Format

Send to

Choose Destination
J Biol Chem. 2016 Jan 8;291(2):980-8. doi: 10.1074/jbc.M115.692582. Epub 2015 Nov 19.

Increased Glucose-induced Secretion of Glucagon-like Peptide-1 in Mice Lacking the Carcinoembryonic Antigen-related Cell Adhesion Molecule 2 (CEACAM2).

Author information

1
From the Center for Diabetes and Endocrine Research and Departments of Physiology and Pharmacology and.
2
the Institut für Anatomie und Zellbiologie, Universität Würzburg, D-97070 Würzburg, Germany.
3
Neurosciences, College of Medicine and Life Sciences, University of Toledo, Health Science Campus, Toledo, Ohio 43614.
4
the Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
5
the Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 371-8512 Gunma, Japan, and.
6
the Islet Cell and Regenerative Biology, Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215.
7
From the Center for Diabetes and Endocrine Research and Departments of Physiology and Pharmacology and sonia.najjar@utoledo.edu.

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.

KEYWORDS:

CEACAM2; GLP-1; diabetes; enteroendocrine cells; gene knock-out; insulin clearance; insulin resistance; insulin secretion; intestine

PMID:
26586918
PMCID:
PMC4705415
DOI:
10.1074/jbc.M115.692582
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center