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.

概括 越来越多的证据表明人类肥胖和糖尿病与认知功能障碍和痴呆症有关 1-51。尽管 人类中的因果关系是未知的，并且可能是双向的，从啮齿类动物的研究中可以清楚地看出，饮食会诱发 肥胖和相关的代谢功能障碍会导致认知受损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。特别是 对我们回应的融资机会公告的兴趣正在阐明之间的联系 血糖调节和认知。尽管葡萄糖不耐受是 2 型糖尿病 (T2D) 的诊断依据，但最近的一项研究 对 86 篇研究 T2D 和认知的论文进行的系统回顾仅发现两者之间存在微弱关联 血糖和认知能力 68 并且很少有证据表明与血糖和认知能力的其他测量指标相关 外周血糖调节（例如胰岛素浓度、胰岛素作用、胰岛素抵抗）68。这 代表了知识上的重大差距，因为它阻碍了缓解战略的制定 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，以确定外周葡萄糖耐受不良对健康的影响。 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 青少年发病糖尿病 (PYOD) 的发病机制研究 (R01DK111038) 对于葡萄糖耐量或 不耐受，但与年龄、性别、BMI 和中心性肥胖相匹配。 PYOD 队列提供了一个特殊的 研究 T2D 认知障碍的机会，因为参与者处于糖尿病前期，因此不 患有与 T2D 相关的慢性疾病。我们还建议使用新的神经影像范式 开发用于评估中枢胰岛素抵抗（IR），以便我们可以理清中枢和胰岛素抵抗的影响 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物，以研究 IR、多巴胺和神经认知之间的关系。更具体地说，我们的目标是（1）测试是否 外周糖耐量 (IGT) 和/或中枢糖耐量受损影响神经认知功能 与肥胖无关； (2) 测试糖代谢和/或肥胖是否发生变化 预测并先于神经认知的变化； (3) 测试是否存在认知功能障碍和 下降与多巴胺信号传导有关。我们预计这些结果将告知 制定策略以减轻发生神经认知障碍的风险，帮助 识别有风险且可能从额外治疗中受益的个体，提供了一种新颖的方法 药物干预的治疗目标并提供有关认知率的关键信息 衰退。