Differences in hormonal counterregulation to nighttime and daytime hypoglycemia in awake healthy subjects

Disturbances in hormonal counterregulation may be the main reason, why many type 1 diabetic patients are asymptomatic during nighttime hypoglycemia. While it is known that sleep attenuates counterregulatory responses to hypoglycemia, the influence of the time of day on hormonal counterregulation regulation remains obscure. To address this question, we induced hypoglycemia in healthy awake subjects at two different time intervals, i.e. from 2300 to 0045 and from 0900 to 1045. Hypoglycemia was induced and maintained for 45 minutes by infusion of insulin and glucose at a level of about 2.8 mmol/l (50mg/dl). As compared to the morning hypoglycemia, epinephrine response during nocturnal hypoglycemia was markedly enhanced (p<0.001). Baseline ACTH and cortisol levels were higher in the morning than during night-time (p<0.001 for ACTH and cortisol). However, the increase of both hormones during hypoglycemia was stronger at night-time (p=0,096 and p<0.001, respectively), so that in the end of the hypoglycemic clamp, night-time levels were comparable to morning levels. Baseline glucagon levels were significantly higher during night-time than in the morning (p=0.003). In the morning, the increase in glucagon levels was more pronounced than during night-time (p=0.040). However, despite this enhanced increase during morning hypoglycemia, glucagon levels remained constantly lower than during nigh-time hypoglycemia throughout the clamp (p=0.017). Growth hormone increased strongly in response to hypoglycemia, but without any influence of the time of day on this increase (p=0.452). Data shows that most components of hormonal counterregulation against hypoglycemia are influenced by the time of day. Especially the distinctive circadian variation of epinephrine response to hypoglycemia could be clinically important for the treatment of diabetic patients, since this neuroendocrine response is known to play a crucial role in mediating the awareness of and metabolic defensive mechanism against hypoglycemia.