Current and Future Clinical Applications of Zinc Transporter-8 in Type 1 Diabetes Mellitus

Abstract

Objective: To evaluate the utility of zinc transporter-8 (ZnT8) in the improvement of type 1 diabetes mellitus (T1DM) diagnosis and prediction, and to explore whether ZnT8 is a potential therapeutic target in T1DM.

Data sources: A search was conducted within the medical database PubMed for relevant articles published from 2001 to 2015. The search terms are as follows: "ZnT8," "type 1 diabetes," "latent autoimmune diabetes in adults," "type 2 diabetes," "islet autoantibodies," "zinc supplement," "T cells," "β cell," "immune therapy." We also searched the reference lists of selected articles.

Study selection: English-language original articles and critical reviews concerning ZnT8 and the clinical applications of islet autoantibodies in diabetes were reviewed.

Results: The basic function of ZnT8 is maintaining intracellular zinc homeostasis, which modulates the process of insulin biosynthesis, storage, and secretion. Autoantibodies against ZnT8 (ZnT8A) and ZnT8-specific T cells are the reliable biomarkers for the identification, stratification, and characterization of T1DM. Additionally, the results from the animal models and clinical trials have shown that ZnT8 is a diabetogenic antigen, suggesting the possibility of ZnT8-specific immunotherapy as an alternative for T1DM therapy.

Conclusions: ZnT8 is a novel islet autoantigen with a widely potential for clinical applications in T1DM. However, before the large-scale clinical applications, there are still many problems to be solved.

Figure 1

The expression and structure of ZnT8 (a) are adapted from Kawasaki 2012. The biochemical function and regulation of ZnT8 are shown (b). The solid lines represent the explicit function, and the dashed lines represent the unknown or ambiguity function. The Red Cross presents no effect. GSIS: Glucose-stimulated insulin secretion; IGTT: Intravenous glucose tolerance test; OGTT: Oral glucose tolerance test; Pdx1: pancreatic and duodenal homeobox 1; ZnT8: Zinc transporter-8.

Figure 2

The 5-year cumulative risk of diabetes in relatives of T1DM patients according to the AAbs patterns (a) and age (b). FDR: First-degree relatives; GADA: Autoantibodies against glutamic acid decarboxylase 65; IA-2A: Autoantibodies against insulinoma antigen 2; IA-2βA: Autoantibodies against insulinoma antigen 2β; IAA: Autoantibodies against insulin; T1DM: Type 1 diabetes mellitus.