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 BlockerLevetiracetam). 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.
|Journal||American Journal of Physiology - Endocrinology and Metabolism|
|State||Published - Aug 2018|
Bibliographical noteFunding Information:
was provided by the National Institutes of Health5T32DK-091317 and Juvenile Diabetes Research Foundation3-APF-2017-407-A-N to C. M. Reno and funding from the University of Utah’s Diabetes and Metabolism Research Center and National Institutes of HealthRO1 NS070235 to S. J. Fisher.
Funding was provided by the National Institutes of Health 5T32DK-091317 and Juvenile Diabetes Research Foundation 3-APF-2017-407-A-N to C. M. Reno and funding from the University of Utah’s Diabetes and Metabolism Research Center and National Institutes of Health RO1 NS070235 to S. J. Fisher.
© 2018 the American Physiological Society.
- Cardiac arrhythmias
- Sudden death
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Physiology (medical)