Regulation of insulin action by CEACAM1.
Activation of the tyrosine kinase of the insulin receptor by insulin binding initiates a cascade of signaling pathways that mediates the metabolic and growth-promoting effects of insulin. Insulin action is regulated by the amount of circulating insulin, which is, in turn, partially regulated by insulin clearance in liver. Receptor-mediated insulin endocytosis followed by degradation mediates insulin clearance. Earlier studies in transfected cells suggested that the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), a substrate of the insulin receptor in liver, upregulates receptor-mediated insulin endocytosis and degradation in a phosphorylation-dependent manner. To test this hypothesis, a transgenic mouse, L-SACC1, overexpressing a dominant-negative phosphorylation-defective S503A CEACAM1 mutant in liver was established. The transgenic mouse demonstrated that CEACAM1 increases insulin clearance to maintain insulin sensitivity. Because insulin resistance is the hallmark of type 2 diabetes, understanding the mechanism of CEACAM1 regulation of insulin clearance and action might lead to novel therapeutic strategies against this disease.
Najjar
Sonia M
SM
Department Pharmacology and Therapeutics, Medical College of Ohio, 3035 Arlington Ave., HSci Building, Room 270, Toledo, OH 43614, USA. snajjar@mco.edu
D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D000943:Antigens, Differentiation / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D002272:Carcinoembryonic Antigen; D015815:Cell Adhesion Molecules; D015870:Gene Expression; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000378:metabolism
D015703:Antigens, CD; D000943:Antigens, Differentiation; C069847:CD66 antigens; D002272:Carcinoembryonic Antigen; C486183:Ceacam1 protein, mouse; D015815:Cell Adhesion Molecules; D007328:Insulin; D011972:Receptor, Insulin