Abstract
Carcinoembryonic antigen-related cell adhesion molecule 2 (CEACAM2) regulates food intake as demonstrated by hyperphagia in mice with the Ceacam2 null mutation (Cc2(-/-)). This study investigated whether CEACAM2 also regulates insulin secretion. Ceacam2 deletion caused an increase in β-cell secretory function, as assessed by hyperglycemic clamp analysis, without affecting insulin response. Although CEACAM2 is expressed in pancreatic islets predominantly in non-β-cells, basal plasma levels of insulin, glucagon and somatostatin, islet areas, and glucose-induced insulin secretion in pooled Cc2(-/-) islets were all normal. Consistent with immunofluorescence analysis showing CEACAM2 expression in distal intestinal villi, Cc2(-/-) mice exhibited a higher release of oral glucose-mediated GLP-1, an incretin that potentiates insulin secretion in response to glucose. Compared with wild type, Cc2(-/-) mice also showed a higher insulin excursion during the oral glucose tolerance test. Pretreating with exendin(9-39), a GLP-1 receptor antagonist, suppressed the effect of Ceacam2 deletion on glucose-induced insulin secretion. Moreover, GLP-1 release into the medium of GLUTag enteroendocrine cells was increased with siRNA-mediated Ceacam2 down-regulation in parallel to an increase in Ca(2+) entry through L-type voltage-dependent Ca(2+) channels. Thus, CEACAM2 regulates insulin secretion, at least in part, by a GLP-1-mediated mechanism, independent of confounding metabolic factors.
Highlights
Carcinoembryonic antigen-related cell adhesion molecule 2 (CEACAM2) is highly homologous to CEACAM1, the protein product of a distinct gene
We report here that CEACAM2 plays a role in insulin secretion via a mechanism implicating the release of the insulinotropic glucagon-like peptide-1 (GLP-1), an incretin that potentiates glucose-stimulated insulin secretion from pancreatic -cells [11,12,13,14,15,16,17]
Expression of CEACAM2 in Endocrine Pancreas—Semiquantitative RT-PCR analysis revealed that Ceacam2 mRNA is expressed at a ratio of ϳ2:1 in fluorescence-activated cell sorter (FACS)-purified mouse pancreatic non--cells relative to -cells (Fig. 1A, panel i), as opposed to the Ceacam1 transcript, which was predominantly expressed in
Summary
Mouse Generation—The generation of Cc2Ϫ/Ϫ mice was described previously [1, 6]. Unless otherwise mentioned, male mice (5–7 months of age) were used. Plasma GLP-1 Measurement in Response to Oral Glucose— Mice (n Ն6/genotype) were fasted overnight, subjected to an oral glucose administration (3 g/kg BWT), and anesthetized with pentobarbital immediately after glucose administration before their retro-orbital blood was drawn 30 min later to measure blood glucose and plasma insulin levels. Western Blot Analysis—Tissues were lysed in 150 mM NaCl, 50 mM HEPES, pH 7.6, containing protease and phosphatase inhibitor, and the protein concentration was determined by BCA protein assay (Pierce) prior to analysis by 7% SDS-PAGE and immunoprobing with specific antibodies These include polyclonal antibodies against mouse CEACAM1 (␣-mCC1) (Ab-231) [9] and mouse CEACAM2 (␣-mCC2) (above), in addition to monoclonal antibodies against tubulin (Sigma) and GAPDH (Santa Cruz Biotechnology, Inc., Dallas, TX) to normalize for the amount of proteins analyzed. Values were represented as mean Ϯ S.E., and p Ͻ 0.05 values were statistically significant
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