Effect of Hypoglycemia on β-Adrenergic Sensitivity in Normal and Type 1 Diabetic Subjects

Abstract

OBJECTIVE The purpose of this study was to assess the potential role of reduced tissue sensitivity to catecholamines in the pathogenesis of hypoglycemia unawareness in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS The effect of a single episode of hypoglycemia on β-adrenergic sensitivity was studied in 10 type 1 diabetic patients with apparently normal awareness of hypoglycemia (age 29 ± 5 years, diabetes duration 13 ± 8 years, HbA1c 7.3 ± 0.9%) and 10 age-matched healthy control subjects. β-adrenergic sensitivity was measured with the isoproterenol test after a hyperinsulinemic euglycemic clamp and after a hyperinsulinemic hypoglycemic clamp. β-adrenergic sensitivity was expressed as the dose of intravenous isoproterenol that increased the heart rate by 25 beats/min (IC25). RESULTS During hypoglycemia, diabetic subjects had an impaired plasma epinephrine response compared with that of the control subjects (16.7 ± 5.0 vs. 40.1 ± 6.8 ng/ml, P = 0.02). In control subjects, the IC25 was lower after hypoglycemia than after euglycemia (0.83 ± 0.22 vs. 1.13 ± 0.21 μg, P = 0.02) indicating an increase in β-adrenergic sensitivity. In diabetic subjects, on the other hand, the IC25 was greater after hypoglycemia than after euglycemia (1.00 ± 0.26 vs. 0.65 ± 0.14 μ, P = 0.04), indicating a decrease in β-adrenergic sensitivity. CONCLUSIONS In normal subjects, a single episode of hypoglycemia increases β-adrenergic sensitivity. In diabetic subjects, in contrast, hypoglycemia reduces β-adrenergic sensitivity. These results provide evidence that in type 1 diabetic patients, some maladaptation of tissue sensitivity to catecholamines contributes to the development of hypoglycemia unawareness. A unifying hypothesis is presented for the pathogenesis of hypoglycemia unawareness in type 1 diabetic patients incorporating the concepts of both a reduced catecholamine response and reduced adrenergic sensitivity.