31 DeAngelis, A. M. Heinrich, G. Dai, T. Bowman, T. A. Patel, P. R. Lee, S. J. Hong, E. G. Jung, D. Y. Assmann, A. Kulkarni, R. N. Kim, J. K. Najjar, S. M. 2008 Diabetes 57 9 2296-303 Sep 1939-327X (Electronic) 18544705 Mice, Transgenic Mice, Inbred C57BL Mice Male Liver/metabolism Lipid Metabolism/*physiology Insulin-Secreting Cells/metabolism Insulin Resistance Insulin/*metabolism Hyperinsulinism/metabolism/physiopathology Glucose Clamp Technique Genes, Dominant Cells, Cultured Carcinoembryonic Antigen/*genetics/*metabolism Body Weight Animals Transgenic Inbred C57BL Genes Cells Cultured Dominant 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 beta-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. DK-54254/DK/NIDDK NIH HHS/United StatesDK-67536/DK/NIDDK NIH HHS/United StatesJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, U.S. Gov't, Non-P.H.S.United States http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18544705