Autonomic Function in Insulin Resistance and Diabetes

描述（由申请人提供）： 该提案描述了一个为期3年的指导培训计划，在此期间，候选人将大大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临床评估方面的额外技能，并增加她设计和开展基于人群的研究的经验。 虽然候选人在心血管疾病流行病学方面接受过正式培训，但她在上述领域没有培训或经验，这些领域对于她的研究领域的成功至关重要。 菲利普格陵兰，临床医生和流行病学家谁主持预防医学系（CDC），将监督候选人的科学和职业发展方面，如本提案中所述的主要导师。此外，心脏病科的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Kiang Liu博士将指导候选人进行拟议的基于人群的研究的设计和招募方面的培训。 这项提案中的研究将集中在自主神经系统（ANS）与糖尿病和糖尿病心血管并发症的发展之间的时间关联上。 心血管疾病（CVD）是糖尿病患者发病和死亡的主要原因，ANS已被提出作为解释糖尿病和CVD之间关联的机制。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系统降解的结果。然而，有证据表明，即使在没有明显糖尿病的情况下，ANS也在葡萄糖和脂肪代谢的调节中发挥作用，这使得ANS功能障碍在疾病的时间序列中早期发生似乎是合理的。 这项研究建议扩展到以前的流行病学研究，已经确定了早期糖尿病中ANS功能障碍的存在，通过使用传统上仅在临床水平使用的工具评估损伤的类型和程度。 PI假设ANS功能（通过自主神经支配、静息自主神经张力以及对物理和药物激发的自主神经反应进行评估）在受损时易使患者发生糖尿病和糖尿病并发症（包括CVD）。具体目标是：1）在两项已建立的流行病学研究中使用可用的测量方法调查ANS功能障碍和糖尿病发展之间的时间顺序; 2）学习实施和比较全面的ANS功能测试;和3）招募人群样本以比较健康人、胰岛素抵抗但非糖尿病的人和糖尿病患者。 从这些调查的数据将被用来修改假设，并制定一个未来的前瞻性检查集中在类型和时间顺序的自主神经功能障碍的人与不同水平的胰岛素抵抗，葡萄糖摄取和代谢。

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.