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Abstract Hypoglycemia is common in people with type 1 diabetes. Sometimes, severe hypoglycemia can be fatal. The underlying mechanisms by which severe hypoglycemia can lead to death are unclear. The sympathetic nervous system is thought to be proarrhythmic. We hypothesized that norepinephrine is the main mediator of severe hypoglycemia‐induced fatal cardiac arrhythmias. To test this hypothesis, adult, non‐diabetic Sprague–Dawley rats were subjected to hyperinsulinemic‐severe hypoglycemic clamps (3 h, 10–15 mg/dL) during two different experiments: (1) intracerebroventricular (ICV) norepinephrine (n = 26) or artificial cerebrospinal fluid (aCSF) (n = 20) infusion or (2) blockade of norepinephrine release by intraperitoneal reserpine (n = 20) or control (n = 29). In experiment 1, brain norepinephrine infusion during severe hypoglycemia led to a 2.5‐fold increase in third‐degree heart block and a 24% incidence of ST elevation compared to no ST elevation in aCSF controls. In experiment 2, reserpine successfully reduced plasma and cardiac norepinephrine levels. During severe hypoglycemia, reserpine completely prevented second and third‐degree heart block and T wave increases, a marker of myocardial infarction, compared to controls. In conclusion, norepinephrine increases while reserpine, used to reduce norepinephrine nerve terminal release, reduces heart block and markers of myocardial infarction during severe hypoglycemia.

Hypoglycemia occurs frequently in people with type 1 and type 2 diabetes. Hypoglycemia activates the counter-regulatory response. Besides peripheral glucose sensors located in the pancreas, mouth, gastrointestinal tract, portal vein, and carotid body, many brain regions also contain glucose-sensing neurons that detect this fall in glucose. The autonomic nervous system innervates the heart, and during hypoglycemia, can cause many changes. Clinical and animal studies have revealed changes in electrocardiograms during hypoglycemia. Cardiac repolarization defects (QTc prolongation) occur during moderate levels of hypoglycemia. When hypoglycemia is severe, it can be fatal. Cardiac arrhythmias are thought to be the major mediator of sudden death due to severe hypoglycemia. Both the sympathetic and parasympathetic nervous systems of the brain have been implicated in regulating these arrhythmias. Besides cardiac arrhythmias, hypoglycemia can have profound changes in the heart and most of these changes are exacerbated in the setting of diabetes. A better understanding of how the brain regulates cardiac changes during hypoglycemia will allow for better therapeutic intervention to prevent cardiovascular death associated with hypoglycemia in people with diabetes. The aim of this paper is to provide a narrative review of what is known in the field regarding how the brain regulates the heart during hypoglycemia.