CANDIDATE: Career Background and Goals: The candidate for this career development award is a PhD-trained scientist who returned to medical school in order to move fully into clinical and translational research. Having completed clinical training in Medicine and Endocrinology, reinforced my basic research skills in an area of metabolic research, and trained in general clinical research skills, I am now seeking a final phase of career development funding to allow me to fill in specific gaps in the training that will allow me to transition to independence as a researcher in the field of cardiovascular disease in diabetes. I have had institutional NIH career development funding for the last three years, in addition to several pilot funding mechanisms and an Endocrine Society Clinical Scholars Lilly Award to fund my initial clinical research training. My ultimate career goal is to continue as a clinician scientist dedicated, through clinical practice and research, to advancing the treatment of metabolic disease and its devastating vascular consequences. With the studies proposed here, I hope to pave a novel path in the management of cardiovascular disease in type 1 diabetes, a metabolocentric approach that addresses insulin resistance in addition to standard glycemic control. As a clinician and a basic researcher, I am in a position to translate the understanding gained from these clinical studies both "to the bedside" and "back to the bench". Training plan: The purpose of this award is to allow me to fill in several methodological gaps that are essential for the pursuit of research in my area of interest while initiating studies that will provide preliminary data for a future R01 application. This training plan includes: (1) specific hands-on teaching by five highly qualified consulting mentors at the University of Colorado in performance of human subject fat and muscle tissue biopsies, measurement of vascular function and compliance, and in vitro and ex vivo measurement of insulin signaling and mitochondrial oxidative capacity, content, and oxidant generation;(2) attendance at a week long training workshop in respirometry offered by Oroboros, Inc, manufacturer of a widely used respirometry device;(3) Coursework through the Colorado Clinical Translational Sciences Institute (CCTSI) in Biostatistics, data management, research team management, and study design;(4) continued involvement with the CACTI study;(5) Volunteer service on the Colorado Institutional Review Board;(6) continued organizational role in the Metabolism and Nutrition interest group and the Exercise and Metabolism meetings to improve my visibility and networking opportunities within the university;and (7) attendance and research presentation at annual ADA and AHA meetings to enhance national networking. ENVIRONMENT: The University of Colorado Anschutz Medical Center provides an ideal environment for the pursuit of my immediate and long-term goals. The CCTSI provides education opportunities, as well as a pilot funding mechanism, an established and expert Clinical Research Center, and data base, biostatistics, and research design support. Groups active in metabolic research include my colleagues in the Division of Endocrinology, the CACTI study group of which I am a member, an active Nutrition and Obesity Research Center with recent funding to develop a Wellness Center focused on obesity and metabolism, an active research group focused on "Investigations in Metabolism, Aging, Gender, and Exercise, and a Cardiovascular Pulmonary Core with expertise and cell culture support for cardiovascular research. Other core facilities include a metabolomics, PCR, microscopy, cell sorting and proteomics cores. A P32 coil for in vivo mitochondrial measurements has recently been purchased by a close colleague and is available for my future use. RESEARCH: Resistance to insulin is an underappreciated and understudied component of type1 diabetes (T1D). Insulin resistance is clearly linked to cardiovascular disease in other populations, and this investigator and the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study have demonstrated that insulin resistance is also associated with cardiovascular disease in T1D. Existing cardiovascular disease risk prediction models that rely heavily on blood pressure and cholesterol profiles do not accurately predict cardiovascular disease events in T1D, suggesting that management of these standard cardiovascular disease risk factors may be inadequate in T1D. Thus, insulin resistance and its consequences in TID are compelling areas for further investigation. Treatment targeted at improving insulin resistance is standard of care for type 2 diabetes and has been shown to improve cardiovascular mortality independent of glucose control and standard cardiovascular risk factors. The effect of insulin sensitizers such as metformin in T1D, especially on measures of blood vessel function and stiffness, measures that correlate with cardiovascular disease risk and are improved by metformin treatment in type 2 diabetes and metabolic syndrome, is largely unstudied. The primary goal of this proposal is to measure the effect of metformin on vascular function and compliance and mitochondrial function in T1D. The long term goal is to identify novel non-glycemic approaches to managing cardiovascular disease risk in T1D. The results of this study may validate a novel approach to T1D treatment that could significantly improve current management of cardiovascular disease risk in this high risk population.
Although blood sugar control in type 1 diabetes has improved dramatically over the last decades, cardiovascular disease incidence has not, and cardiovascular disease remains the primary cause of early mortality in this population. Recent trials suggest that we are approaching the limits of our ability to safely control blood sugars in diabetes. The proposed study uses an intervention expected to increase insulin sensitivity to investigate the effect of insulin sensitization on blood vessel function and mitochondrial health in type 1 diabetes. The results of these studies may identify new methods of managing type 1 diabetes specifically intended to improve cardiovascular outcomes.