title: Severe hypoglycemia-induced lethal cardiac arrhythmias are mediated by sympathoadrenal activation.
abstract: For people with insulin-treated diabetes, severe hypoglycemia can be lethal, though potential mechanisms involved are poorly understood. To investigate how severe hypoglycemia can be fatal, hyperinsulinemic, severe hypoglycemic (10-15 mg/dL) clamps were performed in Sprague-Dawley rats with simultaneous electrocardiogram monitoring. With goals of reducing hypoglycemia-induced mortality, the hypotheses tested were that: 1) antecedent glycemic control impacts mortality associated with severe hypoglycemia; 2) with limitation of hypokalemia, potassium supplementation could limit hypoglycemia-associated deaths; 3) with prevention of central neuroglycopenia, brain glucose infusion could prevent hypoglycemia-associated arrhythmias and deaths; and 4) with limitation of sympathoadrenal activation, adrenergic blockers could prevent hypoglycemia-induced arrhythmic deaths. Severe hypoglycemia-induced mortality was noted to be worsened by diabetes, but recurrent antecedent hypoglycemia markedly improved the ability to survive an episode of severe hypoglycemia. Potassium supplementation tended to reduce mortality. Severe hypoglycemia caused numerous cardiac arrhythmias including premature ventricular contractions, tachycardia, and high-degree heart block. Intracerebroventricular glucose infusion reduced severe hypoglycemia-induced arrhythmias and overall mortality. β-Adrenergic blockade markedly reduced cardiac arrhythmias and completely abrogated deaths due to severe hypoglycemia. Under conditions studied, sudden deaths caused by insulin-induced severe hypoglycemia were mediated by lethal cardiac arrhythmias triggered by brain neuroglycopenia and the marked sympathoadrenal response.
authors.affiliation: Division of Endocrinology, Metabolism, & Lipid Research, Department of Medicine, Washington University, St. Louis, Missouri.
authors.forename: Candace M
authors.initials: CM
authors.lastname: Reno
authors.forename: Dorit
authors.initials: D
authors.lastname: Daphna-Iken
authors.forename: Y Stefanie
authors.initials: YS
authors.lastname: Chen
authors.forename: Jennifer
authors.initials: J
authors.lastname: VanderWeele
authors.forename: Krishan
authors.initials: K
authors.lastname: Jethi
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Fisher
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000209:etiology* / Q000503:physiopathology; D001786:Blood Glucose / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000188:drug therapy / Q000503:physiopathology; D004562:Electrocardiography; D004837:Epinephrine / Q000009:adverse effects; D005947:Glucose / Q000378:metabolism; D007003:Hypoglycemia / Q000139:chemically induced* / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D007328:Insulin / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D008297:Male; D009638:Norepinephrine / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D005947:Glucose; D009638:Norepinephrine; D004837:Epinephrine