Visual Abstract

Severe hypoglycemia leads to fatal cardiac arrhythmias. In mediating the release of calcium from cardiac cells, the ryanodine receptor (RYR2) is implicated in arrhythmias. To test the hypothesis that stability of RYR2 during hypoglycemia mediates cardiac arrhythmias, two studies were performed: 1) genetic disruption of RYR2 stability in mice and 2) pharmacological stabilization of RYR2 in rats. Firstly, wild type (WT) or RYR2 knockin (RYR2 +/-) mice received insulin (10 U/kg subq) to induce hypoglycemia (10-15 mg/dl) for 3 hours with electrocardiography (ECG). RYR2 +/- mice had 71% mortality during severe hypoglycemia compared to no mortality in WT (n = 7/group; p < 0.05; Figure). In RYR2 +/- mice, hypoglycemia induced a 34-fold increase in 2nd degree and 85% incidence of 3rd degree heart block (WT 0%). Secondly, Sprague Dawley rats received vehicle (Veh; n = 18) or a RYR2 stabilizer (JTV; 2.5 mg/kg IV, n = 20) during hyperinsulinemic (0.2 mg/kg/min) hypoglycemic (10-15 mg/dl) clamps for 3 hours with ECG. Mortality due to severe hypoglycemia was 22% in Veh, but stabilization of RYR2 prevented mortality (p < 0.05; Figure) and was associated with a 27-fold decrease in 2nd degree and complete prevention of 3rd degree heart block (Veh 23%).

In conclusion, RYR2 mediates hypoglycemia-induced fatal cardiac arrhythmias in rodents. Stabilizing RYR2 pharmacologically may prevent mortality due to hypoglycemia.

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Disclosure

C. M. Reno: None. Y. Huang: None. C. G. Christensen: None. S. Fisher: None.

Funding

National Institutes of Health (NS070235-01A1, R01DK118082); JDRF (1-FAC-2020-984-A-N)

© 2021 by the American Diabetes Association
2021
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