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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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Plasma Glucose Concentration during Insulin-Induced HypoglycemiaMean ± 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.
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pmed-0040069-g001: Plasma Glucose Concentration during Insulin-Induced HypoglycemiaMean ± 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.

Mentions: Before infusion of insulin, plasma glucose concentration averaged 6.7 ± 0.5 mmol/l in the T1DM patients and 5.8 ± 0.3 mmol/l in the control participants (p = 0.106). Serum insulin levels were higher in the T1DM patients than in the control participants (138 ± 24 pmol/l versus 66 ± 12 pmol/l; p = 0.012). During the insulin infusion, serum insulin levels markedly increased but did not differ between the two groups (1,110 ± 162 pmol/l versus 1,014 ± 120 pmol/l; p = 0.630). The insulin infusion started as soon as the T1DM patient's or control participant's polysomnographic recordings indicated sleep stage 2 or deeper sleep for 3 min, which was between 23:05 and 00:45 h. On average, infusion of insulin started at 23:44 h in the T1DM patients and at 23:36 h in the control participants. The following decrease in plasma glucose concentration as well as its temporal characteristics was similar between the groups (Figure 1). The nadir plasma glucose concentration in the T1DM patients reached 2.22 ± 0.01 mmol/l, and 2.24 ± 0.02 mmol/l in the healthy control participants (p = 0.982).


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)

Plasma Glucose Concentration during Insulin-Induced HypoglycemiaMean ± 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.
© Copyright Policy
Related In: Results  -  Collection

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

pmed-0040069-g001: Plasma Glucose Concentration during Insulin-Induced HypoglycemiaMean ± 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.
Mentions: Before infusion of insulin, plasma glucose concentration averaged 6.7 ± 0.5 mmol/l in the T1DM patients and 5.8 ± 0.3 mmol/l in the control participants (p = 0.106). Serum insulin levels were higher in the T1DM patients than in the control participants (138 ± 24 pmol/l versus 66 ± 12 pmol/l; p = 0.012). During the insulin infusion, serum insulin levels markedly increased but did not differ between the two groups (1,110 ± 162 pmol/l versus 1,014 ± 120 pmol/l; p = 0.630). The insulin infusion started as soon as the T1DM patient's or control participant's polysomnographic recordings indicated sleep stage 2 or deeper sleep for 3 min, which was between 23:05 and 00:45 h. On average, infusion of insulin started at 23:44 h in the T1DM patients and at 23:36 h in the control participants. The following decrease in plasma glucose concentration as well as its temporal characteristics was similar between the groups (Figure 1). The nadir plasma glucose concentration in the T1DM patients reached 2.22 ± 0.01 mmol/l, and 2.24 ± 0.02 mmol/l in the healthy control participants (p = 0.982).

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