Domann, Frederick E., PhD
Aberrant metabolism perturbs epigenetic control during the development of type 2 diabetes
General Research Subject: Insulin Resistance Pre Diabetes
Focus: Genetics\Type 2 Diabetes, Integrated Physiology, Integrated Physiology\Insulin Resistance, Integrated Physiology\Muscle
Type of Grant: Innovation
Project Start Date: July 1, 2013
Project End Date: June 30, 2015
Diabetes Type: Type 2 diabetes
Type 2 diabetes (T2D) is characterized by loss of insulin sensing in peripheral cells and tissues that absorb blood glucose. Normally these tissues absorb glucose in response to insulin but during the development and progression of T2D the ability of these tissues to absorb glucose to keep it within normal limits is impaired. Neither the precise nature of the impairment nor its molecular mechanism(s) have been elucidated to date, however it is clear that diabetes is a disease of aberrant metabolism. Other diseases with altered metabolic parameters also show simultaneous and often mechanistically linked alterations in epigenetic control of gene expression. Epigenetic control mechanisms are likely perturbed by altered metabolism in individuals predisposed to T2D based on impaired glucose uptake or tolerance tests.
A recent study  measured the levels of several thousand metabolites in non-diabetic people at risk for getting T2D. This study found elevations of specific metabolites that were tightly associated with other established risk factors for getting type II diabetes. Based on the structures of these metabolites and the knowledge that a 4-carbon organic acid called butyrate is a potent inhibitor of the epigenetic process of "histone deacetylation", we propose that these metabolites act as novel competitive inhibitors of epigenetic enzymes that control gene expression in the insulin sensing or responding pathways. In this way, elevated systemic levels of abnormal pre-diabetic metabolites impinge on epigenetic control mechanisms in peripheral tissues that are responsible for glucose uptake to contribute to the development and progression of insulin resistant T2D.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
The research will focus on the role of abnormal accumulated metabolites in pre-diabetics on the activity of epigenetic writer enzymes, particularly histone modifying enzymes including histone deacetylases and demethylases. Understanding these effects may lead to novel pharmaceutical strategies to resume insulin sensitivity in type 2 diabetes.
If a person with diabetes were to ask you how your project will help them in the future,
how would you respond?
Our research is aimed at understanding the reasons underlying insulin resistance from a new perspective. Diabetic metabolism is altered in a way that inhibits expression of genes needed for efficient glucose uptake and we will study the mechanism of how these metabolites silence these genes and how these genes might be reactivated through a novel pharmaceutical strategy.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I have several friends and associates that are victims of diabetes; this is a disease whose long-term costs on human health can be ameliorated with existing and new knowledge. It is imperative to find alternative therapies for individuals stricken with diabetes.
In what direction do you see the future of diabetes research going?
It is widely known that diabetes is a metabolic condition, thus a deeper understanding of how this condition arises and contributes to the overall effects of insulin insensitivity will gradually make clear pathways of further intervention to increase the healthspan of diabetics.
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