title: Increased Glucose-induced Secretion of Glucagon-like Peptide-1 in Mice Lacking the Carcinoembryonic Antigen-related Cell Adhesion Molecule 2 (CEACAM2).
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.
authors.affiliation: From the Center for Diabetes and Endocrine Research and Departments of Physiology and Pharmacology and.
authors.forename: Simona S
authors.initials: SS
authors.lastname: Ghanem
authors.affiliation: From the Center for Diabetes and Endocrine Research and Departments of Physiology and Pharmacology and.
authors.forename: Garrett
authors.initials: G
authors.lastname: Heinrich
authors.affiliation: From the Center for Diabetes and Endocrine Research and Departments of Physiology and Pharmacology and.
authors.forename: Sumona G
authors.initials: SG
authors.lastname: Lester
authors.affiliation: the Institut für Anatomie und Zellbiologie, Universität Würzburg, D-97070 Würzburg, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Pfeiffer
authors.affiliation: Neurosciences, College of Medicine and Life Sciences, University of Toledo, Health Science Campus, Toledo, Ohio 43614.
authors.forename: Sumit
authors.initials: S
authors.lastname: Bhattacharya
authors.affiliation: From the Center for Diabetes and Endocrine Research and Departments of Physiology and Pharmacology and.
authors.forename: Payal R
authors.initials: PR
authors.lastname: Patel
authors.affiliation: From the Center for Diabetes and Endocrine Research and Departments of Physiology and Pharmacology and.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: DeAngelis
authors.affiliation: From the Center for Diabetes and Endocrine Research and Departments of Physiology and Pharmacology and.
authors.forename: Tong
authors.initials: T
authors.lastname: Dai
authors.affiliation: From the Center for Diabetes and Endocrine Research and Departments of Physiology and Pharmacology and.
authors.forename: Sadeesh K
authors.initials: SK
authors.lastname: Ramakrishnan
authors.affiliation: From the Center for Diabetes and Endocrine Research and Departments of Physiology and Pharmacology and.
authors.forename: Zachary N
authors.initials: ZN
authors.lastname: Smiley
authors.affiliation: the Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
authors.forename: Dae Y
authors.initials: DY
authors.lastname: Jung
authors.affiliation: the Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
authors.forename: Yongjin
authors.initials: Y
authors.lastname: Lee
authors.affiliation: the Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 371-8512 Gunma, Japan, and.
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Kitamura
authors.affiliation: the Institut für Anatomie und Zellbiologie, Universität Würzburg, D-97070 Würzburg, Germany.
authors.forename: Suleyman
authors.initials: S
authors.lastname: Ergun
authors.affiliation: the Islet Cell and Regenerative Biology, Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215.
authors.forename: Rohit N
authors.initials: RN
authors.lastname: Kulkarni
authors.affiliation: the Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
authors.forename: Jason K
authors.initials: JK
authors.lastname: Kim
authors.affiliation: Neurosciences, College of Medicine and Life Sciences, University of Toledo, Health Science Campus, Toledo, Ohio 43614.
authors.forename: David R
authors.initials: DR
authors.lastname: Giovannucci
authors.affiliation: From the Center for Diabetes and Endocrine Research and Departments of Physiology and Pharmacology and sonia.najjar@utoledo.edu.
authors.forename: Sonia M
authors.identifier: http://orcid.org/0000-0002-6685-5883
authors.initials: SM
authors.lastname: Najjar
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000172:deficiency* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D014851:Wakefulness
chemical_list: D015703:Antigens, CD; C069847:CD66 antigens; D020746:Calcium Channels, L-Type; D015815:Cell Adhesion Molecules; D007328:Insulin; D052216:Glucagon-Like Peptide 1; D005947:Glucose
keywords: CEACAM2; GLP-1; diabetes; enteroendocrine cells; gene knock-out; insulin clearance; insulin resistance; insulin secretion; intestine