| The carcinoembryonic antigen related cell adhesion molecule (CEACAM) family is a group of proteins reported to have potent roles in insulin signaling, lipogenesis, immunity, and tumor suppression. To investigate the role of CEACAM2, we have used a murine model with global Ceacam2 gene deletion. The male Ceacam2 knockout mice showed an increase in insulin release suggesting that CEACAM2 plays an important role in regulating insulin secretion. Due to the low expression of Ceacam2 in beta pancreatic cells, CEACAM2 effect on insulin secretion was caused by an extra-pancreatic mechanism. Consistent to the expression of CEACAM2 in the distal intestinal villi, null CEACAM2 male mice showed a higher excursion of GLP-1 in response to oral administration of glucose, showing that the CEACAM2 effect on insulin secretion is mediated partly via a GLP-1 dependent mechanism. In accordance with the importance of insulin clearance in the kidney to maintain normal plasma insulin levels and CEACAM2 expression in proximal tubule cells, mutant male mice revealed an impairment in renal insulin clearance reflecting its function in regulating insulin extraction in the kidney. These data also imply that CEACAM2 is an insulin receptor substrate that undergoes phosphorylation at its intra cellular phosphorylation sites during insulin stimulation to mediate receptor-mediated endocytosis in proximal tubule cells. Despite the hyperphagia of all age groups, Ceacam2 knockout male mice are insulin sensitive till the age of 9 months. We also show that insulin resistance, obesity and hyperinsulinemia did not start until 9 months of age likely due to reduced energy expenditure and increased free fatty acids. In addition, CEACAM1 levels are reduced during that age group explaining the insulin resistance and reflecting the low insulin clearance (low C/I molar ratio). This illustrates that insulin resistance in these mutant mice is age dependent. These reports expand our understanding of the role of CEACAM2 protein in the regulation of insulin secretion and insulin action. |
