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Diabetes Publish Ahead of Print published online ahead of print June 10, 2008
DOI: 10.2337/db08-0379
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Original Research

CEACAM1: A Link Between Insulin and Lipid Metabolism

Anthony M. DeAngelis, BS1, Garrett Heinrich, BS1, Tong Dai, MD,PhD1, Thomas A. Bowman, DPM1, Payal R. Patel, BS1, Sang Jun Lee, PhD1, Eun-Gyoung Hong, PhD2, Dae Young Jung, PhD2, Anke Assmann, PhD3, Rohit N. Kulkarni, MD3, Jason K. Kim, PhD2, and Sonia M. Najjar, PhD1

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

Objective: Liver-specific inactivation of CEACAM1 by a dominant-negative transgene (L-SACC1 mice) impaired insulin clearance and caused insulin resistance and increased hepatic lipogenesis. To discern whether this phenotype reflects a physiologic function of CEACAM1 rather than the effect of the dominant-negative transgene, we characterized the metabolic phenotype of mice with null mutation of Ceacam1 gene (Cc1-/-).

Research Design and Methods: Mice were originally generated on a mixed C57BL/6x129sv genetic background and then backcrossed twelve times onto the C57BL/6 background. More than 70 male mice of each of 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 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.

Correspondence: sonia.najjar{at}utoledo.edu

Key Words: Obesity • insulin clearance • insulin action • insulin secretion • CEACAM1


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