Wasserman, David H., PhD
Cell signaling and nutrient flux in the liver of insulin resistant conscious mice
General Research Subject: Type 2 Diabetes
Focus: Exercise\Animal, Integrated Physiology\Liver, Signal Transduction (Non-Insulin Action)\Transgenic Models
Type of Grant: Mentor Based Minority Postdoctoral Fellowship
Project Start Date: January 1, 2010
Project End Date: December 31, 2013
Type 2 diabetes is devastating our health care system and compromising the quality of life for millions. Fat accumulation in the liver is a hallmark of Type 2 diabetes as it occurs early in the syndrome and is associated with its severity. Fat accumulation occurs because the ability of the liver to breakdown fat or export it is inadequate. Despite the central role of liver in diabetes the way it works in healthy people, what goes wrong in Type 2 diabetes, and ways to correct what has gone wrong in the diabetic liver are poorly understood. The purpose of the experiments is to define control of metabolism in normal and insulin resistant livers. Studies are based on the finding that, unlike most other tissues, the liver undergoes dramatic deviations in energy state. Energy state is defined as the ratio of the molecules, adenosine monophosphate to adenosine triphosphate. High energy is reflected by a low ratio and low energy is reflected by a high ratio. Physiological conditions like exercise and fasting decrease liver energy status, which may be due to high levels of the hormone, glucagon. The hypothesis tested is that changes in liver energy status coordinate liver metabolic pathways. Insulin resistant liver is characterized by decreased energy status. It is further hypothesized that the insulin resistant liver becomes insensitive to the effects of low energy state. Understanding liver function and its abnormalities in Type 2 diabetes will help identify therapeutic targets to restore liver function to normal.
Mentor: David H. Wasserman, PhD Postdoctoral Fellow: Li Kang, PhD
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
This project explores the pathogenesis of hepatic insulin resistance that occurs in Type 2 diabetes. Fat accumulation in the liver parallels hepatic insulin resistance. Hepatic fat accumulation is a hallmark of Type 2 diabetes as it occurs early in the syndrome and is associated with its severity. Fat accumulation occurs because the ability of the liver to breakdown fat or export it is inadequate. Despite the central role of liver in diabetes the way it works in healthy people, what goes wrong in Type 2 diabetes, and ways to correct what has gone wrong in the diabetic liver are poorly understood. The purpose of this project is to define control of hepatic intermediary metabolism in healthy livers and determine what goes wrong when the liver begins to accumulate fat and the liver becomes resistant to the actions of insulin. By identifying metabolic flux control reactions and signaling steps, we can develop novel strategies for prevention, treatment, and ultimately curing 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?
Fat accumulation in the liver is a hallmark of Type 2 diabetes as it occurs early in the syndrome and is associated with its severity. The accumulation of fat in the liver is a symptom of a defect in metabolism and has its own negative consequences related to insulin resistance. If we can understand why fat accumulates in the liver, we can devise therapeutic strategies to prevent it. If we can accomplish this, many of the other deleterious consequences of insulin resistance will be corrected.
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 dedicated my career to research in diabetes. I began my education with the humble objective of learning how physical exercise affects metabolism. The breakthrough for me came when I realized that exercise provides novel insights into metabolic defects in the person with diabetes. This realization gave my research added signficance by relating it to a very real public health problem. At a personal level it is about the people I know with diabetes. They are colleagues, friends, and relatives. Because of my interest in diabetes, many of my trainees have been people with diabetes wishing to understand their affliction. Diabetes is so much a part of my life that, even though I do not have the syndrome, I greatly empathize with those that are afflicted.
This award will allow my laboratory to accomplish the outstanding research in the proposal. At the same time it will help me to train one of the next generation of diabetes researchers. This award will support Dr. Li Kang. Dr. Kang has the tools to be a major contributor to our understanding of diabetes and is highly committed to a career in academic research.
In what direction do you see the future of diabetes research going?
People with diabetes have extensive extracellular matrix remodeling of insulin sensitive tissues. This important characteristic of the diabetic state has not been studied in detail. The extracellular matrix has a profound impact on endothelial cell function, muscle, liver, and pancreas. Future research will need to address the role of the extracellular matrix in insulin resistant tissue and in pancreas dysfunction. The development of novel animal models will be essential to this objective.
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