CEACAM1 regulates insulin clearance in liver.
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.
Poy
Matthew N
MN
Department of Pharmacology, 3035 Arlington Avenue, HSci Building Room 270, Toledo, Ohio 43614, USA.
Yang
Yan
Y
Rezaei
Khadijeh
K
Fernström
Mats A
MA
Lee
Abraham D
AD
Kido
Yoshiaki
Y
Erickson
Sandra K
SK
Najjar
Sonia M
SM
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002272:Carcinoembryonic Antigen; D015815:Cell Adhesion Molecules; D005230:Fatty Acids, Nonesterified / Q000097:blood; D006946:Hyperinsulinism / Q000235:genetics; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D007515:Islets of Langerhans / Q000502:physiology; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction
D015703:Antigens, CD; D000943:Antigens, Differentiation; C069847:CD66 antigens; D002272:Carcinoembryonic Antigen; C486183:Ceacam1 protein, mouse; D015815:Cell Adhesion Molecules; D005230:Fatty Acids, Nonesterified; D007328:Insulin