Protein Tyrosine Phosphatase 1B and Insulin Action

胰岛素信号转导是维持正常血糖稳态所必需的。胰岛素信号通过一系列酪氨酸磷酸化事件发生，这些事件通过蛋白酪氨酸磷酸酶(PTPs)的作用被去磷酸化终止。在肥胖、胰岛素抵抗的人和啮齿动物的胰岛素靶组织中，特定的PTPs的表达和活性增加。总的目标是确定胰岛素靶组织中蛋白酪氨酸磷酸酶1B(PTP1B)在调节血糖稳态、胰岛素敏感性和肥胖症中的作用。具体目的是：1)确定PTP1B在转基因小鼠个体胰岛素靶组织(肌肉、肝脏或脂肪组织)中的选择性过表达是否会导致胰岛素抵抗、糖耐量异常和/或肥胖。2)确定PTP1B在多个胰岛素反应组织中的过度表达，或在单个胰岛素反应组织中除PTP1B外，另一种酪氨酸磷酸酶的共表达是否加剧了胰岛素抵抗、糖耐量受损或肥胖。为了“模仿”肥胖人类中PTPs的过度表达，我们将培育转基因小鼠，目的一是创造在肌肉、脂肪和肝脏中过度表达PTPs的复合转基因小鼠。3)通过重组PTP1B基因敲除小鼠肌肉、肝脏和脂肪组织中PTP1B的表达，确定PTP1B基因敲除小鼠中哪个组织对胰岛素敏感和肥胖负责。这将通过用我们的PTP1B基因敲除小鼠培育Aim One中的每一种组织特异性转基因株来实现。4)确定PTP1B缺乏是否可以治愈严重的胰岛素抵抗或糖尿病，这些小鼠是胰岛素受体和胰岛素受体底物1基因敲除的复合杂合子。这些研究将有助于更好地理解葡萄糖稳态的调节机制，并将阐明蛋白酪氨酸磷酸酶在与肥胖和2型糖尿病相关的胰岛素抵抗发病机制中的作用。我们的目标是找到新的治疗靶点来降低胰岛素抵抗，预防或改善2型糖尿病。

Insulin signaling is essential for normal glucose homeostasis. Insulin signaling occurs via a cascade of tyrosyl phosphorylation events that are terminated by dephosphorylation through the actions of protein tyrosine phosphatases (PTPs). The expression and activity of specific PTPs is increased in insulin target tissues of obese, insulin resistant humans and rodents. The overall goal is to determine the role of protein tyrosine phosphatase 1B (PTP1B) in insulin target tissues in the regulation of glucose homeostasis, insulin sensitivity and adiposity. Specific aims are: 1) To determine whether overexpression of PTP1B selectively in individual insulin target tissues (muscle, liver or adipose tissue) of transgenic mice results in insulin resistance, glucose intolerance and/or obesity. 2) To determine whether insulin resistance, impaired glucose tolerance or obesity is compounded by overexpression of PTP1B in more than one insulin responsive tissue or by co- overexpression of another tyrosine phosphatase in addition to PTP1B in a single insulin responsive tissue. To "mimic" the overexpression of PTPs in obese humans, we will breed together transgenic mice made in aim one to create compound transgenics overexpressing PTPs in a combination of muscle, fat and liver. 3) To determine which tissue is responsible for the insulin sensitivity and leanness in PTP1B knockout mice by reconstituting PTP1B expression in muscle, liver or adipose tissue individually. This will be achieved by breeding each of the tissue-specific transgenic lines made in aim one with our PTP1B knockout mice. 4) To determine whether PTP1B deficiency can "cure" the severe insulin resistance or diabetes present in mice which are compound heterozygotes for knockout of the insulin receptor and insulin receptor substrate 1. These studies will lead to a better understanding of the mechanisms for regulation of glucose homeostasis and will elucidate the role of protein tyrosine phosphatases in the pathogenesis of insulin resistance that is associated with obesity and type 2 diabetes. Our goal is to find new therapeutic targets to reduce insulin resistance and prevent or ameliorate type 2 diabetes.