Mitogen-activated protein kinases and protein phosphatase 5 mediate glucocorticoid-induced cytotoxicity in pancreatic islets and β-cells

Abstract

Glucocorticoid excess is associated with glucose intolerance and diabetes. In addition to inducing insulin resistance, glucocorticoids impair β-cell function and cause β-cell apoptosis. In this study we show that dexamethasone activates mitogen-activated protein kinases (MAPKs) signaling in MIN6 β-cells, as evident by enhanced phosphorylation of p38 MAPK and c-Jun N-terminal kinase (JNK). In contrast, the integrated stress response pathway was inhibited by dexamethasone. A p38 MAPK inhibitor attenuated dexamethasone-induced apoptosis in β-cells and isolated islets and decreased glucocorticoid receptor phosphorylation at S220. In contrast, a JNK inhibitor augmented DNA fragmentation and dexamethasone-induced formation of cleaved caspase 3. We also show that inhibition of protein phosphatase 5 (PP5) augments apoptosis in dexamethasone-exposed islets and β-cells, with a concomitant activation of p38 MAPK. In conclusion, our data provide evidence that in islets and β-cells, p38 MAPK and JNK phosphorylation work in concert with PP5 to regulate the cytotoxic effects exerted by glucocorticoids.

Keywords: Apoptosis; Glucocorticoids; JNK; Pancreatic islet; Protein phosphatase 5; p38 MAPK.