Neurocognition in youth with prediabetes

糖尿病前期青少年的神经认知

• 批准号: 9767116
• 负责人: SONIA CAPRIO
• 金额: $ 76.11万
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767116
• 关键词: Address; Affect; Age; Anatomy; 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; 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 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 我们回应的融资机会公告的兴趣是阐明葡萄糖之间的联系 调节和认知。尽管葡萄糖不耐受是 2 型糖尿病 (T2D) 的诊断依据，但最近的一项系统研究 对 86 篇研究 T2D 和认知的论文的审查仅发现血糖与认知之间存在微弱关联。 认知 68 并且很少有证据表明与其他外周血糖测量值相关 调节（例如胰岛素浓度、胰岛素作用、胰岛素抵抗）68。这代表了一个重大差距 知识，因为它阻碍了减轻神经认知风险的策略的制定 并发症。拟议的研究直接解决了这一知识差距。更具体地说，我们的目标是 通过纵向评估，提供外周葡萄糖耐受不良对神经认知作用的明确测试 参加青年糖尿病发病机制 (PYOD) 研究的青少年的认知和大脑功能 (R01DK111038) 具有葡萄糖耐受性或不耐受性，但年龄、性别、BMI 和中枢神经系统相匹配的人 肥胖。 PYOD 队列提供了研究 T2D 认知障碍的绝佳机会，因为 参与者处于糖尿病前期，因此没有患有与 T2D 相关的慢性疾病。我们也 建议使用一种新的神经影像学范例来评估中枢胰岛素抵抗（IR），以便我们 可能会解开中枢和外周 IR 对神经认知的影响 46 和纹状体的间接标记 多巴胺信号传导以研究 IR、多巴胺和神经认知之间的关系。更具体地说，我们的 目的是 (1) 测试外周糖耐量 (IGT) 受损和/或中枢 IR 影响是否存在 神经认知功能独立于肥胖； (2) 检测血糖是否变化 新陈代谢和/或肥胖预测并先于神经认知的变化； (3) 测试是否 认知功能障碍和衰退与多巴胺信号传导有关。我们预计这些结果 将为制定减轻神经认知障碍风险的策略提供信息，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。