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Inhibition of Forkhead Box O1 Protects Pancreatic β-Cells against Dexamethasone-Induced Dysfunction

Key Laboratory of Human Functional Genomics of Jiangsu Province (X.Z., W.Y., J.L., Y.Z., F.C., R.Z., Y.S., X.H.), Department of Endocrinology (T.Y., Y.S., X.H.), Jiangsu Diabetes Center, and Department of General Surgery (J.Z.), the First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing 210029, People’s Republic of China

Address all correspondence and requests for reprints to: Xiao Han, Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, People’s Republic of China. E-mail: hanxiao{at}njmu.edu.cn.

Forkhead Box O1 (FoxO1) is a key transcription regulator of insulin/IGF-I signaling pathway, and its activity can be increased by dexamethasone (DEX) in several cell types. However, the role of FoxO1 in DEX-induced pancreatic β-cell dysfunction has not been fully understood. Therefore, in this study, we investigated whether FoxO1 could mediate DEX-induced β-cell dysfunction and the possible underlying mechanisms in pancreatic β-cell line RINm5F cells and primary rat islet. We found that DEX markedly increased FoxO1 mRNA and protein expression and decreased FoxO1 phosphorylation through the Akt pathway, which resulted in an increase in active FoxO1 in RINm5F cells and isolated rat islets. Activated FoxO1 subsequently inhibited pancreatic duodenal homeobox-1 expression and induced nuclear exclusion of pancreatic duodenal homeobox-1. Knockdown of FoxO1 by RNA interference restored the expression of pancreatic duodenal homeobox-1 and prevented DEX-induced dysfunction of glucose-stimulated insulin secretion in rat islets. Together, the results of present study demonstrate that FoxO1 is integrally involved in DEX-induced inhibition of pancreatic duodenal homeobox-1 and glucose-stimulated insulin secretion dysfunction in pancreatic islet β-cells. Inhibition of FoxO1 can effectively protect β-cells against DEX-induced dysfunction.