American Diabetes Association
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Restoration of Hypoglycemia Awareness Alters Brain Activity in Type 1 Diabetes

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posted on 2020-12-17, 21:26 authored by Munachiso Nwokolo, Stephanie A. Amiel, Owen O’Daly, Ian A. Macdonald, Fernando O. Zelaya, Pratik Choudhary

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 T1D IAH adults underwent pseudo-continuous arterial spin labelling functional MRI during a hypoglycemic clamp (5mmol/L-2.6mmol/L), before and after a hypoglycemia avoidance program of structured education (Dose Adjustment for Normal Eating, DAFNE), specialist support and sensor-augmented pump therapy (Medtronic Minimed™ 640G). Hypoglycemic cerebral blood flow (CBF) responses were compared pre- and post-intervention using predefined region of interest analysis of the thalamus, anterior cingulate cortex (ACC), orbitofrontal cortex (OFC) and hippocampus.


Post-intervention, Gold and Clarke scores fell (6.0±1.0 to 4.0±1.6, p=0.0002; 5.7±1.7 to 3.4±1.8, p=0.0008), 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), epinephrine responses did not change (p=0.2). Post-intervention, hypoglycemia induced greater increases in ACC CBF (p=0.01, peak voxel coordinates [6,40,-2]), while thalamic and OFC activity did not change.


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 IAH individuals achieve awareness restoration with education and technology alone.


This study was funded by a project grant from Diabetes UK registered charity no. 215199. Investigator initiated study approval was granted for this study by Medtronic UK who provided Medtronic Minimed ™ 640G insulin pumps, Guardian™ 2 Link transmitters and Enlite™ glucose sensors for use in this study. Medtronic UK had no role in study design, no role in collection, analysis, and interpretation of data, no role in the writing of the report and no role in the decision to submit the paper for publication. M.N. had full access to all the data in the study and had final responsibility for publication submission.