Brain Health Across the Metabolic Continuum in Youth at Risk for T2D

2型糖尿病(T2D)是一个重大的公共健康问题，影响着约3000万美国人。肥胖， 胰岛素抵抗、胰岛素缺乏(β细胞功能障碍)和血糖异常都在T2D和 已知会促进炎症，并最终导致微血管并发症。最近，一项研究 已经确定了成人起病的T2D的与脑相关的并发症，包括区域大脑结构和 功能受损，认知受损，阿尔茨海默病的终身风险增加。令人担忧的是，越来越多的 许多儿童和青少年被诊断为T2D，可能是由于患病率和 肥胖症发病时间较早。青少年起病的T2D似乎比成人起病的T2D的病程更具侵袭性， 微血管并发症起病更早，进展更快。此外，对青少年的研究 据报道，肥胖症和青少年T2D在大脑结构和认知方面存在显著差异， 这表明大脑效应可能遵循与更典型的血管并发症相同的侵袭性过程。 不幸的是，人们对青少年脑部结构和功能不良的相关因素知之甚少。 T2D。为了解决这一关键的知识差距，我们建议研究不同身体质量的年轻人 体重指数(BMI)和代谢紊乱。这种方法将使我们能够理清关键特征之间的关系 T2D风险(例如肥胖)和对大脑构成风险的中间生理变化(例如胰岛素) 抵抗力、炎症、β细胞功能障碍和血糖紊乱)，这些可能导致大脑结构和 在T2D中的函数。我们将确定这些因素中哪些与大脑结构的差异最相关 以及随着时间的推移，这些影响与正常神经发育有何不同。考虑到 这种疾病发生在大脑正在经历戏剧性的发育过程的时候，侵略性的 青年起病的T2D进展的性质和其他器官系统的并发症，这些结果可能提供 指导和论证更长时间的随访、干预性或机械性研究，并具有重要的临床意义 这意味着什么。

Type 2 diabetes mellitus (T2D) is a significant public health problem affecting ~30 million American. Obesity, insulin resistance, insulin deficiency (β cell dysfunction) and dysglycemia all precede the diagnosis of T2D and are known to promote inflammation and ultimately lead to microvascular complications. More recently, research has identified brain-related complications in adult-onset T2D, including reduced regional brain structure and function, impaired cognition, and increased lifetime risk for Alzheimer’s disease. Alarmingly, an increasing number of children and adolescents are being diagnosed with T2D, likely due to the growing prevalence and earlier onset of obesity. Youth-onset T2D appears to have a more aggressive course than adult-onset T2D, with earlier onset and more rapid progression of microvascular complications. In addition, studies of youth with obesity and youth-onset T2D have reported robust differences in regional brain structure and cognition, suggesting that brain effects may follow the same aggressive course as the more typical vascular complications. Unfortunately, little is known about the factors associated with poor brain structure and function in youth with T2D. To address this critical gap in knowledge, we propose to study youth across the spectrum of body mass index (BMI) and metabolic dysfunction. This approach will allow us to disentangle the relationship of key features of T2D risk (e.g. obesity) with intermediary physiologic changes that pose a risk for the brain (e.g. insulin resistance, inflammation, β-cell dysfunction and dysglycemia) that may lead to reduced brain structure and function in T2D. We will determine which of these factors are most associated with differences in brain structure and function among groups, over time, and how these effects differ from normal neurodevelopment. Given that the disease occurs at a time when brains are undergoing dramatic developmental processes, the aggressive nature of youth-onset T2D progression and complications in other organ systems, these results may provide guidance and justification for longer follow-up, interventional or mechanistic studies and have important clinical implications.