Nocturnal Hypoglycemia

Nocturnal hypoglycemia may be considered as the submerged part of the iceberg that constitutes hypoglycemia in insulin therapy. In a study of nocturnal glucose control in young children, episodes of hypoglycemia were observed in 45% of patients studied. The median glucose nadir was 1.9 mmol/L (range: 1.1-3.3) and the median duration of hypoglycemia was 270 min (range: 30-630) (22). There are a number of risk factors for hypoglycemia that are specific to the night. First, the overnight period represents the longest time without food and glucose concentrations are maintained by mobilization of liver glycogen stores and, subsequently, through gluconeogenesis. Adults with diabetes studied during the course of a day during which three mixed meals were ingested were shown to synthesize only one-third of the amount of glycogen that was synthesized by nondiabetic controls (84). This may be, in part, the result of an imbalance in the portal glucagon : insulin ratio, as rates of hepatic glycogen synthesis could be enhanced almost to those of nondiabetic subjects by increasing portal insulin during a hyperinsulinaemic hyperglycaemic clamp (85). It is possible that because mobilization of hepatic glycogen is the main mechanism of preventing hypoglycemia, decreased hepatic glycogen stores might be an important predisposing factor for the development of severe hypoglycemia in patients with type 1 diabetes, particularly overnight.

Second, the problems of mimicking background insulin requirements are exacerbated during the night. Insulin requirements vary from a nadir between 2400 and 0300 to a peak between 0400 and 0800. This so-called "dawn phenomenon" is the result of decreases in intrahepatic and extrahepatic insulin sensitivity, probably as a result of overnight GH secretion (86) and is particularly marked during adolescence. Current insulin replacement regimens lead to overinsulinization in the early part of the night, leading to the risk of hypoglycemia at this time. Then, in the early hours of the morning, insulin concentrations are waning at a time when insulin resistance is at its greatest (see Fig. 3). This may be a particular problem with conventional, nonintensified twice-daily insulin injection therapy, with the evening intermediate-acting insulin given at the time of the evening meal. In adults, delaying the evening injection of the intermediate-acting insulin to bedtime has recently been shown to benefit fasting glucose concentration and reduce risk of nocturnal hypoglycemia (88).

Nocturnal Hypoglycemia

Fig. 3. Glucose (•) and insulin (O) profiles of 16 children taking part in a study of overnight hypoglycemia who had one night of hypoglycaemia and one night without hypoglycaemia for comparison. Data are from the nonhypoglycemic night. Text boxes highlight time of "nadir" and "peak" in insulin resistance overnight. [Data from children taking part in a study of overnight hypoglycemia performed by one of the authors (87). ]

01:00 02:00 03:00 Time (hours)

Fig. 3. Glucose (•) and insulin (O) profiles of 16 children taking part in a study of overnight hypoglycemia who had one night of hypoglycaemia and one night without hypoglycaemia for comparison. Data are from the nonhypoglycemic night. Text boxes highlight time of "nadir" and "peak" in insulin resistance overnight. [Data from children taking part in a study of overnight hypoglycemia performed by one of the authors (87). ]

Third, the main defense against a severe episode of hypoglycemia is the adequate early subjective recognition of falling glucose concentrations. The great majority of episodes of nocturnal hypoglycemia, even when mild, are asymptomatic (22). The precise reason for this lack of awareness is unclear, as even those with good awareness of hypoglycemia during the day will sleep through hypoglycemia at night. However, there was strong evidence for reduced counterregulatory hormone responses during these spontaneous nocturnal hypoglycemic episodes. Epinephrine responses were blunted and there were no significant increments in either glucagon or cortisol concentrations (87). A few studies have looked for differences between daytime and nighttime coun-terregulation. No differences were found in early studies, but the stage of sleep during which hypoglycemia was induced was not considered (89). A study examining coun-terregulatory hormone responses during hypoglycemia induced during slow wave sleep (SWS) in a group of adolescents demonstrated that peak epinephrine responses were significantly lower when hypoglycemia was induced during SWS than when the subjects were awake either during the day or during the night (90). The possibility that counterregulation may be entrained to the sleep stage, reflecting altered cerebral metabolism at different times of the night, deserves further evaluation.

A possible explanation is that cerebral metabolism may be protected during different stages of sleep. Studies of normal sleep in adults have shown that during SWS, cerebral glucose metabolism is decreased, and during rapid eye movement sleep (REM), it is similar to, or even greater, than that seen when the individual is awake (91,92). Therefore, hypoglycemia occurring during SWS may cause less metabolic stress than hypoglycemia occurring at any other time.

Finally, lifestyle can influence nighttime hypoglycemia. In young children, unplanned exercise during the day may lead to delayed hypoglycemia overnight (59,62). In adolescents and adults, alcohol will play an important role in the risk of nocturnal hypoglycemia.

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