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

Schultes B, Jauch-Chara K, Gais S, Hallschmid M, Reiprich E, Kern W, Oltmanns KM, Peters A, Fehm HL, Born J - PLoS Med. (2007)

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, University of Luebeck, Luebeck, Germany. schultes@kfg.uni-luebeck.de

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.

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Counterregulatory Hormonal Responses during Insulin-Induced HypoglycemiaMean ± 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).
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pmed-0040069-g003: Counterregulatory Hormonal Responses during Insulin-Induced HypoglycemiaMean ± 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).

Mentions: In parallel with the awakening response, an above-threshold response of epinephrine (p = 0.005) and ACTH (p = 0.003) to hypoglycemia was observed distinctly more often in the control participants than in the T1DM patients (Table 2). As depicted in Figure 3, control participants responded to hypoglycemia with strong increases in mean concentrations of epinephrine (p = 0.005, for the ANOVA time factor), norepinephrine (p < 0.001), ACTH (p = 0.009), cortisol (p = 0.015), and growth hormone (p = 0.012). In contrast, in the T1DM patients, these responses were weaker and not significant (p = 0.278, p = 0.367, p = 0.166, p = 0.572, and p = 0.740, respectively). ANOVA confirmed differences in hormonal responses to hypoglycemia between the groups for epinephrine (p < 0.001, for the ANOVA “group × time” interaction term), norepinephrine (p = 0.006), ACTH (p = 0.037), and cortisol (p = 0.001). The differences in the responses between groups for growth hormone were not significant (p = 0.084). Glucagon concentrations remained unchanged by hypoglycemia in both healthy control participants (p = 0.153) and T1DM patients (p = 0.842). Overall, glucagon levels were lower in the T1DM patients than in the control participants (p = 0.025).


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

Schultes B, Jauch-Chara K, Gais S, Hallschmid M, Reiprich E, Kern W, Oltmanns KM, Peters A, Fehm HL, Born J - PLoS Med. (2007)

Counterregulatory Hormonal Responses during Insulin-Induced HypoglycemiaMean ± 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).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1808097&req=5

pmed-0040069-g003: Counterregulatory Hormonal Responses during Insulin-Induced HypoglycemiaMean ± 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).
Mentions: In parallel with the awakening response, an above-threshold response of epinephrine (p = 0.005) and ACTH (p = 0.003) to hypoglycemia was observed distinctly more often in the control participants than in the T1DM patients (Table 2). As depicted in Figure 3, control participants responded to hypoglycemia with strong increases in mean concentrations of epinephrine (p = 0.005, for the ANOVA time factor), norepinephrine (p < 0.001), ACTH (p = 0.009), cortisol (p = 0.015), and growth hormone (p = 0.012). In contrast, in the T1DM patients, these responses were weaker and not significant (p = 0.278, p = 0.367, p = 0.166, p = 0.572, and p = 0.740, respectively). ANOVA confirmed differences in hormonal responses to hypoglycemia between the groups for epinephrine (p < 0.001, for the ANOVA “group × time” interaction term), norepinephrine (p = 0.006), ACTH (p = 0.037), and cortisol (p = 0.001). The differences in the responses between groups for growth hormone were not significant (p = 0.084). Glucagon concentrations remained unchanged by hypoglycemia in both healthy control participants (p = 0.153) and T1DM patients (p = 0.842). Overall, glucagon levels were lower in the T1DM patients than in the control participants (p = 0.025).

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, University of Luebeck, Luebeck, Germany. schultes@kfg.uni-luebeck.de

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.

Show MeSH
Related in: MedlinePlus