Mesolimbic Contributions to Autonomic Dysregulation in Insulin Resistance

描述（由申请人提供）：2型糖尿病是美国的一种公共卫生流行病，困扰着2000多万美国人。它是一种复杂的疾病，对包括中枢和自主神经系统在内的许多器官系统具有病理影响。胰岛素抵抗是2型糖尿病的前兆，其特征是对胰岛素的敏感性降低。大脑中对胰岛素敏感的一个关键网络是中脑边缘系统。该网络还在自主功能的控制中发挥作用。了解在胰岛素抵抗中中脑边缘系统的活动是如何改变的，将有助于我们了解胰岛素抵抗导致自主神经失调的途径。本研究将招募11名胰岛素抵抗患者和11名胰岛素敏感性正常的患者。将通过提供空腹血液样本筛选受试者，从中计算HOMA-IR值。符合条件的参与者将完成四次临床访视：（1）初始筛选访视，（2）2小时口服葡萄糖耐量试验，（3）空腹状态下的fMRI扫描，（4）摄入混合餐前负荷后的fMRI扫描。功能磁共振成像扫描将包括一个味觉奖励任务，旨在唤起中脑边缘系统的活动。本研究的目的是确定在胰岛素抵抗中发生的中脑边缘系统的功能改变，并可能解释自主活动的失调。心率变异性是心脏自主调节的标志，将在扫描仪中记录，并与休息时大脑活动的变化进行比较。申请人将接受糖尿病病理生理学的培训，获得功能神经成像方面的专业知识，并进一步研究自主神经功能的中央控制。培训将包括课程作业、与导师和顾问举行会议、出席国家会议和地方座谈会。申请人还将获得招募参与者，收集 数据和撰写科学论文。这项研究将通过整合中枢神经系统在通常伴随2型糖尿病的自主神经系统病理学中的作用来告知和影响糖尿病文献。通过使用受试者内设计，研究的可行性大大增加，使得较小的参与者样本可以产生更可靠的数据。更全面地了解胰岛素抵抗与自主神经失调之间的联系机制，有望指导预防策略的发展，以减缓从胰岛素抵抗到2型糖尿病的进展。 公共卫生相关性：胰岛素抵抗是2型糖尿病的前兆，并改变自主神经系统的活动。大脑的中边缘系统对胰岛素敏感，并参与自主神经功能的控制。这项拟议中的研究将比较有和没有胰岛素抵抗的人之间的中脑边缘系统和自主神经活动。这项研究将有助于了解胰岛素抵抗导致2型糖尿病并发症的途径。

DESCRIPTION (provided by applicant): Type 2 diabetes is a public health epidemic in the United States, afflicting more than 20 million Americans. It is a complex disease with pathologic effects on numerous organ systems including central and autonomic nervous systems. Insulin resistance is a precursor to type 2 diabetes and is marked by a reduced sensitivity to insulin. A key network of the brain that is sensitive to insulin is the mesolimbic system. This network also plays a role in the control of autonomic function. Understanding how mesolimbic activity is altered in insulin resistance will help us understand pathways by which insulin resistance leads to autonomic dysregulation. The present study will recruit 11 individuals with insulin resistance and 11 individuals with normal insulin sensitivity. Participants will be screened by providing a fasting blood sample from which HOMA-IR values will be calculated. Qualifying participants will complete four clinical visits: (1) An initial screening visit, (2) A 2-hour oral glucose tolerance est, (3) An fMRI scan while in a fasting state, (4) An fMRI scan after consuming a mixed-meal preload. The fMRI scan will include a taste-reward task designed to evoke activity in the mesolimbic system. The goal of the present proposal is to identify functional alterations the mesolimbic system that occur in insulin resistance and may explain dysregulation in autonomic activity. Heart rate variability, a marker of autonomic regulation of the heart, will be recorded i the scanner and compared across days in conjunction with changes in resting brain activity. The applicant will receive training in the pathophysiology of diabetes, gain expertise in functional neuroimaging, and further study the central control of autonomic functioning. Training will include coursework, meetings with mentors and consultants, attendance of national conferences and local colloquia. The applicant will also gain experience in recruiting participants, collecting data, and writing scientific papers. This research will inform and influence the diabetes literatur by integrating the role of the central nervous system in the pathology of the autonomic nervous system that often accompanies type 2 diabetes. By using a within-subject design, the feasibility of the study is greatly increased such that a smaller participant sample can yield more reliable data. A more comprehensive understanding of the mechanisms that link insulin resistance to autonomic dysregulation, promises to guide the development of preventative strategies for slowing the progression from insulin resistance to type 2 diabetes. PUBLIC HEALTH RELEVANCE: Insulin resistance is a precursor to type 2 diabetes and alters the activity of the autonomic nervous system. The mesolimbic system of the brain is sensitive to insulin and is involved in the control of autonomic function. The proposed study will compare mesolimbic and autonomic activity between people with and without insulin resistance. This research will help understand pathways through which insulin resistance leads to complications of type 2 diabetes.