Attie, Alan D.
Genes and Pathways Leading to Type 2 Diabetes
General Research Subject: Type 2 Diabetes
Focus: Genetics\Type 2 Diabetes, Integrated Physiology\Insulin Secretion and Islet Hormones, Islet Biology\Hormone Secretion and Exocytosis
Type of Grant: Mentor Based Postdoctoral Fellowship
Project Start Date: July 1, 2011
Project End Date: June 30, 2015
Although most people who are afflicted with type 2 diabetes are obese, most obese people do not develop diabetes. The laboratory of Alan Attie has reproduced this dichotomy in mice by studying two mouse strains that when made obese, differ in diabetes susceptibility. The objective of this work is to identify the genes and pathways responsible for the difference in diabetes susceptibility of the two mouse strains. The premise for this work is that the same genes or the same pathways might be involved in human diabetes. The Attie laboratory also uses other methods for finding genes related to diabetes. These methods exploit technology that can comprehensively assess the level at which virtually any gene in the genome is being expressed. By taking advantage of the genetic model system, the laboratory is finding genetically controlled networks of genes that are coordinately dysregulated in tissues that play a key role in diabetes progression. The lab has made great progress in the past several years and now has a collection of genes that are highly relevant to diabetes and diabetes related physiology. There is a good likelihood that some of the genes or pathways identified in these studies can be targeted with new therapeutic agents to prevent or ameliorate diabetes. Indeed, several of them are currently being screened for small molecule inhibitors that can eventually lead to drug development.
Mentor: Attie, Alan Ph.D. Postdoctoral Fellow: Wang, Chen-Yu
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Our project covers the genetics of obesity-induced type 2 diabetes. Although most people with type 2 diabetes are obese, most obese people are not diabetic. We seek to discover the genetic factors that distinguish diabetes-prone from diabetes-resistant individuals. Our work has identified several new genes that affect diabetes susceptibility. In addition, we have identified gene loci that affect a common pathological feature of diabetes, hepatic steatosis (fatty liver). We have also found a gene that affects glucose tolerance and kidney function. A major effort in our laboratory is devoted understanding what regulates the ability of pancreatic -cells to proliferate in response to insulin resistance.
Role in preventing treating and/or curing diabetes
1. Better definition of diabetes
Our current definition of diabetes, hyperglycemia and/or glucose intolerance beyond a particular threshold, fails to reflect the fact that it is a highly heterogeneous disease. By identifying genes and pathways that, when dysregulated, can lead to diabetes, we might develop diagnostic tools to better sub-divide diabetic patients and thus predict what kinds of treatments are likely to be most successful.
2. Novel pathways for therapeutic targeting
Some of the genes we have identified can be targeted by small molecule therapeutics. By sharing our results with pharmaceutical companies, we hope to develop new anti-diabetes drugs.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Our own work has generated several exciting leads and we are in communication with several pharmaceutical companies to see if they might be developed as drug discovery projects.
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 is diabetic and asks me this question literally every week. The painful answer is that translation of basic research into cures takes a long time. But, it is important to emphasize that pharmaceutical companies do very little basic research and that many of the most important clues that can lead to cures do not necessarily come from targeted research or research initially thought to be relevant to the disease. For example, much prior work on the enzymology proteases preceded and enabled the very successful work leading to the development of Sitagliptin and other DPP4 inhibitors.
In what direction do you see the future of diabetes research going?
This field is extremely fascinating and rewarding. It covers almost
every area of biology and thus forces us to be well-rounded scientists.
It is rewarding because of its tremendous implications for human health
I see that the combination vast amounts of new information and insights, combined with great improvements in technology will accelerate the pace of discovery. I believe we will soon develop a more nuanced definition of diabetes in terms of sub-categories. In turn, I hope this focuses the therapeutic goals further. I see improvements in the various '-omics' technologies and believe those will provide many new insights and windows into novel pathways that lead to diabetes.
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