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TIMP-1 Transgenic Mice Recover From Diabetes Induced by Multiple Low-Dose Streptozotocin

¹ Department of Nephrology, Kidney Center and Key Lab of the People’s Liberation Army (PLA), General Hospital of PLA, Beijing, China
² Department of Nephrology, 2nd Xiangya Hospital, Institute of Nephrology, Central South University, Changsha, Hunan Province, China

Address correspondence and reprint requests to Xiangmei Chen, MD, Department of Nephrology, Kidney Center and Key Lab of PLA, General Hospital of PLA, Fuxing Road 28, Beijing 100853, P.R. China. E-mail: xmchen{at}public.bta.net.cn

Key Words: BrdU, 5-bromo-2-deoxyuridine • HBSS, Hanks’ buffered saline solution • H&E, hematoxyline & eosin • MLDS, multiple low-dose streptozotocin • MMP, matrix metalloproteinase • RT, reverse transcription • TIMP, tissue inhibitor of metalloproteinase • TUNEL, transferase biotin-dUTP nick-end labeling

Type 1 diabetes results from autoimmune destruction of the insulin-producing ß-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 ß-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. ß-Cell mass increased in parallel as a result of enhancement of ß-cell replication. Thus, our results have demonstrated for the first time that overexpression of TIMP-1 in ß-cells enhances the replication of pancreatic islets ß-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.

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