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?

  1. Joel T. Dunn1,2,
  2. Iain Cranston1,
  3. Paul K. Marsden2,
  4. Stephanie A. Amiel1 and
  5. Laurence J. Reed3
  1. 1Diabetes Research Group, King's College London School of Medicine, King's College, London, U.K
  2. 2Positron Emission Tomography Imaging Centre, King's College London School of Medicine, King's College, London, U.K
  3. 3Section of Neurobiology of Addiction, Division of Psychological Medicine, Institute of Psychiatry, King's College, London, U.K
  1. Address correspondence and reprint requests to Prof. Stephanie A. Amiel, Medical School Building, King's College London School of Medicine, King's College Hospital Campus, Bessemer Road, London, SE5 9PJ, U.K. E-mail: stephanie.amiel{at}


OBJECTIVE—Loss of ability to recognize hypoglycemia (hypoglycemia unawareness) increases risk of severe hypoglycemia threefold in insulin-treated diabetes. 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 (FDG) positron emission tomography (PET), in 13 men with type 1 diabetes—6 with hypoglycemia awareness and 7 with hypoglycemia unawareness—at euglycemia (5 mmol/l) and hypoglycemia (2.6 mmol/l), in random order.

RESULTS—Epinephrine responses to hypoglycemia were reduced in hypoglycemia unawareness (P < 0.0003), as were symptoms. Statistical parametric mapping (SPM) of FDG uptake using SPM2 at a statistical threshold of P < 0.005 showed increased FDG uptake in left amygdala in hypoglycemia awareness, but not in hypoglycemia unawareness (region of interest analysis −0.40 ± 1.03 vs. 3.66 ± 0.42, respectively; P = 0.007), and robust increase in bilateral ventral striatum during hypoglycemia (region of interest analysis hypoglycemia unawareness 3.52 ± 1.02 vs. awareness 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 in hypoglycemia unawareness.

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 hypoglycemia unawareness, particularly failure of amygdala and orbifrontal cortex 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.


  • Published ahead of print at on 27 July 2007. DOI: 10.2337/db07-0666.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received May 21, 2007.
    • Accepted July 23, 2007.
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  1. Diabetes vol. 56 no. 11 2766-2773
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