Katsanos, Christos , PhD
Regulation of the plasma triglyceride extraction in muscle in insulin resistance
General Research Subject: Insulin Resistance Pre Diabetes
Focus: Insulin Action, Insulin Action\Insulin Resistance, Integrated Physiology\Insulin Resistance, Nutrition-Clinical
Type of Grant: Clinical Translational Research
Project Start Date: July 1, 2012
Project End Date: June 30, 2015
Obesity has reached epidemic proportions in our society. Obesity results in accumulation of fat not only in adipose tissue, but also in muscle. It is this increased accumulation of fat into sites such as muscle, which do not have a primarily role for fat storage, that lead to abnormal glucose metabolism and increase the risk for the development of Type 2 diabetes. Ingested fat is transported in the blood in the form of triglycerides, whose removal by the muscle is increased in obese compared to healthy individuals, and in parallel with an increase in the uptake of the ingested fat into the muscle.
This research is designed to determine the role of the distribution of the blood flow within the microvesseles in muscle in the disposal of circulating triglycerides into the muscle. The research is focused on the response to insulin, because the physiological response to this hormone is to increase the blood flow distributed into the muscle microvessels, and this response is impaired in obese subjects. Identifying the mechanisms that are responsible for abnormal removal and increased disposal of circulating lipid into muscle in obesity is important in order to develop appropriate interventions to reduce and normalize the disposal of fat into muscle, thus preventing the development of Type 2 diabetes.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
The project investigates fat metabolism in the pre-diabetic state, which is typically a prelude to Type 2 Diabetes, and which is generally known as the “insulin-resistant” state.
Increased accumulation of fat in muscles impairs the activation of muscle molecular pathways that are implicated in the uptake of blood glucose by the muscle, which is quantitatively the most important tissue responsible for the uptake of blood glucose, ultimately leading to Type 2 diabetes. The mechanism(s) that contribute to the increased accumulation of fat in skeletal muscle in the pre-diabetic/insulin-resistant state are not understood.
This project investigates mechanisms that contribute to disposal of blood lipids into the muscle in an effort to explain the increased accumulation of fat in the skeletal muscle in the pre-diabetic/insulin-resistant state, and with an emphasis in a circumstance that such blood lipids are elevated as in the postprandial/fed state. The proposed studies are specifically focused on the regulation of the blood flow by blood insulin through the smallest of the muscle blood vessels, called capillaries, as a mechanism regulating the disposal of blood lipids into the muscle.
Findings from this project will lead to an understanding of physiological mechanisms involved in lipid delivery from blood into the muscle, and provide evidence with important clinical implications for developing interventions towards preventing excessive uptake of blood lipids by the muscle of insulin-resistant individuals, thus preventing 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?
We know that during the period that follows meal ingestion there is increased uptake of dietary (i.e. ingested) fat into muscles in both pre-diabetic persons as well as persons with Type 2 diabetes when compared to healthy persons. This response contributes to fat accumulation in the muscle of persons in the pre-diabetic state or with established diabetes and impairs the overall uptake of blood glucose into the muscles.
By knowing the mechanisms that are responsible for the increased uptake of dietary fat into the muscles of pre-diabetic persons, which are the persons that this project is specifically focused on, clinicians will be able to utilize specific and targeted interventions to either reverse the pre-diabetic state, or prevent or slow down its progression to Type 2 diabetes.
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 son whose farther recently diagnosed with Type 2 Diabetes, I am particularly interested in diabetes research. I am specifically interested in the physiological/pathophysiological mechanisms that contribute to the progression of the metabolic environment towards Type 2 Diabetes, and the extent to which these mechanisms can be either reversed or slowed down, and in a way that prevents or at least delays the onset of Type 2 Diabetes.
This award will allow us to investigate specific mechanisms for which we already have preliminary evidence from our laboratory that are responsible for regulating the disposal of blood fat into the muscle, a tissue that, as opposed to adipose tissue, is not specifically designed for excessive fat accumulation/storage. By extending these findings and providing well-documented relevant evidence, and given that it is already known that excessive fat accumulation in muscle contributes to impaired blood glucose metabolism, we will be able to then test specific interventions related to nutrition and exercise to benefit individuals that are in the pre-diabetic state by preventing excessive fat accumulation in their muscles. Our ultimate goal is to test and develop successful interventions to improve nutrient metabolism in individuals at risk for developing Type 2 Diabetes. Such interventions will have direct implications in the lives of these individuals. This award will provide the overall foundation for this line of research in our laboratory.
In what direction do you see the future of diabetes research going?
I believe that in the future there will be more emphasis placed towards efforts to prevent Type 2 Diabetes. I also believe that, with time, more research efforts will focus on the pre-diabetic state (i.e., insulin-resistant state) as accumulated evidence suggests that in the pre-diabetic state (i.e., even in the absence of established Type 2 Diabetes) there is an overall increased risk for diseases, such as cardiovascular disease.
Given the increased health care costs, I think that more effort will soon be placed in educating individuals at risk for developing pre-diabetes/Type 2 Diabetes in lifestyle approaches, such as nutrition and exercise, for the incorporation of such approaches in the everyday life of these individuals. With respect to that, research efforts will also need to provide evidence for lifestyle approaches that are cost effective, less time consuming, and feasible, as well as educational approaches that are successful.
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