Long-Term Intensive Therapy of IDDM Patients With Clinically Overt Autonomic Neuropathy: Effects on Hypoglycemia Awareness and Counterregulation

To test the hypothesis that hypoglycemia unawareness and impaired counterregulation are reversible after meticulous prevention of hypoglycemia in IDDM patients with diabetic autonomic neuropathy (DAN), 21 patients (8 without DAN [DAN⁻]; 13 with DAN [DAN⁺]; of the latter, 7 had orthostatic hypotension [DAN⁺PH⁺] and 6 did not [DAN⁺PH⁻]) and 15 nondiabetic subjects were studied during stepped hypoglycemia (plateau plasma glucose decrements from 5.0 to 2.2 mmol/l) before and 6 months after prevention of hypoglycemia (intensive therapy). After 6 months, frequency of mild hypoglycemia decreased from ∼20 to ∼2 episodes/patient-month while HbA_1c increased from 6.2 ± 0.3 to 6.9 ± 0.2% (P < 0.05). Responses of adrenaline improved more in DAN⁻ patients (from 1.17 ± 0.12 to 2.4 ± 0.22 nmol/l) than in DAN⁺PH⁻ (from 0.75 ± 0.25 to 1.56 ± 0.23 nmol/l) and DAN⁺PH⁺ patients (from 0.80 ± 0.24 to 1.15 ± 0.27 nmol/l, P < 0.05) but remained lower than in nondiabetic subjects (4.9 ± 0.37 nmol/1, P < 0.05), whereas glycemic thresholds normalized only in DAN⁻, not DAN⁺. Autonomic symptoms of hypoglycemia improved but remained lower in DAN⁻ (6.2 ± 0.6) than in nondiabetic subjects (8.1 ± 1.1) and lower in DAN⁺PH⁺ (4 ± 0.8) than in DAN⁺PH⁻ subjects (5.1 ± 0.8, P < 0.05), whereas neuroglycopenic symptoms normalized (NS). Cognitive function deteriorated less before than after prevention of hypoglycemia (P < 0.05). Thus, intensive therapy with emphasis on preventing hypoglycemia reverses hypoglycemia unawareness in DAN⁺ patients despite marginal improvement of adrenaline responses, results in low frequency of hypoglycemia despite impaired counterregulation, and maintains HbA_1c in the range of intensive therapy. We conclude that DAN, long IDDM duration per se, and antecedent recent hypoglycemia contribute to different extents to impaired adrenaline responses and hypoglycemia unawareness.