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A role for CEACAM proteins in energy balance and peripheral insulin action

Heinrich, Garrett

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2010, Doctor of Philosophy in Biomedical Sciences (Ph.D.), University of Toledo, College of Medicine.
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 -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.
Sonia Najjar, Ph.D. (Committee Chair)
David Giovannucci, Ph.D. (Committee Member)
Edwin Sanchez, Ph.D. (Committee Member)
Guillermo Vazquez, Ph.D. (Committee Member)
Silvana Obici, M.D. (Committee Member)
263 p.

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Citations

  • Heinrich, G. (2010). A role for CEACAM proteins in energy balance and peripheral insulin action [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1272976279

    APA Style (7th edition)

  • Heinrich, Garrett. A role for CEACAM proteins in energy balance and peripheral insulin action. 2010. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1272976279.

    MLA Style (8th edition)

  • Heinrich, Garrett. "A role for CEACAM proteins in energy balance and peripheral insulin action." Doctoral dissertation, University of Toledo, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=mco1272976279

    Chicago Manual of Style (17th edition)