Investigating the polyol pathway in the human brain

 描述（由申请人提供）：2型糖尿病（T2DM）在年轻和老年人群中的患病率不断上升，导致T2DM的终生暴露增加。越来越多的证据表明，慢性高血糖和T2DM会对脑功能产生许多不良影响，特别是神经血管疾病和认知障碍。然而，这些关联背后的潜在机制仍不清楚。本申请的目的是评价多元醇途径作为高血糖症CNS效应的潜在介体的作用。多元醇途径（葡萄糖→山梨糖醇→果糖）是一种替代葡萄糖途径，存在于整个人体，包括大脑。除了果糖的生成，多元醇途径活性也与氧化应激增加有关，并与糖尿病并发症有关，包括糖尿病视网膜病变、神经病变和心血管疾病。然而，这条通路在大脑中的作用仍不清楚。该K23应用将通过使用核磁共振波谱（MRS）研究多元醇途径在介导高血糖症的中枢神经系统效应中的潜在作用，该波谱允许无创测量脑代谢物以及代谢研究方法来改变外周葡萄糖水平。在本申请中，在健康个体以及控制不良的T2DM个体中进行的基于生理学的人体研究的结果将提供关于多元醇途径是否有助于人类大脑中葡萄糖内源性产生果糖以及通过该途径的过度活动是否与大脑中氧化应激增加的测量值相关的见解。 这项研究应用将利用耶鲁大学医学院丰富的学术环境，一个多学科独立研究人员团队已经联合起来，利用尖端的成像方法来研究代谢中的核心问题。Hwang博士是此次K23申请的候选人，他将在使用MRS以及代谢技术（如葡萄糖钳夹方法）进行和分析研究方面获得重要经验。这项研究的结果将为未来针对多元醇通路的研究奠定基础，以对抗糖尿病的中枢神经系统影响，并将帮助Hwang博士建立长期的职业生涯，作为一名独立的研究者，拥有使用最先进的成像模式来了解糖尿病对中枢神经系统的影响的专业知识。

 DESCRIPTION (provided by applicant): The rising prevalence of type 2 diabetes mellitus (T2DM) amongst both younger and older individuals has led to increases in the lifetime exposure to T2DM. A growing body of evidence suggests that chronic hyperglycemia and T2DM leads to many adverse effects on brain function, particularly neurovascular disorders and cognitive impairment. However, the underlying mechanisms behind these associations remain unclear. The purpose of this application is to evaluate the role of the polyol pathway as a potential mediator of the CNS effects of hyperglycemia. The polyol pathway (glucose  sorbitol  fructose) is an alternate glucose pathway that is present throughout the human body, including the brain. In addition to fructose generation, polyol pathway activity has also been associated with increased oxidative stress and has been linked to the complications of diabetes including diabetic retinopathy, neuropathy and cardiovascular disease. However, the role of this pathway in the brain remains unclear. This K23 application will investigate the potential role of the polyol pathway in mediating the central nervous system effects of hyperglycemia by using nuclear magnetic resonance spectroscopy (MRS) which allows for the non-invasive measurements of brain metabolites as well as metabolic study methodology to alter peripheral glucose levels. The results from the physiology-based human studies in both healthy individuals as well as individuals with poorly controlled T2DM in this application will provide insights regarding whether the polyol pathway contributes to the endogenous production of fructose from glucose in the human brain as well as whether excessive activity through the pathway is associated with measures of increased oxidative stress in the brain. This research application will capitalize on the rich academic environment at Yale School of Medicine where a team of multidisciplinary independent investigators have joined together to utilize cutting edge imaging methodologies to investigate central questions in metabolism. Dr. Hwang, the Candidate for this K23 application, will gain important experience in the conduct and analysis of studies using MRS as well as metabolic techniques such as glucose clamp methodology. The findings from this study will lay the foundation for future studies targeting the polyol pathway to combat the central nervous system effects of diabetes and will help Dr. Hwang establish a long-term career as an independent investigator with an expertise in using state-of-the-art imaging modalities to understand the central nervous system effects of diabetes.