Neurocognition in youth with prediabetes

糖尿病前期青少年的神经认知

• 批准号: 10413361
• 负责人: SONIA CAPRIO
• 金额: $ 20.94万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10413361
• 关键词: Address; Age; Body mass index; Brain; Chronic; Cognition; Cognitive; Corpus striatum structure; Dementia; Development; Diabetes Mellitus; Diagnostic; Diet; Dopamine; Enrollment; Etiology; Evaluation; Funding Opportunities; Gender; Glucose Intolerance; Human; Impaired cognition; Impairment; Individual; Insulin; Insulin Resistance; Intervention; Knowledge; Link; Longitudinal Studies; Measures; Metabolic dysfunction; Neurocognition; Neurocognitive; Neurocognitive Deficit; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Paper; Participant; Pathogenesis; Pathogenicity; Peripheral; Pharmacology; Prediabetes syndrome; Research; Risk; Rodent; Role; Signal Transduction; Testing; Work; Youth; aged; blood glucose regulation; cohort; diet-induced obesity; glucose metabolism; glucose tolerance; interest; neuroimaging; new therapeutic target; systematic review

SUMMARY Accumulating evidence links human obesity and diabetes with cognitive dysfunction and dementia 1-51. While the causality is unknown in humans, and likely bi-directional, it is clear from work in rodents that diet induced obesity and associated metabolic dysfunction cause impaired cognition52-56. The mechanisms supporting this effect and the relative contribution of adiposity, diet and metabolic dysfunction remain unknown. Of particular interest to the funding opportunity announcement to which we respond is elucidating the link between glucose regulation and cognition. Although glucose intolerance is diagnostic of type 2 diabetes (T2D), a recent systematic review of 86 papers examining T2D and cognition only found a weak association between glycaemia and cognition 68 and there is even less evidence for an association with other measures of peripheral glucose regulation (e.g., insulin concentration, insulin action, insulin resistance)68. This represents a major gap in knowledge because it impedes the development of strategies to mitigate the risk of neurocognitive complications. The proposed research directly addresses this gap in knowledge. More specifically, we aim to provide a definitive test of the role of peripheral glucose intolerance on neurocognition, by longitudinal evaluation of cognitive and brain function in youth enrolled in the Pathogenesis of Youth Onset Diabetes (PYOD) study (R01DK111038) who are either glucose tolerant or intolerant but matched for age, gender, BMI and central adiposity. The PYOD cohort provides an exceptional opportunity to study cognitive impairment in T2D because the participants are pre-diabetic and thus do not suffer from chronic conditions associated with T2D. We also propose to use a new neuroimaging paradigm developed to assess central insulin resistance (IR) so that we may disentangle the effects of central and peripheral IR on neurocognition 46 and an indirect marker of striatal dopamine signaling to investigate the relation between IR, dopamine and neurocognition. More specifically, our aims are to (1) To test whether impaired peripheral glucose tolerance (IGT) and/or central IR influence neurocognitive function independently from adiposity; (2) To test whether change in glucose metabolism and/or adiposity predicts and precedes change in neurocognition; and (3) To test whether cognitive dysfunction and decline is associated with dopamine signaling. We anticipate that these results will inform the development of strategies to mitigate the risk of developing neurocognitive impairment, aid in the identification of individuals who are at-risk and who might benefit from additional therapy, provide a novel therapeutic target for pharmacological intervention and provide critical information about the rate of cognitive decline.

总结 越来越多的证据将人类肥胖和糖尿病与认知功能障碍和痴呆联系起来1-51。而 在人类中的因果关系尚不清楚，可能是双向的，从啮齿动物的研究中可以清楚地看出，饮食诱导 肥胖和相关的代谢功能障碍导致认知受损52 -56。支持这一点的机制 肥胖、饮食和代谢功能障碍的影响和相对贡献仍然未知。特别 对我们回应的资助机会公告的兴趣正在阐明 葡萄糖调节和认知。虽然葡萄糖耐受不良是2型糖尿病（T2 D）的诊断，但最近的一项研究表明， 对86篇研究T2 D和认知的论文进行了系统性回顾，仅发现T2 D和认知之间存在弱相关性。 高血压和认知68，甚至更少的证据表明与其他指标的关联。 外周葡萄糖调节（例如，胰岛素浓度、胰岛素作用、胰岛素抵抗）68.这 这是一个重大的知识差距，因为它阻碍了制定战略，以减轻 神经认知并发症的风险。拟议的研究直接解决了这一差距， 知识更具体地说，我们的目标是提供一个明确的测试外周葡萄糖耐受不良的作用， 神经认知，通过对参加该项目的青少年的认知和大脑功能进行纵向评估 青年型糖尿病（PYOD）发病机制研究（R 01 DK 111038），受试者为葡萄糖耐量或 不耐受，但年龄、性别、BMI和中心性肥胖相匹配。PYOD队列提供了一个特殊的 有机会研究T2 D的认知障碍，因为参与者是糖尿病前期， 患有与T2 D相关的慢性疾病。我们还建议使用一种新的神经影像学范式 开发用于评估中枢胰岛素抵抗（IR），以便我们可以解开中枢和 外周IR对神经认知的影响46和纹状体多巴胺信号传导的间接标记，以研究 IR、多巴胺与神经认知的关系。更具体地说，我们的目标是（1）测试是否 外周葡萄糖耐量受损（IGT）和/或中枢IR影响神经认知功能 （2）检测葡萄糖代谢和/或肥胖的变化是否与肥胖无关; 预测和神经认知的变化;（3）为了测试认知功能障碍和 下降与多巴胺信号有关。我们预计这些结果将为 制定策略以减轻发生神经认知障碍的风险， 识别处于风险中的个体和可能从额外治疗中受益的个体，提供了一种新的 药物干预的治疗靶点，并提供有关认知障碍发生率的关键信息。 下降