Severe hypoglycemia-induced sudden death is mediated by both cardiac arrhythmias and seizures

Candace M. Reno, Allie Skinner, Justin Bayles, Y. Stefanie Chen, Dorit Daphna-Iken, Simon J. Fisher

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


We previously demonstrated that insulin-induced severe hypoglycemia-associated sudden death is largely mediated by fatal cardiac arrhythmias. In the current study, a pharmacological approach was taken to explore the potential contribution of hypoglycemic seizures and the sympathoadrenergic system in mediating severe hypoglycemia-associated sudden death. Adult Sprague-Dawley rats were randomized into one of four treatment groups: 1) saline (SAL), 2) anti-arrhythmic ( 1 blocker atenolol), 3) antiseizure (levetiracetam), and 4) combination antiarrhythmic and antiseizure ( 1 BlockerLevetiracetam). All rats underwent hyperinsulinemic severe hypoglycemic clamps for 3.5 h. When administered individually during severe hypoglycemia,  1 blocker reduced 2nd and 3rd degree heart block by 7.7-and 1.6-fold, respectively, and levetiracetam reduced seizures 2.7-fold, but mortality in these groups did not decrease. However, it was combined treatment with both  1 blocker and levetiracetam that remarkably reduced seizures and completely prevented respiratory arrest, while also eliminating 2nd and 3rd degree heart block, leading to 100% survival. These novel findings demonstrate that, in mediating sudden death, hypoglycemia elicits two distinct pathways (seizure-associated respiratory arrest and arrhythmia-associated cardiac arrest), and therefore, prevention of both seizures and cardiac arrhythmias is necessary to prevent severe hypoglycemia-induced mortality.

Original languageEnglish
Pages (from-to)E240-E249
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Issue number2
StatePublished - Aug 2018

Bibliographical note

Publisher Copyright:
© 2018 the American Physiological Society.


  • Cardiac arrhythmias
  • Diabetes
  • Hypoglycemia
  • Seizures
  • Sudden death

ASJC Scopus subject areas

  • General Medicine


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