title: β-Cell preservation and regeneration in diabetes by modulation of β-cell Ca²⁺ homeostasis.
abstract: Ca(2+) extrusion from the β-cell is mediated by two processes the Na/Ca exchanger (NCX) and the plasma membrane Ca(2+) -ATPase (PMCA). Gain of function studies show that overexpression of NCX or PMCA leads to endoplasmic reticulum (ER) Ca(2+) depletion with subsequent ER stress, decrease in β-cell proliferation and β-cell death by apoptosis. Interestingly, chronic exposure to cytokines or high free fatty acid concentrations also induce ER Ca(2+) depletion and β-cell death in diabetes. Loss of function studies show, on the contrary, that heterozygous inactivation of NCX1 (Ncx1(+/-)) leads to an increase in β-cell function (insulin production and release), and a fivefold increase in both β-cell mass and proliferation. The mutation also increases β-cell resistance to hypoxia, and Ncx1(+/-) islets show a two to four times higher rate of diabetes cure than Ncx1(+/+) islets when transplanted in diabetic animals. Thus, down-regulation of the Na/Ca exchanger leads to various changes in β-cell function that are opposite to the major abnormalities seen in diabetes. This provides a unique model for the prevention and treatment of β-cell dysfunction in diabetes and following islet transplantation.
authors.affiliation: Laboratoire de Pharmacodynamie et de Thérapeutique, Université Libre de Bruxelles, Faculté de Médicine, B-1070, Brussels, Belgium. herchu@ulb.ac.be
authors.forename: A
authors.initials: A
authors.lastname: Herchuelz
authors.forename: E
authors.initials: E
authors.lastname: Nguidjoe
authors.forename: L
authors.initials: L
authors.lastname: Jiang
authors.forename: N
authors.initials: N
authors.lastname: Pachera
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002118:Calcium / Q000378:metabolism*; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D006706:Homeostasis; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D016381:Islets of Langerhans Transplantation; D051379:Mice; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000378:metabolism; D012038:Regeneration / Q000235:genetics; D019831:Sodium-Calcium Exchanger / Q000235:genetics* / Q000378:metabolism
chemical_list: D019831:Sodium-Calcium Exchanger; D053499:Plasma Membrane Calcium-Transporting ATPases; C506959:Atp2b2 protein, mouse; D002118:Calcium