In vivo expression and functional characterization of the zinc transporter ZnT8 in glucose-induced insulin secretion

Abstract

Insulin-secreting pancreatic beta cells are exceptionally rich in zinc. In these cells, zinc is required for zinc-insulin crystallization within secretory vesicles. Secreted zinc has also been proposed to be a paracrine and autocrine modulator of glucagon and insulin secretion in pancreatic alpha and beta cells, respectively. However, little is known about the molecular mechanisms underlying zinc accumulation in insulin-containing vesicles. We previously identified a pancreas-specific zinc transporter, ZnT-8, which colocalized with insulin in cultured beta cells. In this paper we studied its localization in human pancreatic islet cells, and its effect on cellular zinc content and insulin secretion. In human pancreatic islet cells, ZnT-8 was exclusively expressed in insulin-producing beta cells, and colocalized with insulin in these cells. ZnT-8 overexpression stimulated zinc accumulation and increased total intracellular zinc in insulin-secreting INS-1E cells. Furthermore, ZnT-8-overexpressing cells display enhanced glucose-stimulated insulin secretion compared with control cells, only for a high glucose challenge, i.e. >10 mM glucose. Altogether, these data strongly suggest that the zinc transporter ZnT-8 is a key protein for both zinc accumulation and regulation of insulin secretion in pancreatic beta cells.

A low-risk ZnT-8 allele (W325) for post-transplantation diabetes mellitus is protective against cyclosporin A-induced impairment of insulin secretion

“…Cells expressing either ZnT-8 variant responded to increasing glucose levels with increasing levels of insulin secretion (Figure 2a), indicating that these altered b-cells exhibit glucose-sensitive insulin secretion. 24 Similar to a previous study by Chimienti et al, 13 ZnT-8 overexpression resulted in greater insulin secretion by INS-1E cells than by mock-transfected control cells (Figure 2a), supporting a role for ZnT-8 in the regulation of insulin secretion. As CsA has been shown to lead to deterioration of b-cell function, 21,22 and particularly insulin secretion, we investigated whether ZnT-8 variants show differential susceptibility to CsA with respect to GSIS.…”

“…More efficient accumulation of zinc in secretory granules in cells expressing ZnT-8 W325, as demonstrated by previous studies, 13,25 appears to account for this effect. Importantly, the different effects of the two variants on insulin secretion became more pronounced when b-cell insulin secretion was suppressed by CsA.…”

“…ZnT-8 was identified as a zinc transporter that is mainly present in insulin secretory granules (see Figure 1) to enable cellular efflux of zinc into secretory vesicles. 7,13 ZnT-8 knockout and knockdown experiments in vivo and in vitro have confirmed that ZnT-8 is important for vesicular distribution of zinc in b-cells. 11,14 However, the precise role of subcellular distribution of zinc by ZnT-8 in pancreatic b-cell physiology is still elusive.…”

Risk Factors for Type 1 Diabetes Recurrence in Immunosuppressed Recipients of Simultaneous Pancreas–Kidney Transplants

“…ZnT8 is a cation efflux protein involved in the insulin secretory pathway 30, 31 and is encoded by the SLC30A8 gene. SLC30A8 polymorphisms affect the amino acid sequence at residue 325, an essential determinant of antigenicity 32.…”

Zinc and diabetes

“…ZnT3 mRNA was similarly barely 5 detected by RNASeq in purified mouse β cells [36], in line with our findings in mouse islets [34]. The role of this particular transporter in controlling β cell Zn 2+ thus remains unclear.Finally, ZnT8 expression is largely restricted to the pancreas, where it is expressed exclusively, and at similar levels, in β and α cells in both mouse and man [43,44]. 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.…”