Defective awakening response to nocturnal hypoglycemia in patients with type 1 diabetes mellitus

Abstract

Background: Nocturnal hypoglycemia frequently occurs in patients with type 1 diabetes mellitus (T1DM). It can be fatal and is believed to promote the development of the hypoglycemia-unawareness syndrome. Whether hypoglycemia normally provokes awakening from sleep in individuals who do not have diabetes, and whether this awakening response is impaired in T1DM patients, is unknown.

Methods and findings: We tested two groups of 16 T1DM patients and 16 healthy control participants, respectively, with comparable distributions of gender, age, and body mass index. In one night, a linear fall in plasma glucose to nadir levels of 2.2 mmol/l was induced by infusing insulin over a 1-h period starting as soon as polysomnographic recordings indicated that stage 2 sleep had been reached. In another night (control), euglycemia was maintained. Only one of the 16 T1DM patients, as compared to ten healthy control participants, awakened upon hypoglycemia (p = 0.001). In the control nights, none of the study participants in either of the two groups awakened during the corresponding time. Awakening during hypoglycemia was associated with increased hormonal counterregulation. In all the study participants (from both groups) who woke up, and in five of the study participants who did not awaken (three T1DM patients and two healthy control participants), plasma epinephrine concentration increased with hypoglycemia by at least 100% (p < 0.001). A temporal pattern was revealed such that increases in epinephrine in all participants who awakened started always before polysomnographic signs of wakefulness (mean +/- standard error of the mean: 7.5 +/- 1.6 min).

Conclusions: A fall in plasma glucose to 2.2 mmol/l provokes an awakening response in most healthy control participants, but this response is impaired in T1DM patients. The counterregulatory increase in plasma epinephrine that we observed to precede awakening suggests that awakening forms part of a central nervous system response launched in parallel with hormonal counterregulation. Failure to awaken increases the risk for T1DM patients to suffer prolonged and potentially fatal hypoglycemia.

Figure 1. Plasma Glucose Concentration during Insulin-Induced Hypoglycemia

Mean ± standard error of the mean plasma glucose concentration in 16 control participants (open circles) and in 16 patients with T1DM (filled circles) during insulin-induced hypoglycemia and the subsequent 30 min. Grey horizontal bars indicate intervals of wakefulness (determined by polysomnography) in ten out of 16 healthy individuals awakening upon hypoglycemia. The black horizontal line represents time awake for the only T1DM patient who awoke during hypoglycemia. There were no differences (p > 0.45) between T1DM patients and healthy control participants in glucose infusion rates during the 1-h hypoglycemic interval or between the study participants (from either group) who did and did not wake up.

Figure 2. Sleep, Plasma Glucose, and Epinephrine Concentrations in Five Individuals during Insulin-Induced Hypoglycemia

The panels depict time courses of polysomnographically recorded sleep (black line) in parallel with plasma glucose (green line) and epinephrine (red line) concentrations during the 1-h insulin infusion (0 to 60 min). (A and B) Data from two healthy control participants who displayed the typical awakening response to hypoglycemia. (C) Data from a healthy control participant who did not awaken during hypoglycemia and remained in slow-wave sleep (sleep stages 3 and 4). (D) Data from the only one of the 16 T1DM patients who awakened during hypoglycemia. (E) Data from a typical T1DM patient who did not awaken during hypoglycemia. Note that all study participants who woke up (A, B, and D) show marked rises in epinephrine levels that always start before awakening. Note also that awakening occurred fairly abruptly in most cases (e.g., B and D), and was not preceded by a gradual lightening of sleep. (Left x-axis refers to sleep stages—awake and sleep stages 1 to 4).

Figure 3. Counterregulatory Hormonal Responses during Insulin-Induced Hypoglycemia

Mean ± standard error of the mean counterregulatory hormone concentrations during insulin-induced hypoglycemia in the 16 healthy control participants (open circles) and in the 16 T1DM patients (filled circles).