We have performed a careful assessment of several counterregulatory hormones in children with T1DM sampled overnight after a sedentary afternoon and after exercise in the afternoon in order to examine whether antecedent afternoon exercise blunts counterregulatory hormone responses to spontaneous nocturnal hypoglycemia during the following night. Despite lower mean glucose levels and an increased incidence of hypoglycemia overnight after exercise, circulating concentrations of glucagon, GH, cortisol, and norepinephrine did not differ in these young subjects between the two nights. Most important, with the exception of epinephrine and GH, there was very little difference in counterregulatory hormone concentrations during hypoglycemia in comparison to values during the hour before and after hypoglycemia and to values at other times during the same night. Even though epinephrine concentrations rose above detectable levels significantly more frequently during nocturnal hypoglycemia in our cohort (21 vs 6%), epinephrine levels remained below the detection limits of the assay during hypoglycemia in the large majority of patients (i.e., 79%). These findings are remarkable and suggest that whether or not there was antecedent exercise, diabetic children have overall diminished counterregulatory hormone responses to spontaneous overnight hypoglycemia.
Detailed physiological studies have shown that hypoglycemia and exercise may reciprocally impair each other’s hormonal counter-regulatory responses. Antecedent hypoglycemia blunts the counter-regulatory responses to exercise, and antecedent exercise blunts the counter-regulatory responses to subsequent hypoglycemia in both healthy volunteers and subjects with T1DM (4
). Our findings of decreased hormone counterregulation during spontaneous hypoglycemia overnight are nearly identical to those previously reported by Jones and colleagues (17
) who used the hypoglycemic clamp technique to demonstrate that in children with T1DM deep sleep markedly impairs catecholamine and cortisol responses to hypoglycemia in comparison to the responses to the same hypoglycemic stimulus when subjects are awake during the day or during the night. In our study, the decreased catecholamine responses to nocturnal hypoglycemia stand in sharp contrast to the vigorous plasma norepinephrine and more consistent epinephrine responses to moderate afternoon exercise in the same subjects. In the Jones study, the impairment in counterregulatory responses during deep sleep was nearly identical in the non-diabetic and diabetic children, providing further evidence that the defects in counterregulatory hormone responsiveness were due to the sleep state itself. Their studies were performed in a sleep laboratory and hypoglycemia was induced relatively early in the night as soon as the subjects achieved stage 3–4 sleep. Our findings extend those of Jones, et al. by demonstrating that sleep-induced impairments of catecholamine and cortisol responses occurred throughout the overnight period at presumably different stages of sleep. In addition, we observed diminished catecholamine and cortisol responses to nocturnal hypoglycemia under basal rather than hyperinsulinemic conditions and in response to spontaneous rather than acute, induced reductions in plasma glucose.
Pathophysiologic mechanisms leading to the development of hypoglycemia-associated autonomic failure have not been established and are controversial. Davis and colleagues have suggested that repeated activation of the hypothalamic-pituitary-adrenal axis leading to increases in plasma cortisol plays an important role in the development of hypoglycemia-associated autonomic failure in diabetic patients (18
). In these studies, daytime hypoglycemic clamps were used to stimulate brisk cortisol responses. On the other hand, recent data showed a comparable blunting of epinephrine responses to hypoglycemia in patients with T1DM whether they had hydrocortisone treatment or metyrapone-induced cortisol blockade before hand (20
). In our recent work, our subjects showed small, clinically and statistically insignificant increases in cortisol concentrations during episodes of spontaneous nocturnal hypoglycemia. As previously reported, there was no significant increase in cortisol concentrations during antecedent exercise, whether or not hypoglycemia occurred during exercise (8
). Our data imply that episodes of hypoglycemia during the overnight period may be less likely to contribute to hypoglycemia-associated autonomic failure than daytime hypoglycemic events that stimulate a substantial rise in cortisol concentrations.
Insulin-induced hypoglycemia is a powerful secretagogue of GH that has long been used as a stimulation test of pituitary function in children with short stature. As in the Jones study (17
), nocturnal hypoglycemia was able to stimulate GH responses in our subjects. Nevertheless, mean GH concentrations were not different on the nights following exercise or sedentary days or whether hypoglycemia occurred or not. Whether or not some of the nocturnal spikes in GH in our subjects were stimulated by hypoglycemia, the net effect was that there was no discernable difference in GH concentrations on nights with versus nights without hypoglycemia. Since GH plays only a minor role in acute glucose counterregulation (21
), it is not surprising that the nocturnal increases in circulating GH concentrations that were observed in our subjects did not provide an effective defense against hypoglycemia. The failure to see a rise in glucagon concentrations during nocturnal hypoglycemia was also expected (1
). It is possible that higher hormonal responses could have been observed with more frequent sampling after the hypoglycemic episode, however since we designed the studies to treat the patients after any reported low glucose, the potential yield of such sampling was likely quite low.
The counterregulatory hormone responses to hypoglycemia may be influenced by gender and a greater blunting of hormonal counterregulation to hypoglycemia after antecedent exercise in males than females with T1DM has been reported (22
). Out of 29 subjects that developed overnight hypoglycemia we had 14 boys and 15 girls. We observed no significant gender differences in the responses except for norepinephrine. The clinical significance of this is unknown.
Numerous studies have shown that peripheral utilization of glucose is increased by exercising versus resting muscle in subjects with diabetes, even in the face of similar circulating concentrations of insulin. A recent study in adolescents with type 1 diabetes indicates that such increases in peripheral glucose utilization extend well into the night following exercise in the late afternoon (23
). Thus, children with type 1 diabetes on fixed basal insulin replacement regimens are at triple jeopardy for hypoglycemia on nights following increased physical activity than on sedentary days: peripheral glucose utilization is increased, counterregulatory hormone responses are impaired and insulin concentrations are unchanged. These data support the use of lower basal insulin doses on nights following exercise, which in patients receiving continuous subcutaneous insulin infusion therapy can be pre-programmed as an alternate basal rate into the pump. These observations also underscore the urgent need for real-time continuous glucose sensing systems that can accurately predict and alert the patient or the parent of impending hypoglycemia, especially during the overnight period.