CEACAM AND INSULIN ACTION

CEACAM 和胰岛素作用

• 批准号: 7022228
• 负责人: Sonia M. Najjar
• 金额: $ 31.86万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7022228
• 关键词: DNA replication; autosomal dominant trait; clathrin; disease /disorder model; endocytosis; genetically modified animals; glycoproteins; hormone metabolism; hormone regulation /control mechanism; hyperinsulinism; insulin; insulin receptor; insulin sensitivity /resistance; intermolecular interaction; laboratory mouse; liver function; membrane proteins; noninsulin dependent diabetes mellitus; obesity; phosphomonoesterases; phosphorylation; polymerase chain reaction; protein sequence; terminal nick end labeling; western blottings

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.

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。在资助的前四年中，我们已经证明肝脏CEACAM1在胰岛素受体内吞复合物的形成中发挥着关键作用，以促进胰岛素的摄取和降解，这一事件构成了肝脏中胰岛素清除的基本机制。使用表达显性失活突变体 CEACAM1 的转基因小鼠，我们发现肝脏中 CEACAM1 的功能失活会损害胰岛素清除率，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 Ceacam1 缺陷 (Cc1-/-) 小鼠研究由 CEACAM1 功能改变引起的代谢综合征的发病机制。与含有单个 Ceacam 基因的人类基因组相反，小鼠基因组含有两个基因（Cc1 和 Cc2），其蛋白质产物的组织分布不同，其中 CEACAM1 是主要的肝脏亚型，CEACAM2 是主要的肝脏亚型。肾脏和胰腺 B 细胞。我们提供的初步数据显示，个体 Cc1/- 和 Cc2-/- 敲除会产生具有明显不同机制的代谢异常。 Cc1-/- 缺失小鼠会出现胰岛素清除受损和胰岛素抵抗，但没有糖尿病，而 Cc2-/- 小鼠会出现糖尿病，但胰岛素分泌受损。我们还发现，在啮齿类动物和高脂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，在目标 1 中，我们将研究 Cc1-/- 小鼠的胰岛素抵抗机制是否是由于胰岛素清除受损所致。在目标 2 中，我们将确定恢复 CEACAM1 表达是否可以逆转肥胖啮齿动物的代谢异常。在目标 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 的表达是否可以挽救 Cc2-/- 小鼠的糖尿病表型。在目标 4 中，我们将通过生成缺乏两种亚型 (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。拟议的研究应描绘胰岛素抵抗糖尿病的一种新机制，该机制强调胰岛素代谢在调节胰岛素敏感性中的作用，这与胰岛素信号传导不同。