REDUCED BETA-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 subj ects with type 1 diabetes underwent a standardized insulin infusion pr otocol to produce a stepwise decrease in plasma glucose to 45-min plat eaus of 4.3, 3.6, 3.0, and 2.3 mmol/l. Glycemic thresholds, maximum re sponses for adrenergic and neuroglycopenic symptoms, and counterregula tory hormones were determined. Patients were classified as hypoglycemi a unaware if the initiation of adrenergic symptoms occurred at a plasm a glucose level 2 SD below that of nondiabetic volunteers. beta-Adrene rgic sensitivity was measured as the dose of isoproterenol required to produce an increment in heart rate of 25 beats per minute above basel ine (I-25) in resting subjects. RESULTS - Subjects with type 1 diabete s and hypoglycemia unawareness experienced the onset of adrenergic sym ptoms 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 counter-regulatory hormone secretion (epinephrine 2.9 +/- 0.2 vs. 4.1 +/- 0.2 mmol/l; norepinephr ine 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) respo nses were reduced in the unaware group. I-25 was greater in unaware su bjects than in subjects without unawareness (1.5 +/- 0.3 vs. 0.8 +/- 0 .2 mu g), where I-25 was not different from that of controls (0.8 +/- 0.2 mu g). CONCLUSIONS - We conclude that subjects with type 1 diabete s and hypoglycemia unawareness have reduced beta-adrenergic sensitivit y, which may contribute to their impaired adrenergic warning symptoms during hypoglycemia.