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CEACAM1 regulates insulin clearance in liver

Nature Genetics volume 30, pages 270276 (2002) | Download Citation

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Abstract

We hypothesized that insulin stimulates phosphorylation of CEACAM1 which in turn leads to upregulation of receptor-mediated insulin endocytosis and degradation in the hepatocyte. We have generated transgenic mice over-expressing in liver a dominant-negative, phosphorylation-defective S503A-CEACAM1 mutant. Supporting our hypothesis, we found that S503A-CEACAM1 transgenic mice developed hyperinsulinemia resulting from impaired insulin clearance. The hyperinsulinemia caused secondary insulin resistance with impaired glucose tolerance and random, but not fasting, hyperglycemia. Transgenic mice developed visceral adiposity with increased amounts of plasma free fatty acids and plasma and hepatic triglycerides. These findings suggest a mechanism through which insulin signaling regulates insulin sensitivity by modulating hepatic insulin clearance.

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Acknowledgements

We thank D. Accili, S.F. Previs and G.I. Shulman for critical reading of the manuscript and for helpful scientific discussions, and E.M. Rubin and N. Beauchemin for providing the apolipoprotein A-1 promoter cDNA and anti-mouse BGP antibodies, respectively. We thank S. Robson, E. Tietz and S. Lilly for assistance in immunohistochemistry and microscopy, and T. Dai and R. Ruch for assistance in primary hepatocytes. We also thank the Ohio University Edison Biotechnology Institute Collaborative Transgenics, Athens, Ohio for performing DNA microinjections as part of their service grant support (to S.M.N.). This work was chiefly supported by two grants from the National Institutes of Health–National Institute of Diabetes & Digestive & Kidney Diseases (to S.M.N.), and partially by Sigma-Tau Research (to S.M.N.) and the Department of Veterans Affairs (to S.K.E.). M.N.P. was partially supported by the Institutional Pre-doctoral National Research Service Award fellowship from the National Institutes of Health.

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  1. Departments of Pharmacology and Therapeutics, 3035 Arlington Avenue, HSci Building Room 270, Toledo, Ohio 43614, USA.

    • Matthew N. Poy
    • , Yan Yang
    • , Khadijeh Rezaei
    • , Mats A. Fernström
    •  & Sonia M. Najjar
  2. Physical Therapy, Medical College of Ohio, 3035 Arlington Avenue, HSci Building Room 270, Toledo, Ohio 43614, USA.

    • Abraham D. Lee
  3. Second Department of Internal Medicine, Kobe University School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Japan.

    • Yoshiaki Kido
  4. Department of Medicine, San Francisco and the Veterans Affairs Medical Center, University of California, San Francisco, California, USA.

    • Sandra K. Erickson

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The authors declare no competing financial interests.

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Correspondence to Sonia M. Najjar.

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https://doi.org/10.1038/ng840

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