News & Research

    University of Colorado, Aurora, Colorado

Autoimmunity towards Zinc transporter 8 (SLC30A8) in human type 1 diabetes

General Research Subject: Type 1 Diabetes

Focus: Immunology

Type of Grant: Mentor Based Postdoctoral Fellowship

Project Start Date: July 1, 2008

Project End Date: June 30, 2012

Research Description

Funded by Valerie & Peter Kompaniez

Type 1 diabetes results from the attack of the immune system on the insulin-producing pancreatic beta cell of the pancreas directed against target autoantigens that are normal components of the tissue but that are mistaken as foreign. Knowing what these targets are and what features the immune system recognizes in them is key to progress in diagnosing the disease before clinical onset and to developing new treatments. Our laboratory recently discovered a new autoantigen, ZnT8, that is specifically localized to the beta cell where it normally plays a role in adding the metal zinc to insulin to help with its storage in the cell.

This is the first new autoantigen to be discovered in 10 years and it has some special features that make it a promising diagnostic and therapeutic agent. In this proposal we will study the immune response to ZnT8 looking at the autoantibodies that are produced to it in human subjects, the cells of the immune system (B-lymphocytes) that produce these antibodies and the cells (T-lymphocytes) that cause the destruction of the pancreatic islets. The primary objectives are to determine precisely which parts of the ZnT8 molecule that the antibodies and the immune cells bind to. With this information we aim not only to determine who will develop diabetic but how we might prevent it for example by using the autoantigen as an vaccine or means to trap and destroy the autoreactive cells that cause the disease.

Reseacher Profile

Mentor: John Hutton, PhD   Postdoctoral Fellow: Masanori Fuse, PhD

What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?

Our current work is focused on the discovery and characterization of molecular targets of autoimmunity in type 1 diabetes, in particular the cation diffusion transporter ZnT8 (Slc 30A8) and the islet isoform of the enzyme glucose 6 phosphatase (IGRP). Both molecules are specifically localized in the pancreatic ß-cell, the former is a major new target of circulating autoantibodies molecules in human disease, the latter a major target of autreactive T-cells. Both are being investigated in terms of their immunological contribution to disease, their biological function, cell biology and the transcription-regulation of their expression. We have generated gene knock-out animals which have been backcrossed on to a diabetes susceptible background (NOD) for 7 generations.

This work will enhance our understanding how particular molecules are selected for an autoimmune response and provide potential therapeutic agents in the form of recombinant proteins, antibodies and peptides with which to treat the disease as well as powerful diagnostic agents to detect type 1 diabetes earlier and to monitor the progression of the disease and responses to treatment.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond?

Type 1 diabetes (T1D) results from progressive loss of pancreatic islet mass through autoimmunity targeted at a diverse, yet limited, series of molecules that are expressed selectively in the pancreatic ß-cell. Recent work has lead to the discovery of two molecules ZnT8 (Slc30A8) and IGRP that are the target of the immune system which can be used to diagnose and monitor changes in disease progression but also to generate new therapies. Such therapies could take the form of injection of the protein under the skin as a form of vaccine that which halt or slow the progression of disease.

Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?

Early in 1970s I made a commitment to pursue research in the area of diabetes initially looking at metabolic changes associated with diabetic complications and then as to how the pancreatic ß-cell works. The commitment was based on the realization that is a major disease afflicting humanity and the conviction that effective treatment needed to be based on a solid scientific understanding of what causes the disease in both its forms. The award will enable me to bring a young scientist into my laboratory, to instill them with the knowledge that we have gained over the years and hopefully to inspire them to commit their future research to the cure of these diseases.

In what direction do you see the future of diabetes research going?

We are looking towards the future of individual genome sequencing and large scale genomic approaches to the understanding of the complex genetics of type 1 and type 2 diabetes. In this context it is of interest that both the molecules of interest here were implicated in the pathogenesis of both T1D and T2D using genome wide association studies. However this is only 'an association' and we have yet to prove a causal link and find how these molecules contribute to disease. We are entering an era of personalized medicine in which genetic information from each individual will likely determine how that person will be treated and with what drug. It is a major challenge to harness this technology to define new therapeutic targets and how these will be used to treat the disease and its complications.