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Objective: Impaired awareness of hypoglycemia (IAH) affects one-quarter of adults with type 1 diabetes and significantly increases the risk of severe hypoglycemia. Differences in regional brain responses to hypoglycemia may contribute to the susceptibility of this group to problematic hypoglycemia. This study investigated brain responses to hypoglycemia in hypoglycemia aware (HA) and IAH adults with type 1 diabetes, using three-dimensional pseudo-continuous arterial spin labeling (3D pCASL) functional MRI to measure changes in regional cerebral blood flow (CBF)., Research Design and Methods: Fifteen HA and 19 IAH individuals underwent 3D pCASL functional MRI during a two-step hyperinsulinemic glucose clamp. Symptom, hormone, global, and regional CBF responses to hypoglycemia (47 mg/dL [2.6 mmol/L]) were measured., Results: In response to hypoglycemia, total symptom score did not change in those with IAH ( P = 0.25) but rose in HA participants ( P < 0.001). Epinephrine, cortisol, and growth hormone responses to hypoglycemia were lower in the IAH group ( P < 0.05). Hypoglycemia induced a rise in global CBF (HA P = 0.01, IAH P = 0.04) but was not different between groups ( P = 0.99). IAH participants showed reduced regional CBF responses within the thalamus ( P = 0.002), right lateral orbitofrontal cortex (OFC) ( P = 0.002), and right dorsolateral prefrontal cortex ( P = 0.036) and a lesser decrease of CBF in the left hippocampus ( P = 0.023) compared with the HA group. Thalamic and right lateral OFC differences survived Bonferroni correction., Conclusions: Responses to hypoglycemia of brain regions involved in arousal, decision making, and reward are altered in IAH. Changes in these pathways may disrupt IAH individuals' ability to recognize hypoglycemia, impairing their capacity to manage hypoglycemia effectively and benefit fully from conventional therapeutic pathways to restore awareness., (© 2019 by the American Diabetes Association.)