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Attenuation of Counterregulatory Responses to Recurrent Hypoglycemia by Active Thalamic Inhibition: A Mechanism for Hypoglycemia-Associated Autonomic Failure

¹From the Departments of Pediatrics (A.M.A.), Neurology and Radiology (W.J.P. and T.O.V), Neurological Surgery (W.J.P.), Anatomy and Neurobiology (J.L.P.) and Medicine (P.E.C.), Washington University School of Medicine, St. Louis, Missouri and the Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, North Carolina (W.J.P.)

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 to initial hypoglycemia in healthy individuals.

Research Design and Methods: We used [¹⁵O]water and positron emission tomography to measure regional cerebral blood flow (CBF) 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 hours 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).

Conclusion: 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.

Key Words: Hypoglycemia • Diabetes • Hypoglycemia-Associated Autonomic Failure • Positron Emission Tomography • Thalamus

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