Zn²⁺‐transporter‐8: A dual role in diabetes

Abstract

Diabetes mellitus arises from defects in insulin secretion or action, or both. In pancreatic islets, insulin production is linked with zinc transport mediated by zinc transporter ZnT-8, a product of the SLC30A8 gene. Therefore, altered activity of ZnT-8 is expected to be associated with impaired glucose-induced insulin response and promote progression from glucose intolerance to diabetes. Recent findings do emerge with a role of SLC30A8 in diabetes. Genome-wide association scans for type 2 diabetes (T2D) susceptibility loci revealed and then replicated a highly significant association between the R allele of the R325W variant of SLC30A8 (marker rs13266634) and susceptibility to T2D in Caucasians. A role of ZnT-8 as a new major self-antigenic determinant in type 1 diabetes (T1D) was found. Marker rs13266634 was also shown to modulate anti-ZnT-8 self-antibody specificity in islet autoimmunity. Hence, these findings suggest for a dual role of SLC30A8 in diabetes, which is consisted in conferring genetic susceptibility to T2D and being a major islet self-antigen in T1D as well. Here we characterize an emerging role of ZnT-8 in diabetes and discuss potential mechanisms of its involvement in the etiology of both forms of diabetes.

Zinc supplementation in prediabetes: A randomized double‐blind placebo‐controlled clinical trial

“…The molecular mechanism by which zinc supplementation helps improve blood glucose and HOMA parameters (HOMA‐IR and HOMA‐β) are not fully established. Insulin production and efficient packaging into vesicles is closely linked with the transport of zinc into β‐cells . Furthermore, zinc significantly inhibits human islet amyloid polypeptide aggregation and fibrillogenesis in the pancreas, preventing β‐cell dysfunction and death in T2DM .…”

Zinc transporter expression in zebrafish (Danio rerio) during development

“…We highlight that there is marked increase in expression of ZnT8 at 6 hpf (~646 fold increase) that corresponds with embryonic synthesis of proinsulin (Kinkel et al 2009) and peaks at 48hpf (~5000 fold increase) that corresponds with organogenesis. ZnT8 appears to play a critical role in the synthesis and transport of zinc into secretory vesicles and formation of zinc-insulin complexes (Chistiakov et al 2009). Loss of ZnT8 in pancreatic β cells reduces insulin content and loss of insulin release (Fu et al 2009; Lemaire et al 2009).…”

Trace Element Status in Type 2 Diabetes: A Meta-Analysis

“…The transport of zinc into the beta-cells of the pancreas is essential for insulin production and its efficient packaging into vesicles. (5) Moreover, zinc finger protein 407 (6) and zinc-alpha2-glycoprotein (7, 8) have been shown to enhance the expression of the Glucose transporter type 4 (GLUT 4) protein in adipocytes and skeletal muscles, thereby mediating insulin-induced glucose uptake into these cells. Manganese is another trace element involved in carbohydrate metabolism.…”