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。在资金的头四年中，我们证明了肝CEACAM1在形成胰岛素受体受体内吞作用中起着关键作用，以促进胰岛素摄取和降解，这一事件构成了肝脏中胰岛素清除的基本机制。使用表达显性阴性突变体CECAM1的转基因小鼠，我们已经表明，肝脏中CECAM1的功能失活会损害胰岛素清除率，并导致高胰岛素血症，脂质代谢改变并增加了内脏肥胖。我们建议研究使用CEACAM1缺乏剂（CC1 - / - ）小鼠引起的CEACAM1功能改变的代谢综合征的发病机理。与具有单个CEACAM基因的人类基因组相反，小鼠基因组具有两个基因（CC1和CC2），其蛋白质产物的组织分布有所不同，CEACAM1是肝同工型，CEACAM2是基奇和pancenic和pancreatic b-cellsic b-cellsic b-cells的抗肝同工型，而CeCAM2则是蛋白质产物。我们提供了初步数据，表明单个CC1/ - 和CC2 - / - 敲除具有明显不同机制的代谢异常。 CC1 - / - 无糖尿病的胰岛素清除率和胰岛素抵抗受损，而CC2 - / - 患有胰岛素分泌受损的糖尿病。我们还显示在啮齿动物的其他肥胖和糖尿病模型中，在高脂饮食中的肝CEACAM1表达下降。基于这些观察结果，在AIM 1中，我们将研究CC1 - / - 小鼠中胰岛素抵抗的机制是否是由于胰岛素清除受损而引起的。在AIM 2中，我们将确定恢复CEACAM1表达是否会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，以及胰腺B细胞中CEACAM2表达是否是否挽救CC2 - / - 小鼠的糖尿病表型。在AIM 4中，我们将通过产生缺乏两种同工型（CC1 - / - /CC2 - / - ）的小鼠来研究这两个基因是否起重叠或不同的功能。拟议的研究应描绘出一种胰岛素抗性糖尿病的新型机制，该机制突出了胰岛素代谢在调节胰岛素敏感性中与胰岛素信号传导明显的作用。