CEACAM1: A Link Between Insulin and Lipid Metabolism
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.
School:University of Toledo Health Science Campus
School Location:USA - Ohio
Source Type:Master's Thesis
Keywords:ceacam1 lipid metabolism insulin resistance clearance diabetes
Date of Publication:07/14/2009