Inhibitory effect of zinc on glucose‐stimulated zinc/insulin secretion in an insulin‐secreting β‐cell line

Slepchenko, Kira G.; James, Calvin; Li, Yang V.

doi:10.1113/expphysiol.2013.072348

Cited by 29 publications

(19 citation statements)

References 65 publications

(98 reference statements)

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“…Contrary to the essential physiological roles of zinc ions in proper concentrations, zinc entry was shown to profoundly modulate VACC currents in ventricular myocytes and strongly hamper the β-adrenergic stimulation pathway via inhibiting adenylyl cyclase and alter hormone release in endocrine tissues and hormonal regulation of the heart [6,15]. Furthermore, zinc overloading in the cytoplasm has been diversely implicated in pathological conditions such as stroke, seizures, trauma in the brain, and diabetes [3,16].…”

Section: Introductionmentioning

confidence: 92%

Differential zinc permeation and blockade of L-type Ca2+ channel isoforms Cav1.2 and Cav1.3

Park

Min

Kang

et al. 2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Certain voltage-activated Ca2+ channels have been reported to act as potential zinc entry routes. However, it remains to be determined whether zinc can permeate individual Ca2+ channel isoforms. We expressed recombinant Ca2+ channel isoforms in Xenopus oocytes and attempted to record zinc currents from them using a two-electrode voltage clamp method. We found that, in an extracellular zinc solution, inward currents arising from zinc permeation could be recorded from Xenopus oocytes expressing L-type Cav1.2 or Cav1.3 isoforms, but not from oocytes expressing Cav2.2, Cav2.3, Cav3.1, or Cav3.2. Zinc currents through Cav1.2 and Cav1.3 were blocked by nimodipine, but enhanced by (±)Bay K8644, supporting the finding that zinc can permeate both L-type Cav1.2 and Cav1.3 channel isoforms. We also examined the blocking effects of low concentrations of zinc on Ca2+ currents through the L-type channel isoforms. Low micro-molar zinc potently blocked Ca2+ currents through Cav1.2 and Cav1.3 with different sensitivities (IC50 for Cav1.2 and Cav1.3=18.4 and 34.1 μM) and de-accelerated the activation and inactivation kinetics in a concentration-dependent manner. Notably, mild acidifications of the external zinc solution increased zinc currents through Cav1.2 and Cav1.3, with the increment level for Cav1.3 being greater than that for Cav1.2. In overall, we provide evidence that Cav1.2 and Cav1.3 isoforms are capable of potentially functioning as zinc permeation routes, through which zinc entry can be differentially augmented by mild acidifications.

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Section: Introductionmentioning

confidence: 92%

Differential zinc permeation and blockade of L-type Ca2+ channel isoforms Cav1.2 and Cav1.3

Park

Min

Kang

et al. 2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

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“…A number of previous studies have implicated Zn 2+ in the paracrine regulation of β-cell function [21][22][23][24], and insulin hypersecretion in ZnT8-deficient mice has been linked to insufficient suppression of β-cells due to reduced Zn 2+ release [7]. In view of their exceptional Zn 2+ sensitivity (IC 50 (Zn 2+ ) = 1-10 μM) [12], we hypothesized that a lack of β-cell Ca v 2.3 channels may have similar functional consequences and result in impaired feedback inhibition of insulin secretion.…”

Section: Dedtc Zn 2+ Chelation Reverses Tonic Suppression Of Ca V 23mentioning

confidence: 99%

Diethyldithiocarbamate-mediated zinc ion chelation reveals role of Cav2.3 channels in glucagon secretion

Drobinskaya

Neumaier

Pereverzev

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Peptide-hormone secretion is partially triggered by Ca2+ influx through voltage-gated Ca2+ channels (VGCCs) and gene inactivation of Zn2+-sensitive Cav2.3-type VGCCs is associated with disturbed glucose homeostasis in mice. Zn2+ has been implicated in pancreatic islet cell crosstalk and recent findings indicate that sudden cessation of Zn2+ supply during hypoglycemia triggers glucagon secretion in rodents. Here we show that diethyldithiocarbamate (DEDTC), a chelating agent for Zn2+ and other group IIB metal ions, differentially affects blood glucose and serum peptide hormone level in wild-type mice and mice lacking the Cav2.3-subunit. Fasting glucose and glucagon level were significantly higher in Cav2.3-deficient compared to wild-type mice, while DEDTC Zn2+-chelation produced a significant and correlated increase of blood glucose and serum glucagon concentration in wild-type but not Cav2.3-deficient mice. Glucose tolerance tests revealed severe glucose intolerance in Zn2+-depleted Cav2.3-deficient but not vehicle-treated Cav2.3-deficient or Zn2+-depleted wildtype mice. Collectively, these findings indicate that Cav2.3 channels are critically involved in the Zn2+-mediated suppression of glucagon secretion during hyperglycemia. Especially under conditions of Zn2+ deficiency, ablation or dysfunction of Cav2.3 channels may lead to severe disturbances in glucose homeostasis.

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“…However, the improved glucose tolerance did not appear to be due to enhanced insulin secretion, which was reduced in islets isolated from these animals. This is likely instead to be , acting to inhibit insulin secretion through an autocrine/paracrine loop (86,88) . Whether the enhanced Zn 2+ secretion has any effects on neighbouring α-cells, or on hepatic insulin clearance (79) , is yet to be investigated.…”

Section: +mentioning

confidence: 99%

Intracellular zinc in insulin secretion and action: a determinant of diabetes risk?

et al. 2015

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Zinc is an important micronutrient, essential in the diet to avoid a variety of conditions associated with malnutrition such as diarrhoea and alopecia. Lowered circulating levels of zinc are also found in diabetes mellitus, a condition which affects one in twelve of the adult population and whose treatments consume approximately 10 % of healthcare budgets. Zn 2+ ions are essential for a huge range of cellular functions and, in the specialised pancreatic β-cell, for the storage of insulin within the secretory granule. Correspondingly, genetic variants in the SLC30A8 gene, which encodes the diabetes-associated granule-resident Zn 2+ transporter ZnT8, are associated with an altered risk of type 2 diabetes. Here, we focus on (i) recent advances in measuring free zinc concentrations dynamically in subcellular compartments, and (ii) studies dissecting the role of intracellular zinc in the control of glucose homeostasis in vitro and in vivo. We discuss the effects on insulin secretion and action of deleting or overexpressing Slc30a8 highly selectively in the pancreatic β-cell, and the role of zinc in insulin signalling. While modulated by genetic variability, healthy levels of dietary zinc, and hence normal cellular zinc homeostasis, are likely to play an important role in the proper release and action of insulin to maintain glucose homeostasis and lower diabetes risk.

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Inhibitory effect of zinc on glucose‐stimulated zinc/insulin secretion in an insulin‐secreting β‐cell line

Cited by 29 publications

References 65 publications

Differential zinc permeation and blockade of L-type Ca2+ channel isoforms Cav1.2 and Cav1.3

Differential zinc permeation and blockade of L-type Ca2+ channel isoforms Cav1.2 and Cav1.3

Diethyldithiocarbamate-mediated zinc ion chelation reveals role of Cav2.3 channels in glucagon secretion

Intracellular zinc in insulin secretion and action: a determinant of diabetes risk?

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