Carcinoembryonic antigen-related cell adhesion molecule 1: a link between insulin and lipid metabolism.
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(-/-)).


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.
Center for Diabetes and Endocrine Research and the Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio, USA.
Anthony M
AM
DeAngelis
Garrett
G
Heinrich
Tong
T
Dai
Thomas A
TA
Bowman
Payal R
PR
Patel
Sang Jun
SJ
Lee
Eun-Gyoung
EG
Hong
Dae Young
DY
Jung
Anke
A
Assmann
Rohit N
RN
Kulkarni
Jason K
JK
Kim
Sonia M
SM
Najjar
D000818:Animals; D001835:Body Weight; D002272:Carcinoembryonic Antigen / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D005799:Genes, Dominant; D015309:Glucose Clamp Technique; D006946:Hyperinsulinism / Q000378:metabolism / Q000503:physiopathology; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000378:metabolism; D050356:Lipid Metabolism / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
D002272:Carcinoembryonic Antigen; C486183:Ceacam1 protein, mouse; D007328:Insulin