Zinc transporters and their role in the pancreatic β‐cell

Abstract

Zinc is an essential nutrient with tremendous importance for human health, and zinc deficiency is a severe risk factor for increased mortality and morbidity. As abnormal zinc homeostasis causes diabetes, and because the pancreatic β‐cell contains the highest zinc content of any known cell type, it is of interest to know how zinc fluxes are controlled in β‐cells. The understanding of zinc homeostasis has been boosted by the discovery of multiprotein families of zinc transporters, and one of them – zinc transporter 8 (ZnT8) – is abundantly and specifically expressed in the pancreatic islets of Langerhans. In this review, we discuss the evidence for a physiological role of ZnT8 in the formation of zinc‐insulin crystals, the physical form in which most insulin is stored in secretory granules. In addition, we cross‐examine this information, collected in genetically modified mouse strains, to the knowledge that genetic variants of the human ZnT8 gene predispose to the onset of type 2 diabetes and that epitopes on the ZnT8 protein trigger autoimmunity in patients with type 1 diabetes. The overall conclusion is that we are still at the dawn of a complete understanding of how zinc homeostasis operates in normal β‐cells and how abnormalities lead to β‐cell dysfunction and diabetes. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00199.x, 2012)

Longitudinal three-dimensional visualisation of autoimmune diabetes by functional optical coherence imaging

“…As we have previously shown, xfOCM imaging can be used to identify pancreatic islets in surgically exposed pancreases of live animals; the strong light scattering observed correlates strongly with insulin-producing beta cells [17]. As OCM is sensitive to changes in refractive index and because pancreatic beta cells have a high zinc content [27], we hypothesised that the origin of the strong OCM signal is dominantly caused by the zinc-insulin crystals in the pancreatic beta cells. To test this hypothesis, thick pancreas sections of ZnT8-KO mice, which lack zinc-insulin crystals in the secretory granules of beta cells [24,27], were subjected to immunohistochemistry (IHC) using antiinsulin antibodies and analysed simultaneously by OCM and confocal fluorescence microscopy.…”

Zinc and diabetes

“…In β cells, ZnT8 transports Zn 2+ from the cytosol to the ISG and thus plays a critical a role in hormone storage as described above. It is the only Zn 2+ transporter showing such dramatic tissuespecific expression and its expression level is the highest of all isoforms in both β and α cells, making it the most strongly expressed Zn 2+ transporter in the islet [30]. The relationship between ZnT8/SLC30A8 variants and T2D risk will be described in more detail later.…”

“…Several ZnT are expressed in the β cell ( Figure 1, for review [30]). ZnT1, ubiquitously present in tissues, is the only member of the family localised at the plasma membrane, exporting zinc to the extracellular media [31].…”

“…In the mouse pancreatic islet mRNA expression, albeit quite low in some cases, has been detected for most of the ZIP family members, ZIP6 ZIP7 and ZIP9 being the most expressed [30]. Concordantly, ZIP6 and ZIP7 are prominent zinc influx transporters in murine and human primary β cells [34,46].…”

“…MT1 and MT2 are the major isoforms found in the pancreas and in the β cell specifically [30,34]. In response to high glucose (16.7 mM for 24 h), the cytosolic Zn 2+ concentration is increased and is associated with an increase in MT1 and MT2 expression.…”