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β‐Cell preservation and regeneration in diabetes by modulation of β‐cell Ca 2+ homeostasis
Author(s) -
Herchuelz A.,
Nguidjoe E.,
Jiang L.,
Pachera N.
Publication year - 2012
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/j.1463-1326.2012.01649.x
Subject(s) - endoplasmic reticulum , endocrinology , plasma membrane ca2+ atpase , medicine , unfolded protein response , cell growth , islet , homeostasis , programmed cell death , cell , microbiology and biotechnology , apoptosis , insulin , glucose homeostasis , biology , chemistry , insulin resistance , atpase , biochemistry , enzyme
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.