HIERARCHICAL BRAIN AND PHYSIOLOGICAL RESPONSES TO HYPOGLYCEMIA AND HAAF IN T1DM

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 DESCRIPTION (provided by applicant): Hypoglycemia is the limiting factor in the glycemic control of diabetes, causing morbidity and death. Recurrent hypoglycemia causes both defective glucose counterregulation and loss of hypoglycemic symptoms during subsequent hypoglycemia, constituting the clinical syndrome of hypoglycemia-associated autonomic failure (HAAF). The mechanisms underlying the signaling of these responses during hypoglycemia and the loss of these responses during HAAF are thought to involve the brain. To date no effective clinical method has shown to reduce the incidence of hypoglycemia without the risk of compromising glycemic control. Thus, a better understanding of the mechanisms underlying the loss of the hypoglycemic responses may help us identify new and innovative therapeutic targets. We hypothesize that there is hierarchical activation of several hypoglycemia-sensitive brain regions that form a functional network in response to declining blood glucose levels, and a potential loss of the connectivity in this network leads to HAAF in individuals with T1DM. With a multidisciplinary approach we will test this hypothesis, using integrated quantitative brain imaging measurements of regional blood flow (ASL-MRI) and functional connectivity (BOLD rs-fMRI) during hyperinsulinemic euglycemic (~90mg/dL) - stepped hypoglycemic (~65-55-45mg/dL) clamps in 20 type 1 diabetic (T1DM) patients with HAAF, 20 T1DM without HAAF and in 20 healthy young adults in a model of HAAF. By determining the changes in BOLD signal during HAAF in DM, we will identify a neuroimaging biomarker that characterizes the effects of HAAF in vivo in T1DM patients to predict outcomes in planned prospective interventional studies.