Diazoxide prevents diabetes through inhibiting pancreatic beta-cells from apoptosis via Bcl-2/Bax rate and p38-beta mitogen-activated protein kinase.
Increased apoptosis of pancreatic beta-cells plays an important role in the occurrence and development of type 2 diabetes. We examined the effect of diazoxide on pancreatic beta-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 beta-cell apoptosis, ameliorated changes of islet morphology and insulin secretory function, and increased insulin stores significantly in islet beta-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 p38beta 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 beta-cell apoptosis via increasing p38beta MAPK, elevating Bcl-2/Bax ratio, and ameliorating insulin secretory capacity and action.
Huang
Qin
Q
Department of Endocrinology, Changhai Hospital, Shanghai 200433, People's Republic of China. qinhuang20@yahoo.com.cn
Bu
Shizhong
S
Yu
Yongwei
Y
Guo
Zhiyong
Z
Ghatnekar
Gautam
G
Bu
Min
M
Yang
Linhui
L
Lu
Bin
B
Feng
Zhengkang
Z
Liu
Shanrong
S
Wang
Fengqi
F
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D019540:Area Under Curve; D001786:Blood Glucose / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D003981:Diazoxide / Q000494:pharmacology*; D005215:Fasting; D018149:Glucose Intolerance / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000201:enzymology / Q000473:pathology*; D008297:Male; D015221:Potassium Channels / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D020334:Rats, Inbred OLETF; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000959:Antihypertensive Agents; D001786:Blood Glucose; D007328:Insulin; D015221:Potassium Channels; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C117780:mitochondrial K(ATP) channel; D048051:p38 Mitogen-Activated Protein Kinases; D003981:Diazoxide