Endothelin - Mechanisms in Hypertension and Obesity

项目概要 胰岛素抵抗在美国是一个主要的健康问题。 糖尿病，并经常出现在肥胖患者中，两者都是糖尿病的主要危险因素。 心血管疾病目前，与胰岛素相关的机制 阻力还没有完全被理解。ET-1是一种血管活性肽， 与胰岛素抵抗相关的内皮细胞， 肥胖患者。ET-1激活两种受体ETA和ETB。我们先前已经 显示在啮齿类动物中抑制ETB受体，无论是遗传上还是 改善胰岛素耐受性，降低空腹血糖。 此外，ETB功能的丧失减少了肥胖，这表明脂肪组织 作为ET-1诱导的胰岛素信号传导改变的可能靶点。已经 先前表明，激活培养的脂肪细胞上的ETB受体抑制了 胰岛素的抗脂肪分解作用。此外，阻断ETB受体 降低II型糖尿病GK大鼠模型的空腹血糖， 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 在肥胖患者中观察到的ET-1增加可能会促进胰岛素抵抗 通过ETB受体。因此，我们假设ET-1/ETB的激活可能是由于ET-1/ETB的激活导致的。 受体促进IR并损害脂肪细胞中的葡萄糖代谢。为了验证这一 假设，我们将利用体内和体外技术，使用两种新的 小鼠模型。一个可以让我们过度表达ETB受体，另一个 这将使我们能够在脂肪细胞中特异性地敲除ETB受体。我们将 测试以下具体目标： 具体目的1：检验ETB受体激活抑制胰岛素的假设 在培养的脂肪细胞中的信号传导。 具体目标2：检验ETB受体激活导致胰岛素分泌的假设 体内抗性。

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.