Pérez-Arana, GonzaloBlandino-Rosano, ManuelPrada-Oliveira, ArturoAguilar-Diosdado, ManuelSegundo, Carmen2013-01-082013-01-082010-06-01Pérez-Arana G, Blandino-Rosano M, Prada-Oliveira A, Aguilar-Diosdado M, Segundo C. Decrease in {beta}-cell proliferation precedes apoptosis during diabetes development in bio-breeding/worcester rat: beneficial role of Exendin-4. Endocrinology. 2010 Jun; 151(6):2538-460013-7227http://hdl.handle.net/10668/727Journal Article; Research Support, Non-U.S. Gov't;In autoimmune type 1 diabetes mellitus, proinflammatory cytokine-mediated apoptosis of beta-cells has been considered to be the first event directly responsible for beta-cell mass reduction. In the Bio-Breeding (BB) rat, an in vivo model used in the study of autoimmune diabetes, beta-cell apoptosis is observed from 9 wk of age and takes place after an insulitis period that begins at an earlier age. Previous studies by our group have shown an antiproliferative effect of proinflammatory cytokines on cultured beta-cells in Wistar rats, an effect that was partially reversed by Exendin-4, an analogue of glucagon-like peptide-1. In the current study, the changes in beta-cell apoptosis and proliferation during insulitis stage were also determined in pancreatic tissue sections in normal and thymectomized BB rats, as well as in Wistar rats of 5, 7, 9, and 11 wk of age. Although stable beta-cell proliferation in Wistar and thymectomized BB rats was observed along the course of the study, a decrease in beta-cell proliferation and beta-cell mass from the age of 5 wk, and prior to the commencement of apoptosis, was noted in BB rats. Exendin-4, in combination with anti-interferon-gamma antibody, induced a near-total recovery of beta-cell proliferation during the initial stages of insulitis. This highlights the importance of early intervention and, as well, the possibilities of new therapeutic approaches in preventing autoimmune diabetes by acting, initially, in the insulitis stage and, subsequently, on beta-cell regeneration and on beta-cell apoptosis.enAgentes hipoglucémicosPéptidosVenenoExenatidaInterferon-gammaDiabetes MellitusAnticuerposAnimalesRatas WistarDistribución aleatoriaCélulas secretoras de insulinaInmunohistoquímicaTest de tolerancia a la glucosaPéptido glucagonoide 1Proliferación celularMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Blood Proteins::Immunoproteins::Immunoglobulins::AntibodiesMedical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Death::ApoptosisMedical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Growth Processes::Cell ProliferationMedical Subject Headings::Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Glucose Metabolism Disorders::Diabetes Mellitus::Diabetes Mellitus, Type 1Medical Subject Headings::Diseases::Animal Diseases::Disease Models, AnimalMedical Subject Headings::Chemicals and Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones::Gastrointestinal Hormones::Proglucagon::Glucagon-Like Peptides::Glucagon-Like Peptide 1Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Clinical Laboratory Techniques::Clinical Chemistry Tests::Blood Chemical Analysis::Glucose Tolerance TestMedical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Physiological Effects of Drugs::Hypoglycemic AgentsMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Immunologic Techniques::ImmunohistochemistryMedical Subject Headings::Anatomy::Endocrine System::Enteroendocrine Cells::Insulin-Secreting CellsMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Cytokines::Interferons::Interferon-gammaMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::PeptidesMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Research Design::Random AllocationMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::RatsMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Rats::Rats, WistarMedical Subject Headings::Anatomy::Fluids and Secretions::Bodily Secretions::VenomsMedical Subject Headings::Organisms::Eukaryota::Animalsresearch article20410202open access10.1210/en.2009-11131945-7170