TYROSINE PHOSPHATASES IN HUMAN OBESITY AND DIABETES

人类肥胖和糖尿病中的酪氨酸磷酸酶

• 批准号: 2906141
• 负责人: BARRY J. GOLDSTEIN
• 金额: $ 20.88万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2906141
• 关键词: adipocytes; biopsy; blood glucose; clinical research; enzyme activity; glucose clamp technique; glucose metabolism; glucose tolerance test; human subject; hyperglycemia; hyperinsulinism; insulin; insulin receptor; insulin sensitivity /resistance; lysozyme; noninsulin dependent diabetes mellitus; obesity; phosphorylation; protein tyrosine phosphatase; striated muscles; tissue /cell culture; weight loss

Protein-tyrosine phosphatases (PTPases) that regulate steady-state insulin signalling by dephosphorylating the active form of the insulin receptor (IR) kinase as well as post-IR substrates in insulin-sensitive cells have been implicated in the pathogenesis of insulin-resistance in disease states, including common conditions such as obesity and non- insulin-dependent diabetes (NIDDM), where the insulin resistance also appears to contribute to increased cardiovascular morbidity and mortality. This project will test the hypothesis that changes in overall tissue PTPase activity and the abundance of specific candidate PTPase enzymes that may regulate the insulin signalling pathway are involved in the insulin resistance in adipose tissue and skeletal muscle in human subjects with obesity and NIDDM. The following major Specific Aims are proposed: Aim 1. Measure PTPase activity against the IR and phosphorylated lysozyme and the abundance of several candidate PTPases in subcutaneous adipose tissue and skeletal muscle from lean and obese (body mass index greater than 30 kg/m2) subjects, both with and without Type II diabetes; Evaluate these cross-sectional data on PTPases for possible associations with tissue-specific insulin sensitivity, body fat content, insulinemia, and hyperglycemia. Aim 2. Use clamp techniques in lean and obese subjects to evaluate the effect of hyperglycemia and hyperinsulinemia on PTPase activity and enzyme in skeletal muscle and adipose tissue; Study whether significant weight loss in a group of non- diabetic obese individuals or achieving glycemic control in a group of recently diagnosed subjects with NIDDM is associated with alterations in adipose tissue and muscle PTPase activity and abundance. Aim 3. Treat isolated human adipose cells with high glucose and/or insulin in vitro to determine whether PTPase activity or abundance is affected by incubation with these components of the diabetic milieu. These studies will determine in two of the major tissues involved in glucose metabolism whether PTPase activity or the abundance of specific PTPases is associated with human insulin resistance and provide further support for potential new therapeutics that could ameliorate insulin resistance by inhibiting PTPases in insulin target tissues.

调节稳态的蛋白质酪氨酸磷酸酶（PTPase） 胰岛素信号传导通过去磷酸化胰岛素的活性形式 受体（IR）激酶以及胰岛素敏感的后IR底物 细胞与胰岛素抵抗的发病机理有关 疾病状态，包括肥胖和非常见状况 胰岛素依赖性糖尿病（NIDDM），其中胰岛素耐药性也 似乎有助于增加心血管发病率和 死亡。 该项目将检验以下假设 总体组织PTPase活性和丰富的特定候选者 可能调节胰岛素信号通路的PTPase酶是 参与脂肪组织和骨骼肌的胰岛素耐药性 在肥胖和NIDDM的人类受试者中。 以下主要特定 提出了目的：目标1。测量针对IR和IR的PTPase活动 磷酸化的溶菌酶和几个候选PTPase的丰度 在皮下脂肪组织和肥胖的骨骼肌中 （体重指数大于30 kg/m2）受试者，无论有没有和没有 II型糖尿病；评估PTPases上的这些横截面数据 可能与组织特异性胰岛素敏感性的可能关联 含量，胰岛素血症和高血糖。 目标2。使用夹具技术 在精益和肥胖的受试者中，以评估高血糖和 骨骼肌中PTPase活性和酶的高胰岛素血症和 脂肪组织；研究一组非 - 是否重大减肥 糖尿病肥胖个体或在一组中获得血糖控制 最近被诊断为NIDDM的受试者与更改有关 在脂肪组织和肌肉PTPase活性和丰度中。 目标3。 用高葡萄糖和/或胰岛素治疗孤立的人脂肪细胞 体外确定PTPase活性或丰度是否受到 与糖尿病环境的这些成分一起孵育。 这些研究将在涉及的两个主要组织中确定 葡萄糖代谢是PTPase活性还是特定的丰度 PTPases与人类胰岛素抵抗有关，并提供进一步的 支持可能改善胰岛素的潜在新疗法 通过抑制胰岛素靶组织中的PTPases来抗性。