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.

Project Narrative: Type 2 diabetes mellitus (T2D) is a significant public health problem affecting ~30 million people. Obesity, insulin deficiency and hyperglycemia all precede the diagnosis of T2D and are long known to promote inflammation and ultimately lead to microvascular complications in adults. 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 early onset and rapid increase in complications. In addition, a few small studies of 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 complications. Unfortunately, little is known about the risk factors associated with alterations in brain structure and function in youth with T2D. To address this critical gap in knowledge, we propose to study youth across the spectrum of obesity and metabolic dysfunction. This approach will allow us to disentangle the relationship of key features of T2D risk (e.g. obesity, insulin resistance, insulin deficiency and dysglycemia) to intermediate changes that pose a risk for the brain (e.g. inflammation) and reduced brain structure and function associated with T2D in youth.