Heterozygous Inactivation of the Na/Ca Exchanger Increases Glucose-Induced Insulin Release, beta-Cell Proliferation, and Mass
| Autor: | Jan Mast, Mario Manto, Nathalie Pachera, Eva D’Amico, Eduard Montanya, Alessandra K Cardozo, André Herchuelz, Evrard Nguidjoe, Geraldine Joanny, Jacques Rahier, Florent Allagnat, Stéphane Schurmans, Sophie Sokolow, Jean-Marie Vanderwinden, Marianne Depreter, Decio L. Eizirik, Abdullah Sener, Serge Bigabwa |
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| Přispěvatelé: | Universitat de Barcelona |
| Rok vydání: | 2011 |
| Předmět: |
Blood Glucose
Male Endocrinology Diabetes and Metabolism medicine.medical_treatment Islets of Langerhans Transplantation Type 2 diabetes Medical and Health Sciences Mice Insulin-Secreting Cells Insulina Insulin Secretion Membrane proteins Insulin Proinsulin Diabetes Proteïnes de membrana Sciences bio-médicales et agricoles Insulin oscillation 5.1 Pharmaceuticals Female Development of treatments and therapeutic interventions medicine.medical_specialty Cèl·lules B Carbohydrate metabolism Biology Autoimmune Disease Sodium-Calcium Exchanger Diabetes Mellitus Experimental Experimental Endocrinology & Metabolism Downregulation and upregulation Diabetes mellitus Internal medicine Diabetes Mellitus Internal Medicine medicine Animals Metabolic and endocrine Cell Proliferation B cells Sodium-calcium exchanger Prevention medicine.disease Glucose Endocrinology Islet Studies Glucosa Calcium |
| Zdroj: | Diabetes (New York, N.Y.), 60 (8 Recercat. Dipósit de la Recerca de Catalunya instname Dipòsit Digital de la UB Universidad de Barcelona Diabetes, vol 60, iss 8 Diabetes |
| Popis: | OBJECTIVE We have previously shown that overexpression of the Na-Ca exchanger (NCX1), a protein responsible for Ca(2+) extrusion from cells, increases β-cell programmed cell death (apoptosis) and reduces β-cell proliferation. To further characterize the role of NCX1 in β-cells under in vivo conditions, we developed and characterized mice deficient for NCX1. RESEARCH DESIGN AND METHODS Biologic and morphologic methods (Ca(2+) imaging, Ca(2+) uptake, glucose metabolism, insulin release, and point counting morphometry) were used to assess β-cell function in vitro. Blood glucose and insulin levels were measured to assess glucose metabolism and insulin sensitivity in vivo. Islets were transplanted under the kidney capsule to assess their performance to revert diabetes in alloxan-diabetic mice. RESULTS Heterozygous inactivation of Ncx1 in mice induced an increase in glucose-induced insulin release, with a major enhancement of its first and second phase. This was paralleled by an increase in β-cell proliferation and mass. The mutation also increased β-cell insulin content, proinsulin immunostaining, glucose-induced Ca(2+) uptake, and β-cell resistance to hypoxia. In addition, Ncx1(+/-) islets showed a two- to four-times higher rate of diabetes cure than Ncx1(+/+) islets when transplanted into diabetic animals. CONCLUSIONS Downregulation of the Na/Ca exchanger leads to an increase in β-cell function, proliferation, mass, and resistance to physiologic stress, namely to various changes in β-cell function that are opposite to the major abnormalities seen in type 2 diabetes. This provides a unique model for the prevention and treatment of β-cell dysfunction in type 2 diabetes and after islet transplantation. JOURNAL ARTICLE SCOPUS: ar.j info:eu-repo/semantics/published |
| Databáze: | OpenAIRE |
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