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Diabetes Publish Ahead of Print published online ahead of print July 27, 2007
DOI: 10.2337/db07-0666
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Original Research

Attenuation of amydgala and frontal cortical responses to low blood glucose concentration in asymptomatic hypoglycemia in Type 1 diabetes: a new player in hypoglycemia unawareness?

Joel T Dunn1,,2, Iain Cranston1, Paul K Marsden2, Stephanie A Amiel1, and Laurence J Reed3

1 Diabetes Research Group, King's College London School of Medicine, King's College, London, UK
2The PET Imaging Centre, King's College London School of Medicine, King's College, London, UK
3Section of Neurobiology of Addiction, Division of Psychological Medicine, Institute of Psychiatry, King's College, London, UK

Correspondence: stephanie.amiel{at}kcl.ac.uk

Key Words: Type 1 diabetes • hypoglycemia unawareness • cerebral metabolic rate • ventral striatum • amygdala.

Objective:Loss of ability to recognize hypoglycemia (hypoglycemia unawareness, HU) increases risk of severe hypoglycemia in insulin-treated diabetes 3-fold. We set out to investigate the cerebral correlates of ‘unawareness’ in Type 1 patients.

Research Design and Methods:Regional changes in brain glucose kinetics were measured using [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) in 13 men with Type 1 diabetes, 6 with hypoglycemia awareness (HA) and 7 with HU, at euglycemia (5mmol/l) and hypoglycemia (2.6mmol/l), in random order.

Results:Epinephrine responses to hypoglycemia were reduced in HU (p<0.0003), as were symptoms. Statistical parametric mapping of FDG uptake using SPM2 at a statistical threshold of p<0.005 showed increased FDG uptake in L amygdala in HA, but not in HU (Region of Interest analysis -0.40+1.03 vs 3.66+0.42, p=0.007) and robust increase in bilateral ventral striatum during hypoglycemia (RoI HU vs HA 3.52+1.02 vs 6.1+0.53, p=0.054). Further analysis at the statistical threshold of p<0.01 showed bilateral attenuated activation of brain stem regions and less deactivation in lateral orbitofrontal cortex (OFC) in HU.

Conclusions:Ventral striatal, amygdala, brain stem and orbitofrontal responses to hypoglycemia indicate engagement of appetitive motivational networks, associated with integrated behavioral responses to hypoglycemia. Reduced responses in these networks in HU, particularly failure of amygdala and OFC responses, suggest habituation of higher behavioral responses to hypoglycemia as a basis for unawareness. New approaches may be needed to restore awareness effectively in practice.


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