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

Abstract

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.

Early differences in islets from prediabetic NOD mice: combined microarray and proteomic analysis

“…Enrichment analysis of the differential genes in NOD vs C57Bl/6 islets revealed dysregulation of genes related to metal ion transport, in line with recent studies showing that pancreatic changes in Zn 2+ levels influence the availability and action of insulin [30,31]. In addition, genes implicated in the regulation of protein kinase activity were affected in NOD islets, which could lead to disturbances in the regulation of several molecular processes.…”

Zinc and diabetes

“…The phosphorylation of insulin receptor (IR) following its binding to insulin leads to the triggering of two main pathways, and stimulate then glucose transport, glycogen synthesis, lipogenesis, etc [27].…”

“…High free Zn 2+ concentrations are toxic for mammalian cells but Zn 2+ also needs to be readily available to perform numerous functions, notably as an enzyme cofactor or structural component of proteins (approximately 3,000 genes within the human genome present a Zn 2+ binding domain) [27], particularly in the context of the β cell. Cellular Zn 2+ homeostasis must therefore be tightly regulated and three protein families are involved: the metallothioneins (MTs), the zinc importers (ZIP, SLC39A) and the zinc transporters (ZnT, SLC30A).…”

“…To further investigate the role ZnT8 in vivo in the maintenance of glucose homeostasis, several groups (including ours) have developed ZnT8 null mouse models, either with global deletion or deletion restricted largely or exclusively to the β cell depending on the Cre delete strain deployed (for review see [27]). Although variations between the models are observed, and may be attributed to differences in genetic background, housing conditions, alterations in the microbiome etc [79], in the majority of cases null mice display impaired or unaltered glucose tolerance: no study reported an improvement in this metabolic parameter.…”

Avaliação sistemática do uso do Dried Blood Spot para determinação de elementos químicos em sangue capilar visando estudos de biomonitoramento no Brasil

“…O Zn atua também no metabolismo de glicose. Após a insulina ser clivada forma-se um monômero que, no interior da célula, entra em contato com o zinco formando um cristal dimérico possibilitando que a insulina seja armazenada e secretada (CHAUSMER, 1998;LIN;HUANG, 2015;RANASINGHE et at., 2015;RUTTER et al, 2015). Assim, elevadas Atualmente, mais de 95% dos recém-nascidos nos EUA são testados para doenças metabólicas hereditárias usando o DBS e a aplicação foi estendida para muitos outros campos, incluindo o monitoramento de drogas terapêuticas, elementos tóxicos e essenciais (ARAMENDÍA, 2012;LI;TSE, 2010).…”