Shoelson, Steven E., MD, PhD
Obesity-Induced Inflammation in Insulin Resistance, Type 2 Diabetes and Cardiovascular Disease
General Research Subject: Type 2 Diabetes
Focus: Integrated Physiology\Insulin Resistance
Type of Grant: Mentor Based Postdoctoral Fellowship
Project Start Date: July 1, 2008
Project End Date: June 30, 2012
Our studies attempt to determine why weight gain and obesity are unhealthy and promote diabetes and associated heart disease. We have found that inflammation, the body¡¦s normal response to infection, is also activated by weight gain and obesity, albeit to lesser degrees than is seen in acute infection. We have therefore realized that insulin resistance and type 2 diabetes have immunological underpinnings similar to those seen for type 1 diabetes. This discovery has provided us with multiple avenues of attack, both in basic science terms for better understanding and clinically to identify pharmacological routes for reversal. In one series of more basic studies we are identifying specific cell types that appear to either cause or prevent the onset of type 2 diabetes. Perhaps most importantly for patients with diabetes, we have useful, cheap and safe drugs that can be used today in patients with the disease to test whether ¡§anti-inflammatory¡¨ approaches can be used to treat or prevent diabetes and/or associated cardiovascular complications. In fact we are currently conducting large, phase 3 clinical trials in (1) patients with diabetes, and (2) patients with metabolic syndrome and cardiovascular disease. The mentored fellow will have numerous opportunities to conduct more basic, preclinical studies to test mechanism, and/or more clinical work by either assisting in the trials or using patient samples to ask specific questions about pathogenesis and pharmacology.
Mentor: Steven E. Shoelson Postdoctoral Fellow: Hagit Shapiro, MS, 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 studies are helping to define the molecular links between weight gain and inactivity and an increased risk for developing type 2 diabetes. Previous studies convincingly showed that obesity and fatty liver (fat accumulation in fat and liver cells, respectively) lead to what we refer to as inflammation in these tissues. This causes additional infection-fighting blood cells to join in and together all of these cells increase inflammation throughout the body by secreting cytokines (inflammatory hormones). We see evidence of this through the insulin resistance caused in multiple tissues, including muscle. We have hypothesized that obesity and sedentary lifestyle increase the risk for cardiovascular disease - a very common complication of diabetes - through a similar mechanism. The postdoctoral fellow funded by this award will help to determine how the inflammation associated with weight gain fat accumulation is initiated, how it impacts metabolism, and whether anti-inflammatory drugs have potential for reversing risk for type 2 diabetes and atherosclerosis in parallel.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond? The studies described above derived from an interesting and very old set of previous observations. Salicylates, a class of drugs that include aspirin, had been used intermittently as long ago as 1875 in the treatment of diabetes. We rediscovered this old literature and using modern approaches have identified an inflammatory pathway as the target of this effect. Our previous studies showed that activation of this pathway causes insulin resistance and diabetes; studies described in this research grant ask whether activation of this pathway also increases risk for heart attacks and stroke. Since salicylates represent a safe and inexpensive route for treating this form of inflammation, we also have the potential for both treating patients with diabetes and cardiovascular disease and preventing the development of these conditions in predisposed individuals. The postdoctoral fellow funded by this award will help test these questions in animals, and additional studies will look at the effects of salicylates in humans as treatments and preventions for diabetes and associated cardiovascular disease. It is possible that patients with diabetes could be taking these or related drugs in the not too distant future, providing the clinical trials continue to be positive.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts? My professional goal has been to understand the molecular underpinnings of diabetes and its complications, and to use this information to guide the development of better therapies. Studies in the lab including those funded by this award will help to ensure that these aspirations are fulfilled.
In what direction do you see the future of diabetes research going? I hope to see a continuing increase in translational research as we continue to improve our more basic understanding of the pathophysiology in type 2 diabetes and its complications. I hope that the ADA helps to sponsor an increasing amount of clinical research.
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