Avoidance of hypoglycemia restores hypoglycemia awareness by increasing β-adrenergic sensitivity in type 1 diabetes

Background: Lack of awareness of hypoglycemia is a major limiting factor in the management of type 1 diabetes. Objective: To examine whether reduction in the number of episodes of hypoglycemia restores hypoglycemia awareness by influencing beta -adrenergic sensitivity in patients with type 1 diabetes. Design: Controlled interventional study. Setting: Research unit and outpatient diabetes clinic of a university hospital. Patients: 10 men with type 1 diabetes and hypoglycemia unawareness (mean age[+/-SD], 46+/-6 years; mean duration of diabetes, 20 +/- 10 years). Intervention: Strict avoidance of hypoglycemia. Measurements: beta -Adrenergic sensitivity was measured by isoproterenol testing before and at 2 and 4 months after strict avoidance of hypoglycemia. Hypoglycemia awareness and catecholamine response were measured by performing hypoglycemic clamp (glucose level, 3 mmol/L [54 mg/dL]) before and after 4 months of avoidance of hypoglycemia. Results: After 4 months, the mean (+/-SE) number of episodes of hypoglycemia (glucose level < 3.9 mmol/L [70 mg/dL]) decreased from 8.4 +/- 0.9 to 1.4 +/- 0.3 per week (P < 0.001). Hemoglobin A(1c) values increased from 0.068 +/- 0.003 (6.8% +/- 0.3%) to 0.077 +/- 0.003 (7.7% +/- 0.3%) (P < 0.001). Autonomic symptom scores during hypoglycemic clamp increased from 1.8 +/- 0.6 to 3.3 +/- 0.7 (P = 0.004) and did not significantly differ from those of normal participants (4.7+/-0.8) (P>0.2). Although catecholamine responses to hypoglycemia were unchanged, the dose of isoproterenol necessary to increase heart rate by 25 beats/min (IC25) decreased from 1.96 +/- 0.43 mug before treatment to 1.09 +/- 0.17 mug after 4 months of treatment (P = 0.01), a value similar to that in normal participants (0.85 +/- 0.20 mug) (P > 0.2). Improvements in beta -adrenergic sensitivity (change in IC25-1) were correlated with improvements in autonomic symptoms (r = 0.65; P = 0.04). Conclusions: Avoidance of hypoglycemia in patients with type 1 diabetes who have hypoglycemia unawareness seems to restore hypoglycemia awareness, primarily by increasing beta -adrenergic sensitivity.