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 approximately 20 to approximately 2 episodes/patient-month while HbA1c 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/l, 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 HbA1c 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.