Reduced β-adrenergic sensitivity in patients with type 1 diabetes and hypoglycemia unawareness

OBJECTIVE - We tested the hypothesis that impaired tissue sensitivity to catecholamines contributes to hypoglycemia unawareness in subjects with type 1 diabetes. RESEARCH DESIGN AND METHODS - A total of 21 subjects with type 1 diabetes underwent a standardized insulin infusion protocol to produce a stepwise decrease in plasma glucose to 45-min plateaus of 4.3, 3.6, 3.0, and 2.3 mmol/l. Glycemic thresholds, maximum responses for adrenergic and neuroglycopenic symptoms, and counterregulatory hormones were determined. Patients were classified as hypoglycemia unaware if the initiation of adrenergic symptoms occurred at a plasma glucose level 2 SD below that of nondiabetic volunteers. β-Adrenergic sensitivity was measured as the dose of isoproterenol required to produce an increment in heart rate of 25 beats per minute above baseline (I₂₅) in resting subjects. RESULTS - Subjects with type 1 diabetes and hypoglycemia unawareness experienced the onset of adrenergic symptoms at a lower plasma glucose level than did those with awareness (2.5 ± 0.1 vs. 3.7 ± 0.1 mmol/l, P < 0.001), whereas neuroglycopenic symptoms occurred at similar glucose levels (2.7 ± 0.2 vs. 2.8 ± 0.1 mmol/l). The plasma glucose levels for counterregulatory hormone secretion (epinephrine 2.9 ± 0.2 vs. 4.1 ± 0.2 mmol/l; norepinephrine 2.7 ± 0.1 vs. 3.2 ± 0.2 mmol/l; cortisol 2.5 ± 0.2 vs. 3.3 ± 0.2 mmol/l, P < 0.01) were also lower in subjects with unawareness. The maximal epinephrine (1,954 ± 486 vs. 5,332 ± 1,059 pmol/l, P < 0.01), norepinephrine (0.73 ± 0.14 vs. 1.47 ± 0.21 nmol/l, P = 0.04), and cortisol (276 ± 110 vs. 579 ± 83 nmol/l, P < 0.01) responses were reduced in the unaware group. I₂₅ was greater in unaware subjects than in subjects without unawareness (1.5 ± 0.3 vs. 0.8 ± 0.2 μg), where I₂₅ was not different from that of controls (0.8 ± 0.2 μg). CONCLUSIONS - We conclude that subjects with type 1 diabetes and hypoglycemia unawareness have reduced β-adrenergic sensitivity, which may contribute to their impaired adrenergic warning symptoms during hypoglycemia.