Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1

A Link Between Insulin and Lipid Metabolism

  1. Anthony M. DeAngelis1,
  2. Garrett Heinrich1,
  3. Tong Dai1,
  4. Thomas A. Bowman1,
  5. Payal R. Patel1,
  6. Sang Jun Lee1,
  7. Eun-Gyoung Hong2,
  8. Dae Young Jung2,
  9. Anke Assmann3,
  10. Rohit N. Kulkarni3,
  11. Jason K. Kim2 and
  12. Sonia M. Najjar1
  1. 1Center for Diabetes and Endocrine Research and the Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio
  2. 2Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania
  3. 3Research Division, Joslin Diabetes Center, Boston, Massachusetts
  1. Corresponding author: Sonia M. Najjar, sonia.najjar{at}utoledo.edu

Abstract

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.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 10 June 2008.

  • A.M.D. and G.H. contributed equally to this work. T.A.B. and P.R.P. contributed equally to this work.

  • Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted June 2, 2008.
    • Received March 17, 2008.
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This Article

  1. Diabetes vol. 57 no. 9 2296-2303
  1. All Versions of this Article:
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