Research Article: Defective Awakening Response to Nocturnal Hypoglycemia in Patients with Type 1 Diabetes Mellitus

Date Published: February 27, 2007

Publisher: Public Library of Science

Author(s): Bernd Schultes, Kamila Jauch-Chara, Steffen Gais, Manfred Hallschmid, Eva Reiprich, Werner Kern, Kerstin M Oltmanns, Achim Peters, Horst L Fehm, Jan Born, Leif C Groop

Abstract: BackgroundNocturnal 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 FindingsWe 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).ConclusionsA 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.

Partial Text: Hypoglycemia is the limiting factor in the therapeutic management of type 1 diabetes mellitus (T1DM) [1]. Each year, about 25% of T1DM patients with intensive insulin therapy experience at least one episode of severe hypoglycemia defined by a hypoglycemic state requiring assistance of another person [2,3]. It has been estimated that about 55% of severe hypoglycemic episodes occur during sleep [4]. Mild to moderate hypoglycemic episodes lasting between 1 h and 12 h have been observed in 27%–56% of monitored nights in T1DM patients [5–12]. Although these episodes appear to be asymptomatic most of the time [7,8,11], hypoglycemic episodes during sleep constitute a particular problem in the management of T1DM, since even a single hypoglycemic episode can reduce awareness of, and neuroendocrine counterregulation against, subsequent hypoglycemia [13,14]. Hence, undetected hypoglycemic episodes during sleep may substantially contribute to the development of a hypoglycemia-unawareness syndrome frequently encountered in T1DM patients [15]. Moreover, undetected nocturnal hypoglycemia has been considered to be responsible for a large proportion of sudden deaths in young T1DM patients, i.e., the dead-in-bed syndrome [16]. Such observations suggest that hypoglycemia does not induce proper awakening in these patients, thereby preventing an adequate behavioral control of this potentially dangerous state. However, whether hypoglycemia normally induces awakening in individuals who do not have diabetes, but does not do so in T1DM patients, is at present unclear.

Our data show that a decrease in plasma glucose concentration to a nadir of 2.2 mmol/l within 1 h during sleep induces a wake-up response in most healthy control participants. In contrast, in T1DM patients, the identical hypoglycemic stimulus very rarely causes awakening. The lack of an awakening response was paralleled by an absence of clear-cut counterregulatory hormonal responses to hypoglycemia in the great majority of T1DM patients.



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