Glucocorticoids in vivo induce both insulin hypersecretion and enhanced glucose sensitivity of stimulus-secretion coupling in isolated rat islets.
ABSTRACT 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 Ca(2+) signals by fluorescence microscopy also demonstrated a higher response to glucose in islets from DEX-treated animals. However, no differences in Ca(2+) 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 Ca(2+)-dependent signaling kinases. Unlike calmodulin kinase II, we found an augmented phosphorylation level of protein kinase C alpha 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 beta-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.
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ABSTRACT: Glucocorticoid excess is commonly associated with diabetogenic effects, including insulin resistance and glucose intolerance. The effects of the long-term glucagon-like peptide 1 receptor agonist treatment on the metabolic syndrome-like conditions are not yet fully elucidated. Thus, we aimed to test whether long-term liraglutide treatment could be effective as a therapy to counteract the metabolic dysfunctions induced by chronic glucocorticoid exposure. Mice were given corticosterone or vehicle via their drinking water for five consecutive weeks. In addition, mice were treated with once-daily injections of either PBS or liraglutide. Liraglutide treatment slowed progression towards obesity and ectopic fat deposition in liver that otherwise occurred in corticosterone-treated mice. The drug reduced the increment in serum insulin caused by corticosterone, but did not affect the reduction of insulin sensitivity. Furthermore, liraglutide improved glucose control in mice exposed to corticosterone as evident by a delay in the progression towards post-prandial hyperglycemia and enhanced glucose clearance during a glucose tolerance test. Glucose-stimulated C-peptide levels were higher in those mice that had received liraglutide and corticosterone compared to mice that had been treated with corticosterone alone, indicating a positive role of liraglutide for beta-cell function. Morphometric analysis revealed increased beta- and alpha-cell masses that were associated with more Ki67-positive islet cells in corticosterone-treated mice irrespective of whether they were co-treated with liraglutide or not. Liraglutide had no discernible effect on alpha-cell mass. Liraglutide can be beneficial for subjects at risk of developing metabolic complications as a result of glucocorticoid excess.Diabetology and Metabolic Syndrome 01/2014; 6(1):3. · 1.92 Impact Factor
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ABSTRACT: Glucocorticoids are stress hormones primarily responsible for mobilizing glucose to the circulation. Due to these effects, insulin resistance and glucose intolerance are concerns in patients with endogenous overproduction of glucocorticoids and in patients prescribed glucocorticoid-based therapy. In addition, hypercortisolemic conditions share many characteristics with the metabolic syndrome. The present study reports on a thorough characterization, in terms of glucose control and lipid handling, of a mouse model where corticosterone is given via the drinking water. C57BL/6J mice were treated with corticosterone (100 or 25 µg/ml) or vehicle in their drinking water for five weeks after which they were subjected to insulin or glucose tolerance tests. Glucocorticoid-treated mice displayed increased food intake, body weight gain and central fat deposit accumulations. Additionally, the glucocorticoid treatment led to dyslipidemia as well as accumulation of ectopic fat in liver and skeletal muscle, having a substantial negative impact on insulin sensitivity. Also glucose intolerance and hypertension, both part of the metabolic syndrome, were evident in the glucocorticoid-treated mice. However, the observed effects of corticosterone were reversed after drug removal. Furthermore, the present study reveals insights into β-cell adaptation to the glucocorticoid-induced insulin resistance. Increased pancreatic islet volume due to cell proliferation, increased insulin secretion capacity and increased islet chaperone expression were found in glucocorticoid-treated animals. This model mimics the human metabolic syndrome. It can be a valuable model for studying the complex mechanisms behind the development of the metabolic syndrome and type 2 diabetes, as well as the multifaceted relations between glucocorticoid excess and disease.Journal of Endocrinology 09/2013; · 4.06 Impact Factor
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ABSTRACT: Glucocorticoid (GC)-based therapies can cause insulin resistance (IR), glucose intolerance, hyperglycemia and, occasionally, overt diabetes. Understanding the mechanisms behind these metabolic disorders could improve the management of glucose homeostasis in patients undergoing GC treatment. For this purpose, adult rats were treated with a daily injection of dexamethasone (1 mg/kg b.w., i.p.) (DEX) or saline as a control for 5 consecutive days. The DEX rats developed IR, augmented glycemia, hyperinsulinemia and hyperglucagonemia. Treatment of the DEX rats with a glucagon receptor antagonist normalized their blood glucose level. The characteristic inhibitory effect of glucose on glucagon secretion was impaired in the islets of the DEX rats, while no direct effects were found on α-cells in islets that were incubated with DEX in vitro. A higher proportion of docked secretory granules was found in the DEX α-cells as well as a trend towards increased α-cell mass. Additionally, insulin secretion in the presence of glucagon was augmented in the islets of the DEX rats, which was most likely due to their higher glucagon receptor content. We also found that the enzyme 11βHSD-1, which participates in GC metabolism, contributed to the insulin hypersecretion in the DEX rats under basal glucose conditions. Altogether, we showed that GC treatment induces hyperglucagonemia, which contributes to an imbalance in glucose homeostasis and compensatory β-cell hypersecretion. This hyperglucagonemia may result from altered α-cell function and, likely, α-cell mass. Additionally, blockage of the glucagon receptor seems to be effective in preventing the elevation in blood glucose levels induced by GC administration.PLoS ONE 01/2014; 9(4):e93531. · 3.73 Impact Factor