Continuous Glucose Monitoring Time Below Range Predicts Impaired Epinephrine Response to Hypoglycemia in Patients With Type 1 Diabetes

Hypoglycemia caused by treatment with a sulfonylurea, a glinide, or insulin coupled with compromised defenses against the resulting falling plasma glucose concentrations is a problem for many people with diabetes. It is often recurrent, causes significant morbidity and occasional mortality, limits maintenance of euglycemia, and impairs physiological and behavioral defenses against subsequent hypoglycemia. Minimizing hypoglycemia includes acknowledging the problem; considering each risk factor; and applying the principles of intensive glycemic therapy, including drug selection and selective application of diabetes treatment technologies. For diabetes health-care providers treating most people with diabetes who are at risk for or are suffering from iatrogenic hypoglycemia, these principles include selecting appropriate individualized glycemic goals and providing structured patient education to reduce the incidence of hypoglycemia. This is typically combined with short-term scrupulous avoidance of hypoglycemia, which often will reverse impaired awareness of hypoglycemia. Clearly, the risk of hypoglycemia is modifiable.

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.