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糖尿病中蛋白酪氨酸磷酸酶的研究进展

陈明, 孙金鹏, 刘晶, 于晓^*

山东大学医学院生理学研究所，济南 250012； 美国印第安纳大学医学院生化与分子生物学系，印第安纳州 46202-5122； 解放军第309 医院，北京 100091

摘要

糖尿病是由于胰岛素分泌不足或胰岛素抵抗引起的以血糖升高为特征的代谢性疾病。有研究发现一些蛋白酪氨酸磷酸酶(protein tyrosine phosphatases, PTP)在胰岛素受体信号途径、胰岛素分泌和胰腺β 细胞受自身免疫细胞攻击等生理或病理过程中起重要作用。以PTP1B、TCPTP 和LYP 为代表的PTP 通过将底物去磷酸化，拮抗激酶催化的磷酸化反应，在一些信号通路中起到负相调节的作用。在糖尿病患者中发现这些PTP 的单核苷酸突变使蛋白表达增加或酶活力增强，因而施用这些潜在靶蛋白的小分子抑制剂成为治疗1 型或2 型糖尿病可能的新疗法。而PTPIA-2/IA-2β 的胞内磷酸酶结构域被发现是大量1 型糖尿病患者的自身免疫原，因此可针对PTPIA-2/IA-2β 发展早期诊断并预防1 型糖尿病的试剂盒。

关键词： 糖尿病; 蛋白酪氨酸磷酸酶; 胰岛素; 小分子抑制剂

分类号：R587.1

[Research progress of several protein tyrosine phosphatases in diabetes.] [Ariticle in Chinese]

Chen Ming, SUN Jin-Peng, LIU Jing, YU Xiao^*

Shandong University School of Medicine, Institute of Physiology, Jinan 250012, China； Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202-5122, USA； The 309th Hospital of PLA, Beijing 100091, China

Abstract

Diabetes mellitus is caused by deficiency of insulin secretion from the pancreatic islet β cells and/or insulin resistance in liver,muscle and adipocytes, resulting in glucose intolerance and hyperglycemia. Several protein tyrosine phosphatases, such as PTP1B(PTPN1), TCPTP (PTPN2), LYP (PTPN22), PTPIA-2, PTPMEG2 (PTPN9) or OSTPTP are involved in insulin signaling pathway,insulin secretion and autoreactive attack to pancreatic β cells. Genetic mutation or overexpression of these phosphotases has beenfound to cause or increase the risk of diabetes mellitus. Some population with high risk for type 2 diabetes has overexpressed PTP1B,a prototypical tyrosine phosphatase which down-regulates insulin and leptin signal transduction. Animal PTP1B knockout model andPTP1B specific inhibitor cellular studies indicate PTP1B may serve as a therapeutic target for type 2 diabetes. TCPTP shares morethan 70% sequence identity with PTP1B in their catalytic domain. TCPTP dephosphorylates tyrosine phosphorylated substratesoverlapping with PTP1B but also has its own distinct dephosphorylation sites and functions. Recent research indicates TCPTP mayhave role in type 1 diabetes via dysregultaion of cytokine-mediated immune responses or pancreatic β cell apoptosis. The tyrosinephosphatase LYP, which down-regulates LCK activity in T cell response, can become mutated as R620W which is highly correlated totype 1 diabetes. LYP R620W may be a gain of function mutation which suppresses TCR signaling. Patients bearing the R620W mutanthave impaired T cell responses and increased populations of (CD45RO+CD45RA-) CD4+ T cells. A detailed elucidation of mechanismof R620W in type 1 diabetes and specific LYP inhibitor development will help characterize LYP R620W as a therapeutic target. Areceptor tyrosine phosphatase, PTPIA-2/β is a major autoantigen of type 1 diabetes. A diagnosis kit identifying PTPIA-2/β autoantibodiesis valuable in early detection and prevention of type 1 diabetes. In addition, other phosphatase like OSTPTP and PTPMEG2are involved in type 2 diabetes via regulation of insulin production, β cell growth or insulin signaling. Research into understanding the mechanism of these tyrosine phosphatases in diabetes, such as their precise functions in the regulation of insulin secretion, the insulinresponse and the immune response will strengthen our knowledge of diabetes pathophysiology which may result in new diagnostic andtherapeutic strategies for diabetes.

Key words: diabetes mellitus; protein tyrosine phosphatase; insulin; inhibitor

收稿日期：2009-11-30　　录用日期：2010-01-20

通讯作者：于晓　　E-mail: yuxiao@sdu.edu.cn

引用本文：

陈明, 孙金鹏, 刘晶, 于晓. 糖尿病中蛋白酪氨酸磷酸酶的研究进展[J]. 生理学报 2010; 62 (2): 179-189.

Chen Ming, SUN Jin-Peng, LIU Jing, YU Xiao. [Research progress of several protein tyrosine phosphatases in diabetes.] [Ariticle in Chinese] . Acta Physiol Sin 2010; 62 (2): 179-189 (in Chinese with English abstract).