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Background and Purpose: Glucocorticoids (GCs) are the main treatment for autoimmune and inflammatory disorders and are also used as immunosuppressive therapy for patients with organ transplantation. However, these treatments have several side effects, including metabolic disorders. Indeed, cortico-therapy may induce insulin resistance, glucose intolerance, disrupted insulin and glucagon secretion, excessive gluconeogenesis, leading to diabetes in susceptible individuals. Recently, lithium has been shown to alleviate deleterious effects of GCs in various diseased conditions., Experimental Approach: In this study, using two rat models of GC-induced metabolic disorders, we investigated the effects of Lithium Chloride (LiCl) in the mitigation of deleterious effects of GCs. Rats were treated either with corticosterone or dexamethasone, and with or without LiCl. Animals were then assessed for glucose tolerance, insulin sensitivity, in vivo and ex vivo glucose-induced insulin secretion and hepatic gluconeogenesis., Key Results: We showed that in rats chronically treated with corticosterone, lithium treatment markedly reduced insulin resistance. In addition, in rats treated with dexamethasone, lithium administration improved glucose tolerance, associated with enhanced insulin secretion in vivo. Moreover, liver gluconeogenesis was reduced upon LiCl treatment. The improvement of insulin secretion in vivo appeared to be due to an indirect regulation of β cell function, since the ex vivo assessment of insulin secretion and β cell mass in islets from animals treated with LiCl revealed no difference compared to untreated animals., Conclusion and Implications: Collectively, our data provide evidences for the beneficial effects of lithium to mitigate the adverse metabolic effects of chronic cortico-therapy., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier Masson SAS.)

Since the use of bisphenol A (BPA) has been restricted because of its endocrine disruptor properties, bisphenol S (BPS) has been widely used as a substitute of BPA. However, BPS exerts similar effects on metabolic health as BPA. The effects of maternal exposure to BPA and BPS on the metabolic health of offspring have been largely documented during the past decade. However, the impact of preconceptional paternal exposure to BPS on progenies remains unexplored. In this study we investigated the impact of paternal exposure to BPS before conception, on the metabolic phenotype of offspring. Male Wistar rats were administered BPS through drinking water at the dose of 4 μg/kg/day (BPS-4 sires) or 40 μg/kg/day (BPS-40 sires) for 2 months before mating with females. The progenies (F1) were studied at fetal stage and in adulthood. We showed that preconceptional paternal exposure to BPS for 2 months did not alter the metabolic status of sires. The female offspring of sires exposed to lower or higher doses of BPS showed no alteration of their metabolic phenotype compared to females from control sires. In contrast, male offspring of BPS-4 sires exhibited increased body weight and body fat/lean ratio, decreased insulin sensitivity and increased glucose-induced insulin secretion at adult age, compared to the male offspring of control sires. Moreover, male offspring of BPS-4 sires developed glucose intolerance later in life. None of these effects were apparent in male offspring of BPS-40 sires. In conclusion, our study provides the first evidence of the non-monotonic and sex-specific effects of preconceptional paternal exposure to BPS on the metabolic health of offspring, suggesting that BPS is not a safe BPA substitute regarding the inter-generational transmission of metabolic disorders through the paternal lineage., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purinergic P2Y receptors, by binding adenosine triphosphate (ATP), are known for enhancing glucose-stimulated insulin secretion (GSIS) in pancreatic β cells. However, the impact of these receptors in the actin dynamics and insulin granule exocytosis in these cells is not established, neither in normal nor in glucotoxic environment. In this study, we investigate the involvement of P2Y receptors on the behavior of insulin granules and the subcortical actin network dynamics in INS-1 832/13 β cells exposed to normal or glucotoxic environment and their role in GSIS. Our results show that the activation of P2Y purinergic receptors by ATP or its agonist increase the insulin granules exocytosis and the reorganization of the subcortical actin network and participate in the potentiation of GSIS. In addition, their activation in INS-1832/13 β-cells, with impaired insulin secretion following exposure to elevated glucose levels, restores GSIS competence through the distal steps of insulin exocytosis. These results are confirmed ex vivo by perifusion experiments on islets from type 2 diabetic (T2D) Goto-Kakizaki (GK) rats. Indeed, the P2Y receptor agonist restores the altered GSIS, which is normally lost in this T2D animal model. Moreover, we observed an improvement of the glucose tolerance, following the acute intraperitoneal injection of the P2Y agonist concomitantly with glucose, in diabetic GK rats. All these data provide new insights into the unprecedented therapeutic role of P2Y purinergic receptors in the pathophysiology of T2D., (© 2021 Wiley Periodicals LLC.)

Glucocorticoids (GCs) are widely prescribed for their anti-inflammatory and immunosuppressive properties as a treatment for a variety of diseases. The use of GCs is associated with important side effects, including diabetogenic effects. However, the underlying mechanisms of GC-mediated diabetogenic effects in β-cells are not well understood. In this study we investigated the role of glycogen synthase kinase 3 (GSK3) in the mediation of β-cell death and dysfunction induced by GCs. Using genetic and pharmacological approaches we showed that GSK3 is involved in GC-induced β-cell death and impaired insulin secretion. Further, we unraveled the underlying mechanisms of GC-GSK3 crosstalk. We showed that GSK3 is marginally implicated in the nuclear localization of GC receptor (GR) upon ligand binding. Furthermore, we showed that GSK3 regulates the expression of GR at mRNA and protein levels. Finally, we dissected the proper contribution of each GSK3 isoform and showed that GSK3β isoform is sufficient to mediate the pro-apoptotic effects of GCs in β-cells. Collectively, in this work we identified GSK3 as a viable target to mitigate GC deleterious effects in pancreatic β-cells., (© 2021. The Author(s).)