Makimura, Hideo , MD, PhD
The effects of short term acipimox treatment on skeletal muscle phosphocreatine recovery in obesity
General Research Subject: Insulin Resistance Pre Diabetes
Focus: Integrated Physiology\Fatty Acid Metabolism, Integrated Physiology\Insulin Resistance, Integrated Physiology\Muscle
Type of Grant: Clinical Translational Research
Project Start Date: January 1, 2012
Project End Date: December 31, 2014
We propose a new strategy to improve diabetes risk through improving your body's mitochondria. Mitochondria are the 'power house' of the cell and make energy for your body. Obesity is associated with increased risk for developing diabetes. However, we do not know how obesity leads to diabetes. Previous studies have shown levels of fat in the blood (FFA) are higher in obesity, and elevated FFA can affect how our body uses glucose and responds to insulin. Recent studies have shown that changes in mitochondria may be involved in the development of diabetes and may be affected by FFA. We propose to improve the function of mitochondria in obese people with pre-diabetes by treating with acipimox, a medication which decreases FFA. We will use state of the art techniques to evaluate the mitochondria, including a new magnetic resonance imaging (MRI) technique to measure function of mitochondria in muscle before and after treatment, and support our findings with physiology, microscopy and genetic techniques. We will evaluate clinically meaningful end-points such as glucose, insulin, cholesterol and FFA as well as end-points that inform us of how the mitochondria may be involved in diabetes. We believe that decreasing the levels of fat in the blood will improve the mitochondria's ability to metabolize glucose and fat which may ultimately decrease the risk of developing diabetes mellitus. This is a new study which has never been performed before and may be crucial in understanding how obesity leads to the development of diabetes."
What area of diabetes researcvh does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Our research project is in the field of obesity and insulin resistance, both of which are major risk factors for the development of Type 2 diabetes. Through this project, we hope to better understand the relationship between obesity and increased diabetes risk and the role played by the mitochondria -- the organelle involved in energy production in the body. This project utilizes comprehensive state of the art techniques to evaluate the mitochondria and is the first study to evaluate a strategy to improve the function of the mitochondria by decreasing free fatty acids (FFA; fat in the blood stream). By demonstrating an improvement in diabetes risk through reduction of FFA and improvement in mitochondrial function, this project may lead to the development of a completely new strategy to prevent and treat diabetes related to obesity in the future.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Our research study may lead to new therapies for people who are overweight and at risk for diabetes. This study aims to 1) understand the role that mitochondria, the energy producers in our body, play in increasing your risk for diabetes; and 2) evaluate whether a drug called acipimox can help improve insulin resistance through improvement in mitochondrial function. Ultimately, if successful, this study can lead to a new strategy and a new class of medications to treat diabetes, through improvement in mitochondrial function.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
As an endocrinologist, I am faced with the rising prevalence of obesity and its associated metabolic disorders such as diabetes on a daily basis. As diabetes remains a significant risk factor for heart disease and a leading cause for blindness, kidney disease and amputations in adults in the US, clearly, interventions to improve the risk for diabetes are necessary. Based on my background in basic science research in the field of metabolism and my recent work in clinical research, I believe I have the necessary training to lead a translational, multi-disciplinary research team needed to conduct detailed physiological studies as proposed here. This award is central to our research efforts to help us understand how obesity increases the risk for diabetes and whether interventions to lower FFA improve mitochondrial function. Without this award, detailed, comprehensive studies involving multiple state of the art techniques such as used here, could not be conducted, and efforts to study new treatment strategies for diabetes risk may be delayed significantly, in a time when great advances are needed.
In what direction do you see the future of diabetes research going?
I believe a greater focus on translating the various positive findings from basic and animal research into clinically useful medications and treatment strategies for humans will be necessary in the future. Over the last several decades, we have made tremendous advances in the understanding of basic biology of metabolism and weight regulation and metabolic disorders including diabetes. These findings have led to several promising avenues of research in animal models. However, these findings have not necessarily translated to new treatments for obesity and diabetes in humans. I believe a greater focus on detailed human physiology studies to better understand the human body and its responses to different novel medications, such as proposed here, will be necessary to help identify and develop promising targets for the treatment of obesity and diabetes.
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