Autonomic Function in Insulin Resistance and Diabetes

描述(由申请人提供)： 这份提案描述了一项为期3年的指导培训计划，在此期间，候选人将大幅提高她在心血管和内分泌功能方面的知识，获得心血管自主神经功能的临床评估方面的额外技能，并增加她设计和实施基于人群的研究的经验。虽然应聘者在心血管疾病流行病学方面接受过正式培训，但她在上述对她的研究领域的成功至关重要的参考领域没有培训或经验。预防医学部(DPM)主席、临床医生和流行病学家菲利普·格陵兰博士将监督候选人的科学和职业发展方面，正如本提案中所描述的那样，他是主要导师。此外，心脏科的Alan Kadish博士将监督候选人在心血管电生理学和自主神经张力评估方面的培训，生物统计学家/流行病学家刘江博士将指导候选人在拟议的基于人群的研究的设计和招募方面的工作。这项建议的研究将集中在自主神经系统(ANS)和糖尿病的发展以及糖尿病引起的心血管并发症之间的时间关联。心血管疾病(CVD)是糖尿病患者发病和死亡的主要原因，ANS被认为是解释糖尿病和CVD之间关系的一种机制。ANS功能障碍以前被认为是糖尿病的迟发性并发症，是高血糖相关的微血管退化的结果。然而，有证据表明ANS在糖和脂肪代谢的调节中发挥作用，即使在没有坦率的糖尿病的情况下也是如此，这使得ANS功能障碍发生在疾病的时间序列的早期是可信的。这项研究建议超越以前的流行病学研究，通过使用传统上仅在临床水平使用的工具来评估损害的类型和程度，从而确定早期糖尿病存在ANS功能障碍。PI假设ANS的功能，根据自主神经支配、静息自主神经张力以及对物理和药物刺激的自主神经反应，在受损时易患糖尿病和糖尿病并发症，包括心血管疾病。具体目的是：1)使用现有的测量方法，在两项既定的流行病学研究中调查ANS功能障碍和糖尿病发展之间的时间序列；2)学习实施和比较一套全面的ANS功能测试；以及3)招募人群样本，比较这组ANS功能测试在健康人、胰岛素抵抗但非糖尿病患者和糖尿病患者之间的横截面关系。这些研究的数据将被用来修改假设，并开发未来的前瞻性检查，重点是胰岛素抵抗、葡萄糖摄取和新陈代谢水平不同的人自主神经损伤的类型和时间序列。

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.