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Diazoxide Prevents Diabetes through Inhibiting Pancreatic ß-Cells from Apoptosis via Bcl-2/Bax Rate and p38-ß Mitogen-Activated Protein Kinase

Department of Endocrinology (Q.H., Z.G., L.Y., B.L., Z.F.), Changhai Hospital; Department of Physiology (S.B.), Basic Medicine College; Department of Pathology (Y.Y.), Changhai Hospital; and Department of Histology and Embryology (S.L., F.W.), Basic Medicine College, Second Military Medical University, Shanghai, 200433, People’s Republic of China; and Department of Cell Biology and Anatomy (G.G., M.B.), Medical University of South Carolina, Charleston, South Carolina 29425

Address all correspondence and requests for reprints to: Qin Huang, Department of Endocrinology, Changhai Hospital, 174 Changhai Road, Shanghai 200433, People’s Republic of China. E-mail: qinhuang20{at}yahoo.com.cn or qinhuang{at}smmu.edu.cn.

Increased apoptosis of pancreatic ß-cells plays an important role in the occurrence and development of type 2 diabetes. We examined the effect of diazoxide on pancreatic ß-cell apoptosis and its potential mechanism in Otsuka Long Evans Tokushima Fatty (OLETF) rats, an established animal model of human type 2 diabetes, at the prediabetic and diabetic stages. We found a significant increase with age in the frequency of apoptosis, the sequential enlargement of islets, and the proliferation of the connective tissue surrounding islets, accompanied with defective insulin secretory capacity and increased blood glucose in untreated OLETF rats. In contrast, diazoxide treatment (25 mg·kg^–1·d^–1, administered ip) inhibited ß-cell apoptosis, ameliorated changes of islet morphology and insulin secretory function, and increased insulin stores significantly in islet ß-cells whether diazoxide was used at the prediabetic or diabetic stage. Linear regression showed the close correlation between the frequency of apoptosis and hyperglycemia (r = 0.913; P < 0.0001). Further study demonstrated that diazoxide up-regulated Bcl-2 expression and p38ß MAPK, which expressed at very low levels due to the high glucose, but not c-jun N-terminal kinase and ERK. Hence, diazoxide may play a critical role in protection from apoptosis. In this study, we demonstrate that diazoxide prevents the onset and development of diabetes in OLETF rats by inhibiting ß-cell apoptosis via increasing p38ß MAPK, elevating Bcl-2/Bax ratio, and ameliorating insulin secretory capacity and action.

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