CEACAM1: A Link Between Insulin and Lipid Metabolism

by DeAngelis, Anthony Michael

The pathogenesis of T2DM is complex and is preceeded by the development of insulin resistance. Previous studies have shown CEACAM1 to play a major role in mediating insulin clearance in the liver and that altered CEACAM1 function can cause impaired insulin clearance, hyperinsulinemia, altered fat metabolism, and the development of insulin restance. In this work, three unique strategies were employed in order to gain a better understanding of the physiologic role of CEACAM1 in vivo. First, the metabolic phenotype of Cc1–/– mice which are homozygous for a null mutation of the Ceacam1 gene was characterized. As expected, these mice exhibited an impairment of insulin clearance, hyperinsulinemia, and altered fat metabolism. Moreover, hyperinsulinemiceuglycemic clamp studies revealed that the inbred Cc1–/– mice developed insulin resistance primarily in liver. Finally, despite substantial expression of CEACAM1 in pancreatic ?-cells, insulin secretion in response to glucose in vivo and isolated islets was normal in Cc1–/– mice. This undermines the notion CEACAM1 is involved in regulating insulin secretion in the pancreas and suggests the principal role of CEACAM1 in insulin action is to mediate insulin clearance in liver. Next, an alternative approach at investigating the function of CEACAM1 in vivo was taken by generating a transgenic mouse model (Tg(ApoA1-Cc1)7Smn) overexpressing CEACAM1 specifically in the liver. Analysis of Tg(ApoA1-Cc1)7Smn transgenic mice confirmed expression of the CEACAM1 transgene in a liver specific manner. These mice are currently being utilized to perform a gain of function study in Cc1-/- mice. This will allow us to investigate whether or not restitution of CEACAM1 expression in the liver of Cc1-/- mice is sufficient to ameliorate impaired insulin clearance, insulin resistance, and subsequent metabolic abnormalities. Finally, human expression of CEACAM1 mirrors the combined expression of murine CEACAM1 and CEACAM2. Therefore, we attempted to generate a Cc1–/– / Cc2–/– double knockout mouse line in order to more accurately model CEACAM1 abnormality in humans and provide more accurate insights into the role of CEACAM1 in humans. Despite the unsuccessful first attempt at generating this mouse line, alternative strategies are being employed to simulate the concurrent absence of these two proteins in a mouse model. Taken together, this data highlights the pivotal role CEACAM1 plays in regulating circulating insulin levels through mediating insulin clearance in the liver.