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 coun terregulation are reversible after meticulous prevention of hypoglycem ia in IDDM patients with diabetic autonomic neuropathy (DAN), 21 patie nts (8 without DAN [DAN(-)]; 13 with DAN [DAN(+)]; of the latter, 7 ha d orthostatic hypotension [DAN(+)PH(+)] and 6 did not [DAN(+)PH(-)]) a nd 15 nondiabetic subjects were studied during stepped hypoglycemia (p lateau plasma glucose decrements from 5.0 to 2.2 mmol/l) before and 6 months after prevention of hypoglycemia (intensive therapy). After 6 m onths, frequency of mild hypoglycemia decreased from similar to 20 to similar 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 mo re 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 lowe r in DAN(-) (6.2 +/- 0.6) than in nondiabetic subjects (8.1 +/- 1.1) a nd 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 h ypoglycemia (P < 0.05). Thus, intensive therapy with emphasis on preve nting hypoglycemia reverses hypoglycemia unawareness in DAN(+) patient s despite marginal improvement of adrenaline responses, results in low frequency of hypoglycemia despite impaired counterregulation, and mai ntains HbA(1c) in the range of intensive therapy. We conclude that DAN , long IDDM duration per se, and antecedent recent hypoglycemia contri bute to different extents to impaired adrenaline responses and hypogly cemia unawareness.