CAREER: Autonomic Function in Insulin Resistance and Diabetes

DESCRIPTION (provided by applicant): This proposal describes a 3-year mentored training program during which the candidate will substantially enhance her knowledge in cardiovascular and endocrine function, acquire additional skills in the clinical assessment of cardiovascular autonomic function, and increase her experience designing and conducting a population-based study. While the candidate has formal training in cardiovascular disease epidemiology, she has no training or experience in the above referenced areas that are critical for success in her area of research. Dr. Philip Greenland, a clinician and epidemiologist who Chairs the Department of Preventive Medicine (DPM), will oversee the scientific and career development aspects of the candidate as described in this proposal as the primary mentor. In addition, Dr. Alan Kadish in the Division of Cardiology, will oversee the candidate's training in cardiovascular electrophysiology and in the assessment of autonomic tone, and Dr. Kiang Liu, a biostatistician/epidemiologist will mentor the candidate in the design and recruitment aspects of the proposed population-based study. Research in this proposal will focus on the temporal association between the autonomic nervous system (ANS) and the development of diabetes and cardiovascular complications from diabetes. Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in persons with diabetes, and the ANS has been proposed as a mechanism to explain the association between diabetes and CVD. ANS dysfunction was previously thought to be a late-onset complication of diabetes that was the result of hyperglycemia-associated degradation of the microvasculature. However, evidence that the ANS plays a role in the regulation of glucose and fat metabolism, even in the absence of frank diabetes, makes it plausible that ANS dysfunction occurs early in the temporal sequence for disease. This study proposes to extend beyond previous epidemiological research that has identified the presence of ANS dysfunction in early diabetes, by assessing the type and extent of impairment using tools that have traditionally been used only at the clinical level. The PI hypothesizes that ANS function, as estimated by autonomic innervations, resting autonomic tone, and the autonomic response to physical and pharmacological provocation, predisposes persons to the development of diabetes and diabetes complications, including CVD, when impaired. Specific aims are to: 1) investigate the temporal sequence between ANS dysfunction and the development of diabetes in two established epidemiology studies using available measurements; 2) learn to implement and compare a comprehensive battery of ANS function tests; and, 3) recruit a population sample to compare the cross-sectional relationship between this battery of ANS function tests among healthy persons, persons who are insulin resistant but not diabetic, and persons who are diabetic. Data from these investigations will be used to modify hypotheses and develop a future prospective examination focused on the type and temporal sequence of autonomic impairment in persons with varying levels of insulin resistance, glucose uptake and metabolism.