Defective Awakening Response to Nocturnal Hypoglycemia in Patients with Type 1 Diabetes Mellitus
Bernd Schultes1*, Kamila Jauch-Chara1, Steffen Gais2, Manfred Hallschmid2, Eva Reiprich1, Werner Kern1, Kerstin M. Oltmanns3, Achim Peters1, Horst L. Fehm1, Jan Born2
1 Department of Internal Medicine, University of Luebeck, Luebeck, Germany, 2 Department of Neuroendocrinology, University of Luebeck, Luebeck, Germany, 3 Department of Psychiatry and Psychotherapy, University of Luebeck, Luebeck, Germany
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
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.
Abbreviations: ANOVA, analysis of variance; CV, coefficient of variation; REM, rapid eye movement; T1DM, type 1 diabetes mellitus
* To whom correspondence should be addressed. E-mail: [email protected]
PLoS Med 4(2): e69. Open-access article distributed under the terms of the Creative Commons Attribution License.
Hypoglycemia (low blood sugar) is a frequent complication of insulin-treated diabetes, affecting patients with type 1 diabetes mellitus in particular. In individuals who do not have diabetes, insulin secretion is modified naturally and continuously by the body's own regulatory systems, depending on the blood sugar. However, in diabetes patients there is a lack of natural insulin and so manufactured insulin has to be given by injection after blood sugar testing. Hence, it is not possible for patients with diabetes to modify insulin secretion naturally in response to a change in glucose levels, and so blood glucose levels can rise and fall beyond healthy levels. In individuals who have intensive insulin therapy, hypoglycemia can be a particular problem; each year about 25% of patients on intensive insulin therapy have at least one episode of severe hypoglycemia—which requires the assistance of another person.
When hypoglycemia occurs during the day, diabetes patients can recognize it by a variety of symptoms, e.g., feeling sweaty and lightheaded, and they may either seek help from another person or treat themselves with sugar. Hypoglycemia during sleep may be very common—it has been observed to occur in up to half of the nights when patients with diabetes were monitored. The particular problem with hypoglycemia occurring during sleep is that diabetes patients may not be aware of it and hence may not be able to treat themselves or to seek assistance. It is believed to contribute to some instances of sudden death during sleep in patients with diabetes.
Why Was This Study Done?
It has not been clear whether there is a certain level of blood glucose below which a signal is triggered that provokes awakening from sleep in either diabetes patients or in individuals who do not have diabetes. The authors of this study wanted to compare responses to lowered blood glucose in diabetes patients and in individuals who do not have diabetes and to see whether the responses differed. They also wanted to look at whether there were any other hormonal changes that preceded or followed awakening after hypoglycemia.
What Did the Researchers Do and Find?
They treated two groups; 16 type 1 diabetes mellitus patients and 16 healthy control participants. With careful monitoring, on one night once stage 2 sleep (as measured by a method known as polysomnography) had been reached, they gave insulin to lower the blood glucose to a specific level (2.2 mmol/l), which would when awake give symptoms of hypoglycemia. On another night (the control night) normal blood sugar levels were maintained.
They found that only one of the 16 diabetes patients, as compared to ten healthy control participants, woke when hypoglycemia occurred. 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 substantial hormonal changes, especially with an increase in one hormone, epinephrine (also known as adrenaline), and the increases in this hormone occurred before polysomnographic signs of wakefulness.
What Do These Findings Mean?
It appears that patients with type 1 diabetes mellitus do not awake at a level of hypoglycemia that triggers waking in normal individuals. The hormonal responses that were seen in individuals who awoke may be part of a crucial response system to hypoglycemia. These results help us to understand how diabetes patients respond to hypoglycemia, but further work will need to be done to determine whether it is possible to improve the response. It should be noted, however, that the results are probably not generalizable to patients with type 2 diabetes mellitus, who represent the majority of patients with diabetes.