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, HbA_1c 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.