DESCRIPTION (provided by applicant): Type 1 diabetes mellitus (T1DM) is typically diagnosed in childhood and over time can lead to complications affecting the retina, heart, kidneys, peripheral nerves, and more recently appreciated, the brain. During childhood, the brain undergoes significant structural and functional changes and has a high and rapidly changing metabolic demand; these unique properties have led to the suggestion that the developing brain may be especially vulnerable to glycemic extremes. Accordingly, studies find that early age of onset, accumulated exposure to hyperglycemia and repeated severe hypoglycemia during development are associated with lower cognitive performance and altered brain structure in children with T1DM. Intriguing patterns have been identified, yet substantial individual variability in brain outcomes remains unexplained. More recently, our data and others' have suggested that clinical severity at diagnosis, particularly at younger ages, may contribute to cognitive and brain outcomes, even many years later. However, previous studies have not been designed to differentiate the effects of initial clinical presentation from the cumulative effects of subsequent glycemic extremes on the brain. Thus, the goal of this study is to determine how clinical features at the time of T1DM diagnosis shape the developmental trajectory of the brain and its responses to subsequent glycemic control. We propose to test this hypothesis explicitly by performing sensitive neuroimaging, cognitive testing and quantitative clinical measures on children with T1DM and their non- diabetic siblings at diagnosis and at 3 and 21 months post-diagnosis. Findings may highlight the need for programs aimed at early diagnosis of the disease, DKA prevention, and β-cell preservation, particularly in at- risk youth, in order to minimize long-term negative consequences for brain health and development. Although recent exciting developments raise the possibility of better glycemic control using closed-loop insulin delivery systems or of curing T1DM through β-cell transplants, the risks associated with clinical presentation of T1DM would still remain and need to be better understood.