CEACAM AND INSULIN ACTION

我们将继续研究CEACAM1在胰岛素代谢中的作用。CEACAM1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CEACAM1在胰岛素受体内吞复合物的形成中起关键作用，促进胰岛素的摄取和降解，这一事件构成了肝脏胰岛素清除的基本机制。利用表达显性阴性突变体CEACAM1的转基因小鼠，我们发现CEACAM1在肝脏中的功能失活会损害胰岛素清除，导致高胰岛素血症、脂质代谢改变和内脏脂肪增加。我们拟利用CEACAM1缺陷（Cc1-/-）小鼠研究CEACAM1功能改变引起的代谢综合征的发病机制。人类基因组中只有一个Ceacam基因，而小鼠基因组中有两个基因（Cc1和Cc2），它们的蛋白产物在组织中的分布不同，CEACAM1是主要的肝脏亚型，而CEACAM2是主要的肾脏和胰腺b细胞亚型。我们提供的初步数据显示，个体Cc1/-和Cc2-/-敲除产生代谢异常的机制明显不同。无Cc1-/-的小鼠出现胰岛素清除受损和胰岛素抵抗，而无Cc2-/-的小鼠出现胰岛素分泌受损的糖尿病。我们还发现，在啮齿类动物和高脂肪饮食小鼠的其他肥胖和糖尿病模型中，肝脏CEACAM1表达降低。基于这些观察结果，在Aim 1中，我们将研究Cc1-/-小鼠胰岛素抵抗的机制是否由于胰岛素清除受损。在Aim 2中，我们将确定恢复CEACAM1表达是否能逆转肥胖啮齿动物的代谢异常。在Aim 3中，我们将研究Cc2-/-敲除中b细胞功能障碍的机制，以及恢复胰腺b细胞中CEACAM2的表达是否能挽救Cc2-/-小鼠的糖尿病表型。在Aim 4中，我们将通过产生缺乏两种亚型（Cc1-/-/Cc2-/-）的小鼠来研究这两个基因是否发挥重叠或不同的功能。提出的研究应该描述胰岛素抵抗糖尿病的新机制，强调胰岛素代谢在胰岛素敏感性调节中的作用，而不是胰岛素信号。

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.