Neurocognition in youth with prediabetes

糖尿病前期青少年的神经认知

• 批准号: 10224174
• 负责人: SONIA CAPRIO
• 金额: $ 66.78万
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224174
• 关键词: Address; Affect; Age; Anatomy; Body mass index; Brain; Cardiovascular system; Childhood; Chronic; Cognition; Cognitive; Cohort Studies; Corpus striatum structure; Data; Dementia; Development; Diabetes Mellitus; Diagnostic; Diet; Dopamine; Endocrinology; Enrollment; Etiology; Evaluation; Fatty acid glycerol esters; Funding Opportunities; Gender; Genetic Risk; Glucose; Glucose Clamp; Glucose Intolerance; Glycosylated hemoglobin A; Goals; Growth; Human; Impaired cognition; Impairment; Individual; Inflammation; Insulin; Insulin Resistance; Intervention; Knowledge; Leptin; Link; Liver; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Metabolic dysfunction; Modeling; Motor; Muscle; Neurocognition; Neurocognitive; Neurocognitive Deficit; Neuropsychological Tests; Neuropsychology; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Obesity; Overweight; Paper; Participant; Pathogenesis; Pathogenicity; Performance; Peripheral; Pharmacology; Prediabetes syndrome; Research; Rest; Risk; Rodent; Role; Signal Transduction; Testing; Time; Triglycerides; Work; Youth; aged; blood glucose regulation; brain health; cognitive function; cohort; diet-induced obesity; follow-up; ghrelin; glucose metabolism; glucose tolerance; insulin sensitivity; insulin sensitivity/resistance; 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 积累的证据将人类肥胖和糖尿病与认知功能障碍和痴呆症1-51联系起来。尽管 因果关系在人类中是未知的，并且可能双向，从啮齿动物的工作中可以清楚地表明饮食诱导的 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效果和相对贡献尚不清楚。特别 我们回应的资助机会公告的兴趣是阐明葡萄糖之间的联系 调节和认知。尽管葡萄糖不耐症是2型糖尿病（T2D）的诊断，但最近的系统 对研究T2D和认知的86篇论文的评论仅发现血糖和 认知68，与其他外围葡萄糖相关的证据甚至更少 调节（例如胰岛素浓度，胰岛素作用，胰岛素抵抗）68。这代表了一个主要差距 知识是因为它阻碍了减轻神经认知风险的策略的发展 并发症。拟议的研究直接解决了知识的这一差距。更具体地说，我们的目标是 通过纵向评估，提供了周围葡萄糖不耐症对神经认知的作用的明确检验 青年糖尿病发病机理（PYOD）研究的年轻人认知和大脑功能 （R01DK111038）葡萄糖耐受性或不耐受性，但与年龄，性别，BMI和中心相匹配 肥胖。 PYOD队列为研究T2D的认知障碍提供了极大的机会，因为 参与者是糖尿病前期的，因此不会遭受与T2D相关的慢性疾病。我们也是 建议使用开发出新的神经影像学范式来评估中央胰岛素抵抗（IR），以便我们 可能会消除中央和周围IR对神经认知46的影响和纹状体的间接标记 多巴胺信号传导研究IR，多巴胺和神经认知之间的关系。更具体地说，我们的 目的是（1）测试外周葡萄糖耐受性（IGT）和/或中央红外影响是否受损 神经认知功能独立于肥胖； （2）测试葡萄糖的变化 代谢和/或肥胖预测并在神经认知的变化之前； （3）测试是否 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，以减轻发展神经认知障碍的风险，有助于 识别处于危险的人，可能会从其他疗法中受益，提供新颖 药理干预的治疗靶标，并提供有关认知率的关键信息 衰退。