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Objective: Impaired awareness of hypoglycemia (IAH) in type 1 diabetes (T1D) is a major risk factor for severe hypoglycemia (SH) and is associated with atypical responses to hypoglycemia in brain regions involved in arousal, decision making, and memory. Whether restoration of hypoglycemia awareness alters these responses is unknown. We sought to investigate the impact of awareness restoration on brain responses to hypoglycemia.Research Design and Methods: Twelve adults with T1D and IAH underwent pseudocontinuous arterial spin labeling functional MRI during a hypoglycemic clamp (5-2.6 mmol/L) before and after a hypoglycemia avoidance program of structured education (Dose Adjustment for Normal Eating), specialist support, and sensor-augmented pump therapy (Medtronic MiniMed 640G). Hypoglycemic cerebral blood flow (CBF) responses were compared pre- and postintervention using predefined region-of-interest analysis of the thalamus, anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and hippocampus.Results: Postintervention, Gold and Clarke scores fell (6.0 ± 1.0 to 4.0 ± 1.6, P = 0.0002, and 5.7 ± 1.7 to 3.4 ± 1.8, P = 0.0008, respectively), SH rates reduced (1.5 ± 2 to 0.3 ± 0.5 episodes per year, P = 0.03), hypoglycemic symptom scores increased (18.8 ± 6.3 to 27.3 ± 12.7, P = 0.02), and epinephrine responses did not change (P = 0.2). Postintervention, hypoglycemia induced greater increases in ACC CBF (P = 0.01, peak voxel coordinates [6, 40, -2]), while thalamic and OFC activity did not change.Conclusions: Increased blood flow is seen within brain pathways involved in internal self-awareness and decision making (ACC) after restoration of hypoglycemia awareness, suggesting partial recovery of brain responses lost in IAH. Resistance of frontothalamic networks, involved in arousal and emotion processing, may explain why not all individuals with IAH achieve awareness restoration with education and technology alone. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]