Severe hypoglycemia-induced fatal cardiac arrhythmias are augmented by diabetes and attenuated by recurrent hypoglycemia

Candace M. Reno, Jennifer VanderWeele, Justin Bayles, Marina Litvin, Allie Skinner, Andrew Jordan, Dorit Daphna-Iken, Simon J. Fisher

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


We previously demonstrated that insulin-mediated severe hypoglycemia induces lethal cardiac arrhythmias. However, whether chronic diabetes and insulin deficiency exacerbates, and whether recurrent antecedent hypoglycemia ameliorates, susceptibility to arrhythmias remains unknown. Thus, adult Sprague-Dawley ratswere randomized into four groups: 1) nondiabetic (NONDIAB), 2) streptozotocin-induced insulin deficiency (STZ), 3) STZ with antecedent recurrent (3 days) hypoglycemia (∼40-45 mg/dL, 90 min) (STZ+RH), and 4) insulin-treated STZ (STZ+Ins). Following treatment protocols, all rats underwent hyperinsulinemic (0.2 units kg-1 min-1), severe hypoglycemic (10-15 mg/dL) clamps for 3 h with continuous electrocardiographic recordings. During matched nadirs of severe hypoglycemia, rats in the STZ +RH group required a 1.7-fold higher glucose infusion rate than those in the STZ group, consistent with the blunted epinephrine response. Second-degree heart block was increased 12- and 6.8-fold in the STZ and STZ+Ins groups, respectively, compared with the NONDIAB group, yet this decreased 5.4-fold in the STZ+RH group compared with the STZ group. Incidence of third-degree heart block in the STZ+RH group was 5.6%, 7.8-fold less than the incidence in the STZ group (44%). Mortality due to severe hypoglycemia was 5% in the STZ+RH group, 6.2-fold less than that in the STZ group (31%). In summary, severe hypoglycemia- induced cardiac arrhythmias were increased by insulin deficiency and diabetes and reduced by antecedent recurrent hypoglycemia. In this model, recurrent moderate hypoglycemia reduced fatal severe hypoglycemia- induced cardiac arrhythmias.

Original languageEnglish
Pages (from-to)3091-3097
Number of pages7
Issue number12
StatePublished - Dec 1 2017

Bibliographical note

Funding Information:
Funding. C.M.R. received funding from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (grant 5T32DK091317) and JDRF (grant 3-APF-2017-407-A-N). S.J.F. received funding from the University of Utah’s Diabetes and Metabolism Research Center and the National Institute of Diabetes and Digestive and Kidney Diseases (NS070235). Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. C.M.R. designed and conducted the experiments and wrote the manuscript. J.V. and J.B. conducted the experiments and wrote the manuscript. M.L. designed and conducted the experiments. A.S., A.J., and D.D.-I. conducted the experiments. S.J.F. designed the experiments and edited the manuscript. S.J.F. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Publisher Copyright:
© 2017 by the American Diabetes Association.

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism


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