids are achieved through different nuclear pathways than most of their (metabolic) side effects. Whereas the anti-inflammatory actions of glucocorticoids are mostly achieved by inhibition of genes (‘transrepression’), the side effects of glucocorticoids are mostly consequential to activation of genes (‘transactivation’). The novel compounds are called dissociated glucocorticoid receptor agonists and are designed to specifically induce transrepression. Currently, a great number of pharmaceutical companies are developing glucocorticoid compounds with a dissociated profile . Although these agenta have so far shown promising results in preclinical studies, few data are currently available in humans.
[a] Professor Michaela Diamant, 11 April 1962– 9 April 2014
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