BRIEF TWICE-WEEKLY EPISODES OF HYPOGLYCEMIA REDUCE DETECTION OF CLINICAL HYPOGLYCEMIA IN TYPE-1 DIABETES-MELLITUS

We tested the hypothesis that as few as two weekly brief episodes of s uperimposed hypoglycemia (i.e., doubling the average frequency of symp tomatic hypoglycemia) would reduce physiological and behavioral defens es against developing hypoglycemia and reduce detection of clinical hy poglycemia in patients with type 1 diabetes mellitus (T1DM). Compared with nondiabetic controls, six patients with well-controlled T1DM (HbA (1c), 7.5 +/- 0.7% [mean +/- SD]) exhibited absent glucagon responses and reduced epinephrine (P = 0.0027), norepinephrine (P = 0.0007), pan creatic polypeptide (P = 0.0030), and neurogenic symptom (P = 0.0451) responses to hypoglycemia as expected. In these patients, 2 h of induc ed hypoglycemia (50 mg/dl, 2.8 mmol/l) twice weekly for 1 month, compa red in a random-sequence crossover design with an otherwise identical 2 h of induced hyperglycemia (150 mg/dl, 8.3 mmol/l) twice weekly for 1 month, further reduced the epinephrine (P = 0.0001) and pancreatic p olypeptide (P = 0.0030) responses, tended to further reduce the norepi nephrine and neurogenic symptom responses to hypoglycemia, and reduced cognitive dysfunction during hypoglycemia (P = 0.0271), all assessed in the investigational setting. In the clinical setting, induced hypog lycemia did not alter overall glycemic control, but did reduce the tot al number of symptomatic hypoglycemic episodes detected by the patient s from 49 to 30 per month and lowered the mean +/- SE self-monitored b lood glucose level during symptomatic hypoglycemia from 51 +/- 2 mg/dl (2.8 +/- 0.1 mmol/l) to 46 +/- 3 mg/dl(2.6 +/- 0.2 mmol/l) (P < 0.01). It also reduced the proportion of low regularly scheduled self-monito red values that mere symptomatic by similar to 33%. Thus as little as doubling the frequency of symptomatic hypoglycemia further reduced bot h the key epinephrine response and clinical awareness of developing hy poglycemia, changes reasonably expected to increase the risk of severe iatrogenic hypoglycemia in T1DM.