RECOVERY OF EPINEPHRINE RESPONSE BUT NOT HYPOGLYCEMIC SYMPTOM THRESHOLD AFTER INTENSIVE THERAPY IN TYPE-1 DIABETES

PURPOSE: Patients with intensively treated insulin-dependent diabetes mellitus (IDDM) exhibit more severe defects in counterregulatory hormone secretion and symptom recognition during hypoglycemia than do conventionally treated patients. In this prospective study in patients with preexisting defects in counterregulation, we examined the induction and reversibility of impaired symptomatic and adrenomedullary responses to hypoglycemia in 5 patients with IDDM (diabetes duration of 2 to 16 years; aged 19 to 36 years; 3 women, 2 men) who were receiving intensive therapy. METHODS: Counterregulatory responses were assessed by using a single-step (similar to 2.8 mmol/L plasma glucose) and multiple-step (from similar to 5 mmol/L to 2.2 mmol/L plasma glucose) clamped hypoglycemia procedure. Patients were first studied after a stable period of conventional insulin therapy (glycosylated hemoglobin [HbA(1c)] 9.5 +/- 1.2%), then after 3 to 5 months of intensive therapy (HbA(1c) 6.6 +/- 0.2%), and a third time after resuming conventional therapy (HbA(1c) 8.7 +/- 0.9%). RESULTS: Intensive therapy was associated with a 44% decline (P <0.01) in the average plasma epinephrine increase during hypoglycemia, and the plasma glucose level required to stimulate epinephrine secretion fell from 3.7 +/- 0.2 to 3.0 +/- 0.1 mmol/L (P <0.01). The threshold, but not the magnitude, of the plasma norepinephrine response was similarly altered. Hypoglycemic symptoms also decreased in intensity (by 67%, P <0.01), and the glucose level required for symptom activation fell from 3.4 +/- 0.3 to 2.7 +/- 0.2 mmol/L, P <0.01). When conventional therapy was resumed, the abnormalities in the epinephrine response due to intensive therapy were almost completely reversed. However, the reduction in symptoms and the altered thresholds for plasma norepinephrine were not reversed. CONCLUSIONS: There is dissociation between the treatment-associated defects in hypoglycemia counterregulation in IDDM, and an increase in average glycemia produced by a return to conventional insulin therapy is not sufficient to reverse hypoglycemia unawareness worsened by intensive therapy.