Avoidance of Hypoglycemia Restores Hypoglycemia Awareness by Increasing β-Adrenergic Sensitivity in Type 1 Diabetes

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Abstract
Lack of awareness of hypoglycemia is a major limiting factor in the management of type 1 diabetes. To examine whether reduction in the number of episodes of hypoglycemia restores hypoglycemia awareness by influencing β-adrenergic sensitivity in patients with type 1 diabetes. Controlled interventional study. Research unit and outpatient diabetes clinic of a university hospital. 10 men with type 1 diabetes and hypoglycemia unawareness (mean age [±SD], 46 ± 16 years; mean duration of diabetes, 20 ± 10 years). Strict avoidance of hypoglycemia. β-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. 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 A1c 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 µg before treatment to 1.09 ± 0.17 µg after 4 months of treatment (P = 0.01), a value similar to that in normal participants (0.85 ± 0.20 µg) (P > 0.2). Improvements in β-adrenergic sensitivity (change in IC25−1) were correlated with improvements in autonomic symptoms (r = 0.65; P = 0.04). Avoidance of hypoglycemia in patients with type 1 diabetes who have hypoglycemia unawareness seems to restore hypoglycemia awareness, primarily by increasing β-adrenergic sensitivity.