Attenuation of Counterregulatory Responses to Recurrent Hypoglycemia by Active Thalamic Inhibition

A Mechanism for Hypoglycemia-Associated Autonomic Failure

  1. Ana Maria Arbelaez1,
  2. William J. Powers234,
  3. Tom O. Videen2,
  4. Joseph L. Price5 and
  5. Philip E. Cryer6
  1. 1Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
  2. 2Departments of Neurology and Radiology, Washington University School of Medicine, St. Louis, Missouri
  3. 3Department of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri
  4. 4Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, North Carolina
  5. 5Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri
  6. 6Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
  1. Address correspondence and reprint requests to Philip E. Cryer, MD, Campus box 8127, Washington University School of Medicine, 660 South Euclid Ave., St. Louis, MO 63110. E-mail: pcryer{at}


OBJECTIVE—Hypoglycemia, the limiting factor in the glycemic management of diabetes, is the result of the interplay of therapeutic insulin excess and compromised glycemic defenses. The key feature of the latter is an attenuated sympathoadrenal response to hypoglycemia that typically follows an episode of recent antecedent iatrogenic hypoglycemia, a phenomenon termed hypoglycemia-associated autonomic failure (HAAF) in diabetes. We investigated the role of cerebral mechanisms in HAAF by measuring regional brain activation during recurrent hypoglycemia with attenuated counterregulatory responses and comparing it with initial hypoglycemia in healthy individuals.

RESEARCH DESIGN AND METHODS—We used [15O]water and positron emission tomography to measure regional cerebral blood flow as a marker of brain synaptic activity during hyperinsulinemic hypoglycemic clamps (55 mg/dl [3.0 mmol/l]) in the naïve condition (day 1) and after ∼24 h of interval interprandial hypoglycemia (day 2) in nine healthy adults.

RESULTS—Interval hypoglycemia produced attenuated sympathoadrenal, symptomatic, and other counterregulatory responses to hypoglycemia on day 2, a model of HAAF. Synaptic activity in the dorsal midline thalamus during hypoglycemia was significantly greater on day 2 than day 1 (P = 0.004).

CONCLUSIONS—Greater synaptic activity associated with attenuated counterregulatory responses indicates that the dorsal midline thalamus plays an active inhibitory role in reducing sympathoadrenal and symptomatic responses to hypoglycemia when previous hypoglycemia has occurred, the key feature of HAAF in diabetes.


  • Published ahead of print at on 14 November 2007. DOI: 10.2337/db07-1329.

    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.

    • Accepted November 6, 2007.
    • Received September 18, 2007.
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  1. Diabetes vol. 57 no. 2 470-475
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