Endothelin - Mechanisms in Hypertension and Obesity

项目摘要 在美国，胰岛素抵抗是一个主要的健康问题。它排除了II型 糖尿病，常见于肥胖症患者，两者都是 心血管疾病。目前，与胰岛素相关的机制 抗药性还没有完全被理解。ET-1是一种主要释放的血管活性多肽 通过与胰岛素抵抗相关的内皮细胞，并在 肥胖的病人。ET-1激活ETA和ETB两种受体。我们之前已经 研究表明，抑制啮齿类动物的ETB受体，无论是遗传上的还是 从药理上讲，改善胰岛素耐受性，降低空腹血糖。 此外，ETB功能的丧失会减少肥胖，这表明脂肪组织 作为ET-1诱导的胰岛素信号改变的可能靶点。一直以来 先前研究表明，ETB受体在培养的脂肪细胞上的激活抑制 胰岛素的抗脂作用。此外，对ETB受体的阻断 降低GK大鼠II型糖尿病模型的空腹血糖 改善睡眠呼吸暂停啮齿动物模型的胰岛素敏感性。这些数据表明 肥胖患者ET-1升高可能促进胰岛素抵抗 通过ETB受体。因此，我们假设ET-1/ETB的激活 受体促进胰岛素抵抗，损害脂肪细胞的葡萄糖代谢。为了测试这一点 假设，我们将利用体内和体外技术，使用两种新的 老鼠模型。一个允许我们过度表达ETB受体，另一个允许我们过度表达ETB受体 这将使我们能够敲除脂肪细胞中的ETB受体。我们会 测试以下具体目标： 特定目的1：验证ETB受体激活抑制胰岛素的假设 培养的脂肪细胞中的信号。 特定目标2：检验ETB受体激活导致胰岛素的假设 体内抗药性。

PROJECET SUMMARY Insulin resistance is a major health problem in the U.S. It precludes type II diabetes and is often present in obese patients, both being major risk factors for cardiovascular disease. Currently, mechanisms associated with insulin resistance aren't fully understood. ET-1 is a vasoactive peptide primarily released by endothelial cells that is associated with insulin resistance and increased in obese patients. ET-1 activates two receptors, ETA and ETB. We have previously shown that inhibiting ETB receptors in rodents, either genetically or pharmacologically, improves insulin tolerance and reduces fasting blood glucose. In addition, loss of ETB function reduces adiposity, suggesting the adipose tissue as a possible target for ET-1 induced alteration in insulin signaling. It has been previously shown that activation of ETB receptors on cultured adipocytes inhibits the anti-lipolytic effects of insulin. Furthermore, blockade of ETB receptors reduces fasting blood glucose in the GK rat model of type II diabetes and improves insulin sensitivity in a rodent model of sleep apnea. These data suggest that increased ET-1 observed in obese patients may promote insulin resistance via the ETB receptor. Thus, we hypothesize that activation of the ET-1/ETB receptor promotes IR and impairs glucose metabolism in adipocytes. To test this hypothesis, we will utilize both in vivo and in vitro techniques using two novel mouse models. One will allow us to over-express the ETB receptor, and another that will allow us to knockout the ETB receptor specifically in adipocytes. We will test the following specific aims: Specific aim 1: To test the hypothesis that ETB receptor activation inhibits insulin signaling in cultured adipocytes. Specific aim 2: To test the hypothesis that ETB receptor activation causes insulin resistance in vivo.