Sleep-Related Hypoglycemia-Associated Autonomic Failure in Type 1 Diabetes

Abstract

Given that iatrogenic hypoglycemia often occurs during the night in people with type 1 diabetes, we tested the hypothesis that physiological, and the resulting behavioral, defenses against developing hypoglycemia—already compromised by absent glucagon and attenuated epinephrine and neurogenic symptom responses—are further compromised during sleep in type 1 diabetes. To do so, we studied eight adult patients with uncomplicated type 1 diabetes and eight matched nondiabetic control subjects with hyperinsulinemic stepped hypoglycemic clamps (glucose steps of ∼85, 75, 65, 55, and 45 mg/dl) in the morning (0730–1230) while awake and at night (2100–0200) while awake throughout and while asleep from 0000 to 0200 in random sequence. Plasma epinephrine (P = 0.0010), perhaps norepinephrine (P = 0.0838), and pancreatic polypeptide (P = 0.0034) responses to hypoglycemia were reduced during sleep in diabetic subjects (the final awake versus asleep values were 240 ± 86 and 85 ± 47, 205 ± 24 and 148 ± 17, and 197 ± 45 and 118 ± 31 pg/ml, respectively), but not in the control subjects. The diabetic subjects exhibited markedly reduced awakening from sleep during hypoglycemia. Sleep efficiency (percent time asleep) was 77 ± 18% in the diabetic subjects, but only 26 ± 8% (P = 0.0109) in the control subjects late in the 45-mg/dl hypoglycemic steps. We conclude that autonomic responses to hypoglycemia are reduced during sleep in type 1 diabetes, and that, probably because of their reduced sympathoadrenal responses, patients with type 1 diabetes are substantially less likely to be awakened by hypoglycemia. Thus both physiological and behavioral defenses are further compromised during sleep. This sleep-related hypoglycemia-associated autonomic failure, in the context of imperfect insulin replacement, likely explains the high frequency of nocturnal hypoglycemia in type 1 diabetes.