Heterozygous Inactivation of the Na/Ca Exchanger Increases Glucose-Induced Insulin Release, β-Cell Proliferation, and Mass

Abstract

OBJECTIVEWe have previously shown that overexpression of the Na-Ca exchanger (NCX1), a protein responsible for Ca2+ 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 METHODSBiologic and morphologic methods (Ca2+ imaging, Ca2+ 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.RESULTSHeterozygous 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 Ca2+ 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.CONCLUSIONSDownregulation 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.

Heterozygous inactivation of plasma membrane Ca2+-ATPase in mice increases glucose-induced insulin release and beta cell proliferation, mass and viability

“…2c). The observed ultrastructure perfectly matched the ultrastructure described in the literature [5]. A non-quantitative electron microscopy examination of the samples demonstrated no obvious differences between Pmca2…”

“…In a previous study in mice [5], we showed that heterozygous inactivation of the Na/Ca exchanger (isoform 1: NCX1), a protein responsible for Ca 2+ extrusion from cells [6,7], induced several modifications of the beta cell including an increase in glucose-induced insulin release and beta cell proliferation and mass. Ncx1 +/− islets also displayed an increased resistance to hypoxia and when transplanted into diabetic animals produced a four to seven times higher rate of diabetes cure than Ncx1 +/+ islets [5]. Another mechanism responsible for Ca 2+ extrusion from cells is the plasma membrane Ca 2+ -ATPase (PMCA) [8].…”

“…Two systems responsible for Ca 2+ extrusion are present in the beta cell-the Na/Ca exchanger (NCX) and the plasma membrane Ca 2+ -ATPase (PMCA) [4]. In a previous study in mice [5], we showed that heterozygous inactivation of the Na/Ca exchanger (isoform 1: NCX1), a protein responsible for Ca 2+ extrusion from cells [6,7], induced several modifications of the beta cell including an increase in glucose-induced insulin release and beta cell proliferation and mass. Ncx1 +/− islets also displayed an increased resistance to hypoxia and when transplanted into diabetic animals produced a four to seven times higher rate of diabetes cure than Ncx1 +/+ islets [5].…”

Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in insulin-producing adenomas

“…As noted above, activation of voltage-gated Ca 2+ channels leads to increased intracellular Ca 2+ , a sufficient signal for insulin secretion and cell proliferation (37). Increased expression of CACNA2D2 has previously been shown to increase intracellular Ca 2+ (38), providing a potential link between increased expression of CACNA2D2 and increased insulin secretion and/or cell proliferation.…”

Intracellular Dyssynchrony of Diastolic Cytosolic [Ca 2+ ] Decay in Ventricular Cardiomyocytes in Cardiac Remodeling and Human Heart Failure

“…1 Dyssynchronous activation of ventricular tissue, as it occurs in bundle-branch block, leads to less efficient contraction and worsening of heart failure, whereas resynchronization therapy improves cardiac contractility, morbidity, and mortality in these patients. 2 Dyssynchronous contraction is also observed in hearts with diastolic or systolic heart failure in the absence of overt electric conduction defects, 3 suggesting dysfunction at the level of the cardiomyocyte.…”