Sleep-Related Hypoglycemia-Associated Autonomic Failure in Type 1 Diabetes
Reduced Awakening From Sleep During Hypoglycemia
- From the Division of Endocrinology, Metabolism, and Lipid Research, General Clinical Research Center and Diabetes Research and Training Center, Washington University School of Medicine, St. Louis, Missouri
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.
Address correspondence and reprint requests to Philip E. Cryer, M.D., Campus Box 8127, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. E-mail:.
Received for publication 13 November 2002 and accepted in revised form 10 February 2003.
HAAF, hypoglycemia-associated autonomic failure.