Neurocognition in youth with prediabetes

摘要 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1-51有关。而当 在人类中这种因果关系尚不清楚，而且可能是双向的，从啮齿动物的研究中可以清楚地看到，饮食诱导了 肥胖和相关的代谢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尚不清楚。特别的 对我们回应的融资机会公告的兴趣是澄清 葡萄糖调节与认知。虽然糖耐量异常是2型糖尿病的诊断，但最近的一项研究 对86篇研究T2D和认知的论文的系统回顾发现，T2D和认知之间只有微弱的联系 血糖和认知68，而更少的证据表明与其他指标有关 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 代表着知识上的重大差距，因为它阻碍了制定缓解 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糖耐量异常在 神经认知，通过纵向评估参加调查的青年的认知和脑功能 青年起病糖尿病(PYOD)的发病机制研究(R01DK111038) 不耐受，但在年龄、性别、BMI和中心性肥胖症方面匹配。PYOD队列提供了卓越的 有机会研究T2D中的认知障碍，因为参与者是糖尿病前期，因此不 患有与T2D相关的慢性疾病。我们还建议使用一种新的神经成像范式 开发用来评估中枢胰岛素抵抗(IR)，以便我们可以理清中枢和 外周IR对神经认知的影响46和纹状体多巴胺信号的间接标记物 胰岛素抵抗、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 外周糖耐量受损(IGT)和/或中枢IR影响神经认知功能 独立于肥胖；(2)检测糖代谢和/或肥胖的变化 预测和预测神经认知的变化；以及(3)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告知 制定策略以减轻发生神经认知功能障碍的风险，帮助 识别有风险和可能从额外治疗中受益的个人，提供了一种新的 药物干预的治疗目标，并提供关于认知率的关键信息 拒绝。

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.