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Editorial |
Department of Pediatrics, Barbara Davis Center, University of Colorado Health Sciences Center, Aurora, Colorado 80045-6511
Address all correspondence and requests for reprints to: H. Peter Chase, Professor of Pediatrics, Barbara Davis Center, University of Colorado Health Sciences Center, Mail Stop A140, P.O. Box 6511 Aurora, Colorado 80045-6511.
The article by Raju et al. (1) in this issue of the Journal of Clinical Endocrinology and Metabolism evaluates four treatments for the prevention of nocturnal hypoglycemia in subjects with type 1 diabetes. Preventing nocturnal hypoglycemia is an important issue for all people with diabetes. In the Diabetes Control and Complications Trial (DCCT), approximately 55% of severe lows occurred during the nighttime hours (2). In children, up to 75% of severe lows have been reported to occur during the nighttime hours (3). The fear of severe hypoglycemia is often a limiting factor in attaining optimal glycemic control.
The 21 adults in this study included 11 who were using continuous sc insulin infusion, nine who were using insulin glargine, and one who used only NPH as the usual insulin therapy. The resultant basal insulin therapy from both continuous sc insulin infusion and glargine has consistently resulted in fewer severe nocturnal hypoglycemic events than with an insulin such as NPH, which peaks during the nighttime hours (4). Despite the primary use of basal-bolus insulin therapy, 27% of the laboratory-measured nocturnal glucose levels were less than 70 mg/dl (3.9 mmol/liter), the currently accepted level defining hypoglycemia (5). These results are very similar to the recent data reported by DirecNet for children on a nonexercise night, in which 28% of the 50 children had laboratory-measured glucose levels less than 60 mg/dl (< 3.3 mmol/liter) (6). The chance of a low nocturnal glucose level in that study was almost doubled (48%) if the children had 1 h of active afternoon exercise. Clearly nocturnal hypoglycemia continues to be a major concern for any person with diabetes. Unfortunately, in the current study, neither the snack, with or without acarbose, nor the uncooked cornstarch bar prevented nocturnal hypoglycemia. Only the terbutaline had a significant effect in preventing hypoglycemia, although 19% of values were still in the hypoglycemic range, and the dose used resulted in morning hyperglycemia [193 ± 15 mg/dl (10.7 ± .8 mmol/liter)]. As the authors note, further research will be needed to determine whether there is a more optimal dose of terbutaline that will decrease the incidence of hypoglycemia and not result in hyperglycemia. The use of this therapeutic agent could obviously be very beneficial in people who have had severe nocturnal hypoglycemia and/or hypoglycemia unawareness.
Most care providers do not appreciate the frequency of low blood glucose levels during the night. In this study, the subjects who did not have a snack were hypoglycemic [<70 mg/dl (< 3.9 mmol/liter)] on 57% of the nights, and the average duration of hypoglycemia was more than 2.5 h. With the bedtime snack, the subjects were hypoglycemic on 43% of the nights, with the slight improvement being in the early hours of sleep. Both the acarbose and cornstarch bars continued to result in hypoglycemia in more than 50% of the nights. The subjects were asked to avoid strenuous exercise on the study days. Presumably the hypoglycemia would have been even more frequent had the study nights followed days with strenuous exercise. In a recent report by Bode et al. (7) of glycemic characteristics in subjects with type 1 (n = 60) or type 2 (n = 41) diabetes, 8% of their time was spent in the hypoglycemic range. This amounted to 2.3 h/d for the type 1 subjects and 1.0 h/d for the type 2 subjects, with the episodes more likely to occur nocturnally. Presumably, the duration of hypoglycemia at night is related to the degree of neuroglycopenia and the eventuality of having a severe hypoglycemia event. Perhaps it is surprising that severe hypoglycemia events are not more frequent than they are. In the DCCT, the intensively treated subjects had the likelihood of a severe hypoglycemic event every 1.6 yr (62 events per 100 patient-years) (8). This has apparently decreased with basal/bolus insulin therapy (4), although prospective comparable data to the DCCT are not available.
An obvious question is, Why do people with type 1 diabetes average only one severe hypoglycemic event every 1.6 yr if they have hypoglycemia approximately every other night? The answer is not known. Some severe cases may not be recognized as hypoglycemia (a morning headache or other ubiquitous symptoms). Obviously, sometimes the person awakens and treats the low glucose level. Most likely the main reason severe lows are not more common is that despite reduced counterregulatory hormone production (9), the person manages to increase their glucose levels. This will likely never be fully investigated because it is unethical not to treat a person (subjects in this study were treated) when glucose levels are low.
Before giving up on the traditional use of bedtime snacks to try to prevent nocturnal hypoglycemia, studies using higher carbohydrate content (26 g used in this study) or higher fat content (6 g fat used in this study) might be considered. A previous study (10) did not find a benefit from increasing protein at bedtime. When fat was increased in a breakfast meal, glucose levels remained higher for a longer time period, regardless of whether the carbohydrate was simple or complex, and further studies of fat content in the bedtime snack would be useful (11).
In contrast to the usual bedtime snacks to prevent nocturnal hypoglycemia, the use of a therapeutic medicine without adding extra calories might be advantageous. Increased weight gain has been shown to be a problem for people with type 1 or type 2 diabetes using intensive insulin therapy (12, 13). Rather than a short-term trial as described by Raju et al. (1), a long-term trial of terbutaline would be of interest to evaluate changes in body weight.
Hypoglycemic episodes may interfere with attaining optimal glycemic control in other ways than just the fear factor noted earlier. As noted in the Raju article, secondary high glucose levels are not likely due to the Somogyi phenomenon. They are more likely due to the overeating that is so common with feeling hypoglycemic. The high glucose levels then contribute to a higher hemoglobin A1c level (despite frequent hypoglycemia) as well as a greater risk for the microvascular (8) and the cardiovascular (14) complications of diabetes. Clearly, the prevention of hypoglycemia is a major goal in the treatment of diabetes.
The authors note that the continuous glucose monitoring as used retrospectively in this study would have missed at least 12% of the low glucose levels and had at least 14% false positives (erroneous lows). Although this might not be acceptable to subjects using real-time home continuous glucose monitoring, there is hope that more accurate second-generation glucose monitoring devices are on the horizon. If this is the case, alarms to warn people of a low glucose level, or of a rapidly falling glucose level, should be of great value in preventing severe hypoglycemia. Until this time comes, the search for protective agents, such as terbutaline, may be our best hope.
Footnotes
Abbreviation: DCCT, Diabetes Control and Complications Trial.
Received March 23, 2006.
Accepted March 24, 2006.
References
This article has been cited by other articles:
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  K. Jauch-Chara, M. Hallschmid, S. Gais, K. M. Oltmanns, A. Peters, J. Born, and B. Schultes Awakening and Counterregulatory Response to Hypoglycemia During Early and Late Sleep Diabetes, July 1, 2007; 56(7): 1938 - 1942. [Abstract] [Full Text] [PDF]
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