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

2型糖尿病（T2D）是影响约3000万美国人的重大公共卫生问题。肥胖， 胰岛素抵抗、胰岛素缺乏（β细胞功能障碍）和代谢障碍都先于T2D的诊断， 已知会促进炎症并最终导致微血管并发症。最近，研究 已经确定了成人发病T2D的脑相关并发症，包括局部脑结构减少， 功能，认知受损，并增加阿尔茨海默病的终身风险。令人担忧的是， 许多儿童和青少年被诊断患有T2D，可能是由于患病率不断上升， 肥胖的早期发病。青年发作的T2D似乎比成人发作的T2D具有更具侵略性的病程， 微血管并发症的发病更早，进展更快。此外，对青年人的研究 肥胖和青年发病的T2D已经报道了区域脑结构和认知的显著差异， 这表明脑部影响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，人们对青少年大脑结构和功能不良的相关因素知之甚少。 2型糖尿病为了解决这一关键的知识差距，我们建议研究整个身体质量谱的青年 体重指数（BMI）和代谢功能障碍。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），伴有对大脑构成风险的中间生理变化（例如胰岛素） 抵抗、炎症、β细胞功能障碍和代谢障碍），可能导致大脑结构减少， T2D功能我们将确定这些因素中哪些与大脑结构的差异最相关 以及这些影响与正常神经发育有何不同。鉴于 这种疾病发生在大脑正在经历戏剧性的发育过程的时候， 青年发病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 长期随访、干预性或机制性研究的指导和依据，并具有重要的临床意义 影响

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.