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Prolonged stimulation of insulin-release from MIN6 cells causes zinc depletion and loss of β-cell markers

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)51-59
JournalJournal of Trace Elements in Medicine and Biology
Volume49
Early online date24 Apr 2018
DOIs
Accepted/In press18 Apr 2018
E-pub ahead of print24 Apr 2018
PublishedSep 2018

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Abstract

Zinc is integral for the normal function of pancreatic β-cells in glycaemic control. Large amounts of zinc are secreted from β-cells following insulin exocytosis and regulated replenishment is required, which is thought to be mediated by the ZIP family of zinc importer proteins. Within type 2 diabetic patients, β-cells are stressed through prolonged stimulation by hyperglycaemia and this is thought to be a major factor contributing to loss of β-cell identity and mass. However, the consequences for the β-cell zinc status remain largely unexplored. We used inductively coupled plasma mass spectrometry (ICP-MS) to show that 24 h treatment of MIN6 cells with potassium chloride, mimicking hyperglycaemic stimulation, reduces the total cellular zinc content 2.8-fold, and qPCR to show an increase in mRNA expression for metallothioneins (Mt1 and Mt2) following 4 and 24 h of stimulation, suggestive of an early rise in cytosolic zinc. To determine which ZIP paralogues may be responsible for zinc replenishment, we used immunocytochemistry, western blot and qPCR to demonstrate initial ZIP1 protein upregulation proceeded by downregulation of mRNA coding for ZIP1, ZIP6, ZIP7 and ZIP14. To assign a biological significance to the decreased total cellular zinc content, we assessed expression of key β-cell markers to show downregulation of mRNA for MafA, Mnx-1, Nkx2.2 and Pax6. Our data suggest hyperglycaemia-induced zinc depletion may
contribute to loss of β-cell identity and promote β-cell dedifferentiation through disrupting expression of key transcription factors.

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