Glucocorticoids (GCs) are broadly prescribed for numerous pathological conditions because of their anti-inflammatory, antiallergic and immunosuppressive effects, among other actions. Nevertheless, GCs can produce undesired diabetogenic side effects through interactions with the regulation of glucose homeostasis. Under conditions of excess and/or long-term treatment, GCs can induce peripheral insulin resistance (IR) by impairing insulin signalling, which results in reduced glucose disposal and augmented endogenous glucose production. In addition, GCs can promote abdominal obesity, elevate plasma fatty acids and triglycerides, and suppress osteocalcin synthesis in bone tissue. In response to GC-induced peripheral IR and in an attempt to maintain normoglycaemia, pancreatic β-cells undergo several morphofunctional adaptations that result in hyperinsulinaemia. Failure of β-cells to compensate for this situation favours glucose homeostasis disruption, which can result in hyperglycaemia, particularly in susceptible individuals. GC treatment does not only alter pancreatic β-cell function but also affect them by their actions that can lead to hyperglucagonaemia, further contributing to glucose homeostasis imbalance and hyperglycaemia. In addition, the release of other islet hormones, such as somatostatin, amylin and ghrelin, is also affected by GC administration. These undesired GC actions merit further consideration for the design of improved GC therapies without diabetogenic effects. In summary, in this review, we consider the implication of GC treatment on peripheral IR, islet function and glucose homeostasis.

The cannabinoid CB1 receptor is a well-known player in energy homeostasis and its specific antagonism has been used in clinical practice for the treatment of obesity. The G protein-coupled receptor GPR55 has been recently proposed as a new cannabinoid receptor and, by contrast, its pharmacology is still enigmatic and its physiological role is largely unexplored, with no reports investigating its putative role in metabolism. Thus, we aim to investigate in rats the presence, distribution and putative physiological role of GPR55 in a key metabolic tissue, the endocrine pancreas. We found high Gpr55 mRNA content in pancreatic islets and considerable protein distribution in insulin-secreting β-cells. Activation of GPR55 by the agonist O-1602 increased calcium transients (P<0.01) and insulin secretion (P<0.001) stimulated by glucose. This latter effect was blunted in Gpr55 KO mice suggesting that O-1602 is acting, at least in part, through GPR55. Indeed, acute in vivo experiments showed that GPR55 activation increases glucose tolerance (P<0.05) and plasma insulin levels (P<0.05), suggesting an in vivo physiological relevance of GPR55 systemic stimulation. Taken together, these results reveal the expression of GPR55 receptors in the endocrine pancreas as well as its function at stimulus-secretion coupling of insulin secretion, suggesting a role in glucose homeostasis. In this context, it may also represent a new target for consideration in the management of type 2 diabetes and related diseases.

Activation of insulin signaling and cell cycle intermediates is required for adult β-cell proliferation. Here, we report a model to study β-cell proliferation in living rats by administering three different doses of dexamethasone (0.1, 0.5, and 1.0 mg/kg ip, DEX 0.1, DEX 0.5, and DEX 1.0, respectively) for 5 days. Insulin sensitivity, insulin secretion, and histomorphometric data were investigated. Western blotting was used to analyze the levels of proteins related to the control of β-cell growth. DEX 1.0 rats, which present moderate hyperglycemia and marked hyperinsulinemia, exhibited a 5.1-fold increase in β-cell proliferation and an increase (17%) in β-cell size, with significant increase in β-cell mass, compared with control rats. The hyperinsulinemic but euglycemic DEX 0.5 rats also showed a significant 3.6-fold increase in β-cell proliferation. However, DEX 0.1 rats, which exhibited the lowest degree of insulin resistance, compensate for insulin demand by improving only islet function. Activation of the insulin receptor substrate 2/phosphatidylinositol 3-kinase/serine-threonine kinase/ribosomal protein S6 kinase pathway, as well as protein retinoblastoma in islets from DEX 1.0 and DEX 0.5, but not in DEX 0.1, rats was also observed. Therefore, increasing doses of dexamethasone induce three different degrees of insulin requirement in living rats, serving as a model to investigate compensatory β-cell alterations. Augmented β-cell mass involves β-cell hyperplasia and, to a lower extent, β-cell hypertrophy. We suggest that alterations in circulating insulin and, to a lesser extent, glucose levels could be the major stimuli for β-cell proliferation in the dexamethasone-induced insulin resistance.

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.

Although glucocorticoids are widely used as antiinflammatory agents in clinical therapies, they may cause serious side effects that include insulin resistance and hyperinsulinemia. To study the potential functional adaptations of the islet of Langerhans to in vivo glucocorticoid treatment, adult Wistar rats received dexamethasone (DEX) for 5 consecutive days, whereas controls (CTL) received only saline. The analysis of insulin release in freshly isolated islets showed an enhanced secretion in response to glucose in DEX-treated rats. The study of Ca2+ signals by fluorescence microscopy also demonstrated a higher response to glucose in islets from DEX-treated animals. However, no differences in Ca2+ signals were found between both groups with tolbutamide or KCl, indicating that the alterations were probably related to metabolism. Thus, mitochondrial function was explored by monitoring oxidation of nicotinamide dinucleotide phosphate autofluorescence and mitochondrial membrane potential. Both parameters revealed a higher response to glucose in islets from DEX-treated rats. The mRNA and protein content of glucose transporter-2, glucokinase, and pyruvate kinase was similar in both groups, indicating that changes in these proteins were probably not involved in the increased mitochondrial function. Additionally, we explored the status of Ca2+-dependent signaling kinases. Unlike calmodulin kinase II, we found an augmented phosphorylation level of protein kinase Cα as well as an increased response of the phospholipase C/inositol 1,4,5-triphosphate pathway in DEX-treated rats. Finally, an increased number of docked secretory granules were observed in the β-cells of DEX animals using transmission electron microscopy. Thus, these results demonstrate that islets from glucocorticoid-treated rats develop several adaptations that lead to an enhanced stimulus-secretion coupling and secretory capacity.