Changes in islet plasma membrane calcium-ATPase activity and isoform expression induced by insulin resistance

Alzugaray, María Eugenia; García, María Elisa; Zotto, Hector Herminio del; Raschia, María Agustina; Palomeque, Julieta; Rossi, Juan Pablo F.C.; Gagliardino, Juan José; Flores, Luis

doi:10.1016/j.abb.2009.07.022

Cited by 9 publications

(9 citation statements)

References 53 publications

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“…In the current study, we showed that the PMCA activity in islets from db/db mice was not significantly different compared with that observed in normal mice, in contrast to the previously reported down-regulation of PMCA function in db/db islets and islets with insulin resistance (Roe et al 1994; Hoenig et al 1990; Levy et al 1998; Alzugaray et al 2009). The difference may be due to the different experimental conditions tested and the different cell models used.…”

Section: Discussioncontrasting

confidence: 74%

Alterations of the Ca2+ signaling pathway in pancreatic beta-cells isolated from db/db mice

et al. 2014

Protein Cell

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Upon glucose elevation, pancreatic beta-cells secrete insulin in a Ca2+-dependent manner. In diabetic animal models, different aspects of the calcium signaling pathway in beta-cells are altered, but there is no consensus regarding their relative contributions to the development of beta-cell dysfunction. In this study, we compared the increase in cytosolic Ca2+ ([Ca2+]i) via Ca2+ influx, Ca2+ mobilization from endoplasmic reticulum (ER) calcium stores, and the removal of Ca2+ via multiple mechanisms in beta-cells from both diabetic db/db mice and non-diabetic C57BL/6J mice. We refined our previous quantitative model to describe the slow [Ca2+]i recovery after depolarization in beta-cells from db/db mice. According to the model, the activity levels of the two subtypes of the sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) pump, SERCA2 and SERCA3, were severely down-regulated in diabetic cells to 65% and 0% of the levels in normal cells. This down-regulation may lead to a reduction in the Ca2+ concentration in the ER, a compensatory up-regulation of the plasma membrane Na+/Ca2+ exchanger (NCX) and a reduction in depolarization-evoked Ca2+ influx. As a result, the patterns of glucose-stimulated calcium oscillations were significantly different in db/db diabetic beta-cells compared with normal cells. Overall, quantifying the changes in the calcium signaling pathway in db/db diabetic beta-cells will aid in the development of a disease model that could provide insight into the adaptive transformations of beta-cell function during diabetes development.Electronic supplementary materialThe online version of this article (doi:10.1007/s13238-014-0075-7) contains supplementary material, which is available to authorized users.

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Section: Discussioncontrasting

confidence: 74%

Alterations of the Ca2+ signaling pathway in pancreatic beta-cells isolated from db/db mice

et al. 2014

Protein Cell

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“…The present experiments performed in a validated mouse model of pre‐diabetes (Alzugaray et al . ; Felice et al . ; Sommese et al .…”

Section: Discussionmentioning

confidence: 99%

Calcium‐calmodulin‐dependent protein kinase mediates the intracellular signalling pathways of cardiac apoptosis in mice with impaired glucose tolerance

Federico

Portiansky

Sommese

et al. 2017

The Journal of Physiology

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The impact of cardiac apoptosis in pre-diabetic stages of diabetic cardiomyopathy is unknown. We show that myocytes from fructose-rich diet (FRD) animals exhibit arrhythmias produced by exacerbated Ca /calmodulin-protein kinase (CaMKII) activity, ryanodine receptor 2 (RyR2) phosphorylation and sarcoplasmic reticulum (SR) Ca leak. We tested the hypothesis that this mechanism also underlies cardiac apoptosis in pre-diabetes. We generated a pre-diabetic model in FRD mice. FRD mice showed an increase in oxidative stress, hypertrophy and systolic dysfunction. FRD myocytes exhibited enhanced SR Ca spontaneous events in the absence of SR Ca load alterations vs. control-diet (CD) myocytes. In HEK293 cells, hyperglycaemia significantly enhanced [ H]ryanodine binding and CaMKII phosphorylation of RyR2-S2814 residue vs. normoglycaemia. CaMKII inhibition prevented hyperglycaemia-induced alterations. FRD also evoked cardiac apoptosis in WT mice vs. CD-WT mice. Co-treatment with the reactive oxygen species scavenger Tempol prevented FRD-induced apoptosis in WT mice. In contrast, FRD enhanced oxidative stress but not apoptosis in FRD-SR-AIP mice, in which a CaMKII inhibitor is targeted to the SR. FRD produced mitochondrial membrane depolarization in WT mice but not in S2814A mice, in which the CaMKII phosphorylation site on RyR2 was ablated. Furthermore, FRD decreased mitochondrial area, mean Feret diameter and mean SR-mitochondrial distance vs. CD-WT hearts. This remodelling was prevented in AC3I mice, with cardiac-targeted CaMKII inhibition. CaMKII phosphorylation of RyR2, SR Ca leak and mitochondrial membrane depolarization are critically involved in the apoptotic pathway of the pre-diabetic heart. The FRD-induced decrease in SR-mitochondrial distance is likely to additionally favour Ca transit between the two organelles.

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“…Cytokines appear to downregulate PMCA expression in RINm5F cells [103], and reduced PMCA expression decreases TNF-induced cell death in L929 cells [104]. Insulin resistance also appears to downregulate PMCA expression and increase [Ca 2+ ] i in rat islets [105]. Collectively, these data present a complex picture regarding the role of NCXs and PMCAs warranting further study.…”

Section: Cytokines and Cell Membrane Sources Of [Ca2+]imentioning

confidence: 99%

The central role of calcium in the effects of cytokines on beta-cell function: Implications for type 1 and type 2 diabetes

et al. 2011

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The appropriate regulation of intracellular calcium is a requirement for proper cell function and survival. This review focuses on the effects of proinflammatory cytokines on calcium regulation in the insulin-producing pancreatic beta-cell and how normal stimulus-secretion coupling, organelle function, and overall beta-cell viability are impacted. Proinflammatory cytokines are increasingly thought to contribute to beta-cell dysfunction not only in type 1 diabetes (T1D), but also in the progression of type 2 diabetes (T2D). Cytokine-induced disruptions in calcium handling result in reduced insulin release in response to glucose stimulation. Cytokines can alter intracellular calcium levels by depleting calcium from the endoplasmic reticulum (ER) and by increasing calcium influx from the extracellular space. Depleting ER calcium leads to protein misfolding and activation of the ER stress response. Disrupting intracellular calcium may also affect organelles, including the mitochondria and the nucleus. As a chronic condition, cytokine-induced calcium disruptions may lead to beta-cell death in T1D and T2D, although possible protective effects are also discussed. Calcium is thus central to both normal and pathological cell processes. Because the tight regulation of intracellular calcium is crucial to homeostasis, measuring the dynamics of calcium may serve as a good indicator of overall beta-cell function.

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Changes in islet plasma membrane calcium-ATPase activity and isoform expression induced by insulin resistance

Cited by 9 publications

References 53 publications

Alterations of the Ca2+ signaling pathway in pancreatic beta-cells isolated from db/db mice

Alterations of the Ca2+ signaling pathway in pancreatic beta-cells isolated from db/db mice

Calcium‐calmodulin‐dependent protein kinase mediates the intracellular signalling pathways of cardiac apoptosis in mice with impaired glucose tolerance

The central role of calcium in the effects of cytokines on beta-cell function: Implications for type 1 and type 2 diabetes

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