Bruemmer, Dennis C., MD
Telomere Attrition in Adipose Tissue Senescence and Insulin Resistance
General Research Subject: Type 2 Diabetes
Focus: Integrated Physiology\Insulin Resistance, Obesity\Animal Models, Adipocytes
Type of Grant: Career Development
Project Start Date: January 1, 2009
Project End Date: December 31, 2013
Aging is a major predisposing factor for the development of insulin resistance and type 2 diabetes. One of the best-characterized mechanisms believed to be responsible for aging is the shortening of telomeres. These structures serve as protective capping of the chromosomes and prevent the loss of vital genetic information, which is needed to sustain a cell's activities. Recent epidemiological studies have observed that people with type 2 diabetes have shorter telomeres than healthy people. However, whether the shortening of telomeres associated with human aging is actually a cause of insulin resistance or merely a marker remains unknown. In our preliminary studies we have investigated this relationship and observed that telomere shortening in genetically modified mice results in the development of insulin resistance. Considering these findings, we hypothesize in the current proposal that progressive telomere shortening constitutes an underlying mechanism for the association between type 2 diabetes and aging. In order to test this hypothesis we will undertake a series of studies to characterize glucose metabolism in mice with normal telomere length and in mice with genetically shortened telomere length. We anticipate that these studies may ultimately contribute to our understanding of this prevalent disease and potentially allow us to intervene by remodeling telomere length in humans.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Obesity and aging are two major predisposing factors for insulin resistance and type 2 diabetes. While we are beginning to understand the link between obesity and type 2 diabetes, less is currently known about the mechanisms by which aging contributes the development of type 2 diabetes. One of the most postulated hypotheses thought to be responsible for aging is the telomere hypothesis, which predicts that a causal link exists between the shortening of telomeres and aging. Telomeres are a region at the end of chromosomes, which cap and protect the end of the chromosome from destruction during a lifespan. Loss of telomere function during aging will ultimately alter the function of the cell and limit the regeneration of tissues during the aging process.
Although aging is associated with the development of insulin resistance and type 2 diabetes, it remains unknown whether age-related shortening of telomeres causally contributes to insulin resistance. In this particular project we will use genetic manipulation of telomere length to test whether telomere shortening in different tissues alters glucose metabolism and induces insulin resistance. We anticipate that these studies will contribute to our understanding of the mechanisms underlying age-related insulin resistance. Ultimately, these experiments may potentially provide new therapeutic avenues to prevent the age-related development of insulin resistance by remodeling telomere length in humans.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
The main goal of this application is to identify the mechanisms responsible for the association between aging and insulin resistance/type 2 diabetes. Due to the demographic shift, the largest increases in the prevalence of diabetes are expected among adults aged >75 years. Research over the last decade has already established that aging is associated with the development of insulin resistance and constitutes an independent risk factor for the future development of type 2 diabetes. Therefore, it is of considerable importance to identify the molecular mechanisms that underlie age-induced insulin resistance and the altered renewal capacity of insulin sensitive tissues. Should our studies confirm that telomere shortening associated with organismal aging is a key mechanism responsible for the decline in insulin sensitivity during aging, one could envision several novel therapeutic approaches, including pharmacologic prevention of telomere shortening or stem cell based therapies.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
As a physician and scientist, both my clinical work and my basic research are focused on the prevention and treatment of diabetes and associated cardiovascular diseases. Today the number of people with diabetes has reached epidemic proportions and the largest increases in diabetes are expected among adults aged >75 years, from 1.2 million women and 0.8 million men in 2000 to 4.4 million women and 4.2 million men in 2050. Overall, the world-wide change in demographics is predicated to result in an estimated 60 % increase in the prevalence of diabetes affecting at least over 300 million people by the year 2025. An estimated 65% of these patients with diabetes will ultimately die from cardiovascular causes. Based on this evidence, it should be a priority to understand the molecular mechanisms leading to insulin resistance and the subsequent development of type 2 diabetes. This Career Development Award from the American Diabetes Association will allow us to perform research in this area and to enhance our understanding of the mechanisms linking aging and type 2 diabetes. Using these funds, we will, hopefully, be able to add new pieces to puzzle and contribute to the understanding of the molecular basis of insulin resistance.
In what direction do you see the future of diabetes research going?
Over the last two decades enormous progress has been made in understanding type 2 diabetes and its role as a key risk factor for cardiovascular disease, including myocardial infarction and stroke. The future of biomedical diabetes research will continue to broaden our understanding of diabetes as a risk factor for vascular complications but probably focus more on the prevention of diabetes. Therefore, it will be important to primarily prevent the development of insulin resistance as the earliest form of the disease to ultimately avoid the associated vascular complications. Research addressing these questions will characterize new pathways leading to insulin resistance, identify novel targets for pharmacological approaches, and ultimately provide novel concepts for the prevention and treatment of type 2 diabetes.
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