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.
Department Pharmacology and Therapeutics, Medical College of Ohio, 3035 Arlington Ave., HSci Building, Room 270, Toledo, OH 43614, USA. snajjar@mco.edu
Sonia M
SM
Najjar
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