Glucocorticoids in Vivo Induce Both Insulin Hypersecretion and Enhanced Glucose Sensitivity of Stimulus-Secretion Coupling in Isolated Rat Islets

Instituto de Bioingeniería, and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Universidad Miguel Hernández de Elche, Elche 03202, Spain.
Endocrinology (Impact Factor: 4.5). 10/2009; 151(1):85-95. DOI: 10.1210/en.2009-0704
Source: PubMed


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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Available from: Alex Rafacho, May 15, 2015
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    • "Additionally, ob/ob islets displayed higher glucose-induced ψm hyperpolarization, further supporting an enhanced β-cell mitochondrial performance in obese mice. All these findings are in agreement with previous reports showing similar metabolic responses in a rat model of insulin resistance (Rafacho et al., 2010). Since enhanced NAD(P)H production and Ψm hyperpolarization should be coupled to increased ATP synthesis (Quesada et al., 2006), the mitochondrial responses in ob/ob islets and their higher glucose sensitivity may explain the electrical activity at lower glucose levels compared with controls (Fig. 3). "
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    • "Thus, when í µí»½-cells can no longer compensate, a glucolipotoxicity process progressively develops that induces í µí»½cell death accompanied by hypoinsulinemia, hyperglycemia, and hyperlipidemia [15]. The í µí»½-cell compensations [17] can be rapidly obtained experimentally by 5-day treatment with DEX (5 days) [18] [19] that induces peripheral IR [20] [21], which is associated with increased hepatic gluconeogenesis and lipolysis [8]. "
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    • "Assessment of HPA-axis function revealed that both peak and stress induced corticosterone levels were elevated in NRic-KO mice. The metabolic derangements observed in NRic-KO mice are consistent with the systemic effects of glucocorticoid action to increase hepatic TG [71] and glucose production [72], and promote insulin secretion [73]. Reduced energy expenditure and lower RER, together with decreased body temperature, observed in NRic-KO mice are also consistent with the reported actions of corticosterone to promote preferential oxidation of fat over glucose in muscle [74], while simultaneously decreasing the rate of fat oxidized through non-shivering thermogenesis in brown adipose tissue [75]. "
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