Kahn, C. Ronald , MD
Pathogenesis of obesity and type 2 diabetes and their relationship to insulin resistance
General Research Subject: Obesity
Focus: Insulin Action\Insulin Resistance, Integrated Physiology\Insulin Resistance, Adipocytes
Type of Grant: Mentor Based Postdoctoral Fellowship
Project Start Date: July 1, 2009
Project End Date: June 30, 2013
This is a renewal of my ADA Mentor Award which focuses on the pathogenesis of obesity and type 2 diabetes and their relationship to insulin resistance. Currently my laboratory focuses in two major areas of research which form the basis of these problems: 1) the nature of insulin signaling systems and its defects in type 2 diabetes, and 2) what goes wrong in fat that makes obesity predispose to insulin resistance and type 2 diabetes. In each of these areas we employ the full range of techniques from basic cellular studies to the creation of genetic knockouts mice. We have defined many of the fundamental steps in insulin action, including the nature of signaling by the insulin receptor and its substrates, and the intracellular enzymes that are involved in insulin action.
Using the gene knockout mice, we have defined the role of each of these proteins and each tissue in control of glucose and lipid metabolism. This has led to many surprising discoveries about the role of insulin resistance in tissues such as liver, muscle, fat and brain. More recently, we have focused on understanding the relationship between obesity and insulin resistance and why adipose tissue in different depots exerts different risk of diabetes and metabolic disease. We have identified a potentially important role for fundamental developmental genes in this process. Some of these genes are is differently expressed between intra-abdominal and subcutaneous depots and highly correlated with the level of obesity and the fat distribution.
Mentor: Ronald Kahn, MD Postdoctoral Fellow: Kevin Lee, PhD
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Obesity is an increasing health problem in many countries and is closely associated with insulin resistance and Type 2 diabetes mellitus. However, the topography distribution of fat in the body seems to play a major role in the risk of these disorders. Individuals with peripheral obesity (i.e. subcutaneous fat around the gluteofemoral region and in the lower part of the abdomen) are at little or no risk of the common medical complications of obesity, whereas individuals with upper-body (central) obesity (i.e. fat accumulation in visceral or intra-abdominal depots) are prone to metabolic and cardiovascular complications. This differential risk suggests an important heterogeneity of these different depots with respect to their metabolic function.
One question raise from these observations are the inter-depot variations the result of extrinsic influences (like hormonal and paracrine microenvironment, local nutrient availability, innervation, and anatomic constraints) or from intrinsic properties of adipocytes? Previous work form our lab suggest that the latter may be the case as pre-adipocytes or adipocytes maintain unique gene expression profiles ex-vivo when placed in the same environment. In particular, we have shown that several developmentally important genes are differentially expressed between visceral and subcutaneous fat depots. However, the role of these developmentally important genes in adipose tissue biology has yet to be elucidated.
The goal of this project is to elucidate the role of these developmental genes in adipose tissue biology. This goal will be reached in vivo by ablating these factors specifically in adipocytes of mice. Additionally, the function of these factors can be elucidated using in vitro cellular models under controlled conditions. This project will provide information about the molecular basis of subcutaneous and visceral adipose differences in regard to their influence on pathologies associated to obesity. This comparison might also reveal potential therapeutic targets for the treatment of diabetes.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Obesity is a is an increasing worldwide problem that is closely associated with many detrimental health conditions including cardiovascular disease and Type 2 diabetes. However, not all 'types' of obesity are the same. 'Apple' shaped obesity/overweight (internal/visceral body fat accumulation) present a higher risk for Type 2 diabetes and cardiovascular disease than 'pear' shaped (subcutaneous body fat accumulation). These effects are not due to the anatomical location of the fat, but, instead, to intrinsic differences between the fat cells of the visceral cavity versus those located subcutaneously. Currently we are working on which genes that are differently expressed between the two kinds of fat. Understanding this difference will help us to understand causes of Type 2 diabetes related to obesity/overweight. It will also reveal potential therapeutic targets for the treatment of diabetes.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
About 8 percent of people in the United States have diabetes. The high prevalence of this disease has clearly reached pandemic proportions in the United States and abroad. Almost every single researcher in diabetes field is linked to a diabetic person at a personal level. Personally, several members of my family, including my father and grandmother, have been diagnosed with Type 2 diabetes. This is an extremely important and personal reason for my decision to switch fields after graduate school and start research in diabetes. I decided to perform my postdoctoral training at the Joslin Diabetes Center under Dr. Kahn's supervision to acquire skills and knowledge to study diabetes on a molecular and cellular level. This ADA award will be particularly useful since it will allow me to further my project on the molecular differences between adipose tissue depots.
In what direction do you see the future of diabetes research going?
Diabetes is a very complex disease, resulting from the interplay of both genetic and environmental factors. This diversity of the critical factors triggering the development of the disease makes the development of therapeutic agents very difficult. The development of new powerful technologies such as genetic engineering of mice, genomics, proteomics and advanced cell biological techniques will likely help to unravel the molecular basis of insulin action, insulin delivery and the metabolic disorders associated with diabetes. This will ultimately lead to a better ability to diagnose the disease at earlier stages, to understand its pathogenesis and to help to prevent, treat or cure diabetes.
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