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Published online June 10, 2008
Diabetes 57:2296-2303, 2008
DOI: 10.2337/db08-0379
© 2008 by the American Diabetes Association
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Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1

A Link Between Insulin and Lipid Metabolism

Anthony M. DeAngelis1, Garrett Heinrich1, Tong Dai1, Thomas A. Bowman1, Payal R. Patel1, Sang Jun Lee1, Eun-Gyoung Hong2, Dae Young Jung2, Anke Assmann3, Rohit N. Kulkarni3, Jason K. Kim2, and Sonia M. Najjar1

1 Center for Diabetes and Endocrine Research and the Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio
2 Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania
3 Research Division, Joslin Diabetes Center, Boston, Massachusetts

Corresponding author: Sonia M. Najjar, sonia.najjar{at}utoledo.edu

OBJECTIVE—Liver-specific inactivation of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) by a dominant-negative transgene (L-SACC1 mice) impaired insulin clearance, caused insulin resistance, and increased hepatic lipogenesis. To discern whether this phenotype reflects a physiological function of CEACAM1 rather than the effect of the dominant-negative transgene, we characterized the metabolic phenotype of mice with null mutation of the Ceacam1 gene (Cc1–/–).

RESEARCH DESIGN AND METHODS—Mice were originally generated on a mixed C57BL/6x129sv genetic background and then backcrossed 12 times onto the C57BL/6 background. More than 70 male mice of each of the Cc1–/– and wild-type Cc1+/+ groups were subjected to metabolic analyses, including insulin tolerance, hyperinsulinemic-euglycemic clamp studies, insulin secretion in response to glucose, and determination of fasting serum insulin, C-peptide, triglyceride, and free fatty acid levels.

RESULTS—Like L-SACC1, Cc1–/– mice exhibited impairment of insulin clearance and hyperinsulinemia, which caused insulin resistance beginning at 2 months of age, when the mutation was maintained on a mixed C57BL/6x129sv background, but not until 5–6 months of age on a homogeneous inbred C57BL/6 genetic background. Hyperinsulinemic-euglycemic clamp studies revealed that the inbred Cc1–/– mice developed insulin resistance primarily in liver. Despite substantial expression of CEACAM1 in pancreatic β-cells, insulin secretion in response to glucose in vivo and in isolated islets was normal in Cc1–/– mice (inbred and outbred strains).

CONCLUSIONS—Intact insulin secretion in response to glucose and impairment of insulin clearance in L-SACC1 and Cc1–/– mice suggest that the principal role of CEACAM1 in insulin action is to mediate insulin clearance in liver.


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