Investigating the polyol pathway in the human brain

研究人脑中的多元醇途径

• 批准号: 9089213
• 负责人: Janice Jin Hwang
• 金额: $ 17.87万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9089213
• 关键词: Acute; Adverse effects; Affect; Aldehyde Reductase; Appetite Stimulants; Attention; Blood Glucose; Brain; Bypass; Cardiovascular Diseases; Cardiovascular system; Cerebrospinal Fluid; Chronic; Complications of Diabetes Mellitus; Diabetes Mellitus; Diabetic Retinopathy; Disease; Environment; Euglycemic Clamping; Exposure to; Fasting; Fatty Liver; Feeding behaviors; Foundations; Fructose; Functional disorder; Future; Generations; Glucose; Glucose Clamp; Glutathione; Glycolysis; Goals; Hour; Human; Human body; Hyperglycemia; Image; Impaired cognition; Individual; Infusion procedures; Insulin; Intravenous; Kidney Diseases; L-Iditol 2-Dehydrogenase; Lead; Link; Magnetic Resonance Spectroscopy; Measurement; Measures; Mediating; Mediator of activation protein; Mentored Patient-Oriented Research Career Development Award; Metabolic; Metabolism; Methodology; NMR Spectroscopy; Neuraxis; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Peripheral; Peripheral Nervous System Diseases; Physiological; Physiology; Plasma; Play; Prevalence; Process; Production; Protocols documentation; Research; Research Personnel; Retinal Diseases; Role; Severities; Sorbitol; Techniques; Technology; Testing; Time; Training; Treatment Protocols; Work; base; career; combat; diabetes management; diabetic; experience; glycemic control; healthy weight; imaging modality; improved; inhibitor/antagonist; insight; medical schools; metabolic abnormality assessment; multidisciplinary; neurovascular; non-diabetic; novel; novel strategies; polyol; public health relevance; response; skills

 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.

 描述：2型糖尿病（T2DM）的患病率上升，使年轻人和旧的糖尿病都在终生暴露于T2DM的情况下，越来越多。神经血管和认知障碍，多元型途径的活性也与氧化应激增加有关，并且与包括糖尿病性视网膜病，神经病和心血管疾病在内的糖尿病并发症有关。磁共振光谱（MRS）允许脑代谢产物的不变以及原始代谢研究的甲级学改变外周葡萄糖水平，这是由健康的个体以及患有AS-Indault t2DM的个体的基于生理的人类研究的。该应用将提供有关Whetol途径的见解，从而有助于人脑中葡萄糖的果糖内源性产生，因为S的活动是否与大脑中氧化氧化应激的增加有关。 该研究申请将利用丰富的学术环境耶鲁大学医学学院，其中一组Nvestigators联合使用切割方法来调查代谢中的中心问题。使用MRS和代谢技术，例如葡萄糖夹方法。作为具有使用最先进的成像方式的专业知识来理解糖尿病中枢神经系统影响的知识。