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.
DeAngelis
Anthony M
AM
Center for Diabetes and Endocrine Research and the Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio, USA.
Heinrich
Garrett
G
Dai
Tong
T
Bowman
Thomas A
TA
Patel
Payal R
PR
Lee
Sang Jun
SJ
Hong
Eun-Gyoung
EG
Jung
Dae Young
DY
Assmann
Anke
A
Kulkarni
Rohit N
RN
Kim
Jason K
JK
Najjar
Sonia M
SM
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