Daniels, Mark J., PhD
Structure-function Analysis of the Human beta-cell Zinc Transporter ZnT8 (SLC30A8)
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Islet Biology, Islet Biology\Channels, Islet Biology\Channels, Single Cell Studies, and Calcium Signaling, Other
Type of Grant: Basic Science
Project Start Date: July 1, 2013
Project End Date: June 30, 2016
Diabetes affects over 25 million Americans and has two primary causes -- either the body cannot make insulin or it cannot respond to insulin. Insulin is released by the pancreas in response to increased blood glucose, and signals the body to metabolize the excess glucose for energy. The failure to either produce or respond to insulin greatly increases the risk of heart disease, stroke, high blood pressure, blindness, kidney disease, and nerve damage. The human protein we are studying, called ZnT8, transports zinc into insulin-containing granules to facilitate the storage of insulin. ZnT8 plays a significant role in the development of type I diabetes, and individuals with mutations in this protein have an increased risk for type II diabetes.
The first goal of this project is to solve the molecular structure of ZnT8 and its component domains, which can be used to build a model how the various domains of ZnT8 participate in zinc transport. Thus far, electron microscopy has allowed us to determine a starting model of ZnT8, which will be extended to a higher level of detail using more sophisticated biophysical techniques such as cryoEM and X-ray crystallography. The second goal of this project is to develop assays that complement our structural studies by exploring how various regions of ZnT8 contribute to zinc transport. We believe that a detailed molecular understanding of the structure and function of ZnT8 may lead to novel approaches to treat diabetes.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Our research on diabetes is focused on the biochemistry underlying the disease, specifically the role of a zinc transporter protein, called ZnT8, found in the insulin-secreting beta cells of the pancreas. Those with a mutation in this protein are at higher risk for developing either type I or type II diabetes. Zinc is an essential mineral in the diet since this metal plays a key part in many biological functions.
As part of one of these functions, ZnT8 moves zinc into insulin storage granules inside pancreatic beta cells, where the zinc forms crystals with insulin. These zinc-insulin crystals are the long-term storage form of insulin. The insulin storage granules can then be secreted out of the beta cells to release insulin into the blood stream as needed in response to elevated blood glucose levels.
We are studying the structure and function of the ZnT8 protein in order to figure out how this pump-like protein moves zinc into the insulin storage granules, and thereby seek to understand how mutations in ZnT8 lead to diabetes. This knowledge can then be used to discover drugs that could improve protein function in diabetic patients with ZnT8 mutations and treat their disease.
If a person with diabetes were to ask you how your project will help them in the future,
how would you respond?
My laboratory is studying a protein called ZnT8 (short for the 8th ZiNc Transporter discovered in humans) that helps store insulin in the pancreas. Insulin is released from the pancreas into the bloodstream in response to high levels of glucose and then triggers various tissues to absorb the excess glucose. People with mutations in this protein are at higher risk for developing type I or type II diabetes. We want to find out why this happens, so my lab is trying to figure out what the molecular machinery of ZnT8 looks like in order to learn how this pump-like protein moves zinc into the insulin storage bodies of the pancreas.
This knowledge will also allow us to understand how the mutations of ZnT8 involved in diabetes change the protein's structure and affect its ability to move zinc. We will then be able to discover and design drugs that improve the function of ZnT8, which should help diabetic patients with ZnT8 mutations and could also help those with other forms of the disease. Furthermore, zinc is an important mineral in the body where it plays a key part in many biological functions within cells. Zinc transport proteins related to ZnT8 move this metal to where it is needed in cells, so understanding the structure and function of this protein as it relates to diabetes will also allow us to better understand other diseases potentially affected by defects in zinc transport such as asthma, Alzheimer's disease, and prostate cancer.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
My mother was recently diagnosed with type II diabetes despite a lifetime of good dietary and exercise habits, which suggests that I have a genetic predisposition to this disease. Furthermore, both my wife's parents have diabetes, so my own family is likely at a higher risk as well. Obviously this makes my interest in diabetes research and treatment very personal. I look forward to contributing to efforts that develop either a cure or better treatments for diabetes so that my family, friends, and others will not have to suffer from this disease.
This Basic Science award from the ADA will allow my laboratory to continue its efforts in uncovering the structure and function of the ZnT8 zinc transporter, and to discover its role as a risk factor for diabetes and its role in insulin storage granule development within beta cells of the pancreas. Our desire is for what we discover to be used to create novel treatments for diabetes, either by allowing the design of new compounds or by finding existing drugs that are effective in improving the function of the ZnT8 protein in diabetic patients.
In what direction do you see the future of diabetes research going?
A scientific advance I see coming soon is the ability to know one's personal genome, which will be especially important for those with a family history of diabetes. The cost of DNA sequencing is rapidly decreasing, which will bring a time when it will be practical for individuals to have their own genomic DNA sequenced, although concerns about the privacy of such data will have to be solved. Mutations in ZnT8 and other proteins that are risk factors for diabetes can be identified before the disease causes injury and shows its effects. Together with genetic counseling, this level of knowledge about one's self will allow people to understand some of the diseases they need to watch out for, and will help them to make life choices that will minimize the impact of diabetes and other problems for which they are genetically at risk.
What is also very interesting in diabetes research are recent studies showing that the levels of various components of the blood change in diabetic patients well in advance of full-blown diabetes. Monitoring the levels of these during annual check-ups will become a useful tool for physicians, allowing the treatment of diabetes before significant injury occurs in patients. Furthermore, the lab work involved with such blood analysis could eventually be miniaturized and combined with an insulin pump (and with pumps for other diabetes drugs, including ones improving ZnT8 function) to create an artificial pancreas that can be implanted in diabetic patients. Provided that the associated technical and regulatory hurdles can be overcome, these devices should significantly improve the quality of life for recipients compared to patients with just an insulin pump.
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