TIMP-1 transgenic mice recover from diabetes induced by multiple low-dose streptozotocin.
Type 1 diabetes results from autoimmune destruction of the insulin-producing beta-cells of pancreatic islets, of which the capacity for self-replication in the adult is too limited to restore following extensive tissue injury. Tissue inhibitor of metalloproteinase (TIMP)-1 inhibits matrix metalloproteinase activity and regulates proliferation and apoptosis of a variety of cells types, depending on the context. Here, we show that overexpression of human TIMP-1 in pancreatic beta-cells of transgenic mice counteracts the cytotoxicity and insulitis induced by multiple low-dose streptozotocin (MLDS). Nontransgenic mice developed severe hyperglycemia, hypoinsulinemia, and insulitis 2 weeks after streptozotocin administration and died within 17 weeks. However, MLDS-treated transgenic mice gradually normalized the metabolic parameters and survived. beta-Cell mass increased in parallel as a result of enhancement of beta-cell replication. Thus, our results have demonstrated for the first time that overexpression of TIMP-1 in beta-cells enhances the replication of pancreatic islets beta-cells and counteracts type 1 diabetes, indicating that the TIMP-1 gene may be a potential target to prevent, or even reverse, type 1 diabetes.
Jiang
Hongwei
H
Department of Nephrology, Kidney Center and Key Lab of People's Liberation Army, General Hospital of PLA, Fuxing Road 28, Beijing 100853, PR China.
Zhu
Hanyu
H
Chen
Xiangmei
X
Peng
Youming
Y
Wang
Jianzhong
J
Liu
Fuyou
F
Shi
Suozhu
S
Fu
Bo
B
Lu
Yang
Y
Hong
Quan
Q
Feng
Zhe
Z
Hou
Kai
K
Sun
Xuefeng
X
Cai
Guangyan
G
Zhang
Xueguang
X
Xie
Yuansheng
Y
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003433:Crosses, Genetic; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D006801:Humans; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics; D012075:Remission, Spontaneous; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics* / Q000378:metabolism
D001786:Blood Glucose; D007328:Insulin; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1