CEACAM AND INSULIN ACTION

我们将继续研究CEACAM 1在胰岛素代谢中的作用。CEACAM 1是肝脏中胰岛素受体激酶的底物。在前四年的资助中，我们已经证明肝脏CEACAM 1在胰岛素受体内吞复合物的形成中起着关键作用，以促进胰岛素的摄取和降解，这是构成肝脏胰岛素清除的基本机制的事件。使用表达显性阴性突变CEACAM 1的转基因小鼠，我们已经表明CEACAM 1在肝脏中的功能失活损害胰岛素清除，并导致高胰岛素血症，脂质代谢改变和内脏肥胖增加。我们建议使用Ceacam 1缺陷（Cc 1-/-）小鼠研究由CEACAM 1功能改变引起的代谢综合征的发病机制。与携带单个Ceacam基因的人类基因组相反，小鼠基因组携带两个基因（Cc 1和Cc 2），其蛋白质产物的组织分布不同，CEACAM 1是主要的肝脏同种型，CEACAM 2是肾脏和胰腺b细胞中的主要同种型。我们目前的初步数据显示，个别Cc 1/-和Cc 2-/-敲除发展代谢异常，具有明显不同的机制。Cc 1-/- null小鼠出现胰岛素清除受损和胰岛素抵抗，但无糖尿病，而Cc 2-/-小鼠出现糖尿病，胰岛素分泌受损。我们还发现，在啮齿动物和高脂饮食小鼠的其他肥胖和糖尿病模型中，肝脏CEACAM 1表达降低。基于这些观察结果，在目标1中，我们将研究Cc 1-/-小鼠的胰岛素抵抗机制是否是由于胰岛素清除受损。在目标2中，我们将确定恢复CEACAM 1表达是否逆转肥胖啮齿动物的代谢异常。在目标3中，我们将研究Cc 2-/-敲除中b细胞功能障碍的机制，以及恢复胰腺b细胞中CEACAM 2的表达是否可以挽救Cc 2-/-小鼠的糖尿病表型。在目标4中，我们将通过产生缺乏两种亚型（Cc 1-/-/Cc 2-/-）的小鼠来研究这两个基因是否发挥重叠或不同的功能。拟议的研究应该描绘一个新的机制，胰岛素抵抗性糖尿病，一个突出的作用，胰岛素代谢调节胰岛素敏感性明显不同于胰岛素信号。

We will continue studies of the role of CEACAM1 in insulin metabolism. CEACAM1 is a substrate of the insulin receptor kinase in the liver. In the first four years of funding, we have demonstrated that hepatic CEACAM1 plays a pivotal role in the formation of the insulin-receptor endocytosis complex to promote insulin uptake and degradation, an event that constitutes the basic mechanism of insulin clearance in liver. Using transgenic mice expressing a dominant-negative mutant CEACAM1, we have shown that functional inactivation of CEACAM1 in liver impairs insulin clearance and results in hyperinsulinemia, altered lipid metabolism and increased visceral adiposity. We propose to investigate the pathogenesis of the metabolic syndrome caused by altered CEACAM1 function using Ceacam1-deficient (Cc1-/-) mice. In contrast to the human genome, which harbors a single Ceacam gene, the mouse genome harbors two genes (Cc1 and Cc2), differing in the tissue distribution of their protein products, with CEACAM1 being the predominant liver isoform and CEACAM2 being the predominant isoform in kidney and pancreatic b-cells. We present preliminary data showing that individual Cc1/- and Cc2-/- knockouts develop metabolic abnormalities with apparently different mechanisms. Cc1-/- null mice develop impaired insulin clearance and insulin resistance without diabetes, while Cc2-/- develop diabetes with impaired insulin secretion. We also show decreased hepatic CEACAM1 expression in other models of obesity and diabetes in rodents and in mice on a high-fat diet. Based on these observations, in Aim 1 we will investigate whether the mechanism of insulin resistance in Cc1-/- mice is due to impaired insulin clearance. In Aim 2, we will determine whether restoring CEACAM1 expression reverses the metabolic abnormalities of obese rodents. In Aim 3, we will investigate the mechanism of b-cells dysfunction in Cc2-/- knockouts, and whether restoring CEACAM2 expression in pancreatic b-cells rescues the diabetic phenotype of Cc2-/- mice. In Aim 4, we will study whether the two genes play overlapping or distinct functions by generating mice lacking both isoforms (Cc1-/-/Cc2-/-). The proposed studies should delineate a novel mechanism of insulin-resistant diabetes, one that highlights the role of insulin metabolism in regulating insulin sensitivity distinctly from insulin signaling.