The candidate's previous research experience has focused on studying the basic physics and technological advances of medical imaging, particularly MRI physics. Due to the increasing prevalence of diabetes and afflictions in the own candidate's family, he has become interested in applying his technical skills to investigate the pathogenesis of type 2 diabetes mellitus (T2DM). The overall goal of this proposal is to expand the candidate's training and practical experience in areas of metabolic biology and clinical medicine to position him for a research career using imaging methods to study the processes involved in mitochondrial dysfunction in the setting of insulin resistance and diabetes. The focus of this training is described below. Insulin is an important regulator of glucose metabolism that affects liver, muscle and fat tissue by stimulating glucose uptake from blood and promoting its storage as glycogen in liver and muscle. Abnormally low uptake of glucose, when there are normal insulin levels, is a condition known as insulin resistance (IR). Increased insulin resistance in skeletal muscle is common in both lean and obese diabetic subjects. The increased glucose levels in diabetes lead to production of reactive oxygen species in mitochondria, which probably impairs the ability of mitochondria to produce adequate energy in insulin resistance. The action of insulin resistance in skeletal muscle metabolism is of intense interest in diabetes research and investigators are working on an overall theoretical framework to understand the processes. This type of computer modeling would benefit from intracellular metabolic data acquired directly from the tissues of livings subjects. Noninvasive imaging technologies can measure metabolic processes under a range of physiological conditions, allowing refinement of the models. These data would supplement information obtained from more invasive analyses from excised tissue samples, including transmission electron microscopy and bench top biochemical assays. Phosphorus-31 nuclear magnetic resonance spectroscopy can be used to demonstrate impaired metabolism in subjects with insulin resistance. However the methods used need to be calibrated and optimized to supply highly accurate information for physiological models. Also, positron emission tomography has been used extensively to measure glucose utilization and tissue blood flow in skeletal muscle. The overall goals of the proposed project are to develop these imaging methods to measure the concentrations of various chemicals in skeletal muscle that are important intermediaries of metabolism, measure the rate at which important reactions progress, measure muscle blood flow and measure glucose utilization rate, while the blood glucose level is being strictly controlled in order to develop and refine computer models of molecular and biochemical mechanisms that contribute to insulin resistance in the skeletal muscle of diabetic patients. It is hoped that these tools will lead to improved understanding of the onset of diabetes and allow development of therapies that can alleviate the insulin resistant condition associated with diabetes.
This research examines factors necessary for producing data on humans, noninvasively using magnetic resonance spectroscopic imaging (MRS) and positron emission tomography (PET). The information obtained will be used to evaluate mitochondrial function in patients with insulin resistance syndrome and diabetes. The project consists of a training regime that that is designed to increase the knowledge of contemporary biochemistry to a graduate level. This will be complemented by laboratory and clinical research training in the use of clinical measures of insulin resistance, PET imaging with oxygen-15-water and fluorine-18- deoxyglucose, assays of the metabolism of isolated mitochondria. The project includes a plan to develop, validate and employ both phosphorus-31 MRS imaging and PET imaging to evaluate the metabolic status of the mitochondria in patients and insulin resistant subjects in a minimally invasive manner.
