Insulin requirements vary with age and are approximately 0.5-1 U/kg/day before puberty and 1.5-2 U/kg/day during adolescence, reflecting the insulin resistance that is present during this period of rapid growth and development (Dunger, 1992). Despite numerous developments in terms of novel insulin preparations and modes of delivery, people with type 1 diabetes still experience varying states of insulin deficiency or excess that are difficult to control and predict. This is probably most evident in adolescents with type 1 diabetes in whom peripheral hyperinsulinaemia is achieved in an attempt to replace adequate levels of insulin in the portal circulation during the pubertal growth spurt (Dunger, 1992).
The DCCT highlighted the dilemma faced by all patients with type 1 diabetes (The Diabetes Control and Complications Trial Research Group, 1993). Attempts at improving glycaemic control, by intensifying diabetes management, in an effort to decrease the likelihood of the long-term microvascular complications of diabetes led to a significant increase in the risk of severe hypoglycaemia (SH). In the DCCT, subjects in the intensified treatment group had a three-fold higher risk of SH (The Diabetes Control and Complications Trial Research Group, 1993). A group of 195 adolescents, aged between 13 and 17 years, took part in this trial (The Diabetes Control and Complications Trial Research Group, 1994). Although the benefits of improved glycaemic control in terms of microvascular complications were still significant, the adolescents found it more difficult to achieve the low HbA1c concentration than adults (8.06 ± 0.13 versus 7.12 ± 0.03%; p< 0.001). Despite this, adolescents had a greater tendency towards experiencing severe hypoglycaemia: 85.7 events per 100 patient-years versus 56.9 events in the adult cohort (The Diabetes Control and Complications Trial Research Group, 1994). However, in a European-wide clinical audit, which was designed to look at metabolic control in children and adolescents, it was found that severe hypoglycaemia was as common in those centres where metabolic control was poor, as in
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Figure 9.1 Rates of (a) Severe hypoglycaemia, and (b) average HbA1c by calender year. Reproduced from Bulsara et al. (2004) with permission from The American Diabetes Association hypoglycaemia was as common in those centres where metabolic control was poor, as in those centres that achieved better control as judged by HbA1c, suggesting that research does not always reflect clinical experience (Mortensen et al., 1997).
Since 1993, ample opportunity has been present to refine the approaches to intensive insulin therapy and to improve education both for patients and physicians. Longitudinal studies of the incidence of hypoglycaemia are unusual but one audit study from a large paediatric clinic in Western Australia demonstrated an interesting trend in incidence of SH over a period of ten years (Bulsara et al., 2004). Over the first five years of the study, the incidence increased by 29% in conjunction with a decline in the average HbA1c of about 0.2% per year. Despite a continued improvement in glycaemic control, the incidence of SH appeared to plateau at this clinical centre suggesting that improved diabetes management, from more effective insulin regimens or better education, can improve blood glucose concentrations without a concomitant increase in incidence of hypoglycaemia (Figure 9.1).
The mismatch of insulin delivery and insulin requirements on standard insulin regimens is particularly evident during the night and most episodes of severe hypoglycaemia occur during sleep (Edge et al., 1990a; The Diabetes Control and Complications Trial Research Group, 1997). Current insulin replacement regimens tend to result in hyperinsulinaemia in the early part of the night, although physiological insulin requirement is at its nadir between 24:00-03:00 hours, and so exacerbates the risk of hypoglycaemia at this time (Matyka et al., 1999a; Mohn et al., 1999; Ford-Adams et al., 2003). Insulin requirements then peak between 04:00-08:00 hours and a 'dawn phenomenon' occurs which can lead to fasting hyperglycaemia (Bolli and Gerich, 1984; Edge et al., 1990b) and is thought to result from GH secretion during the later part of the night (De Feo et al., 1990; Edge et al., 1990b)
exacerbated further by the delayed effects of daytime physical activity on muscle glucose metabolism and the prolonged period of fasting that occurs overnight, especially in young children. This suggests that the overnight period is the time of greatest hypoglycaemia risk (The Diabetes Control and Complications Trial Research Group, 1997).
Few studies have examined the impact of insulin regimen on the risk of hypoglycaemia in children. The DCCT did find a significantly higher risk of hypoglycaemia among the 195 adolescents who participated in the study although this was a comparison of overall glycaemic control and not of specific regimens (The Diabetes Control and Complications Trial Research Group, 1994). A number of studies examining prevalence of hypoglycaemia have found an inverse correlation between hypoglycaemia risk and glycated haemoglobin (Table 9.2). The Hvidore Study Group has formed a collaboration between 21 international paediatric centres from 18 countries (Holl et al., 2003). The group surveyed paediatric diabetes management of 2873 children aged up to 18 years in 1995 and restudied 872 of these children in 1998. Although the use of multiple injection regimens increased from 42% to 71% this did not lead to an improvement in glycaemic control as judged by glycated haemoglobin concentrations. Although there was a tendency towards an increase in the frequency of severe hypoglycaemia in the group of children/adolescents who had had an intensification of insulin regimen, this did not reach statistical significance, perhaps because of the low number of events recorded (Holl et al., 2003).
Another study of more than 6000 children has suggested that injection regimen and centre experience, as judged by the size of the clinic, may be significant risk factors for severe hypoglycaemia (Wagner et al., 2005). In this study of children aged up to nine years, an increased risk of hypoglycaemia was observed in those children taking four insulin injections daily or on insulin pump therapy, compared to those children taking one to three injections daily.
It is important to note that even the more recent studies do not include data acquired since the introduction of the insulin analogues or the use of more physiological and intensive insulin regimens. Small studies of a few children in which insulin analogues have been compared with human insulins suggest that the risk of hypoglycaemia may be lower with analogues without compromising glycaemic control (see later section on hypoglycaemia prevention on page 209).
Children with type 1 diabetes have the same nutritional requirements as children without diabetes. However, meals and snacks containing a high proportion of carbohydrate, have to be regularly distributed throughout the day to avoid the extremes of hypo- and hypergly-caemia (Magrath et al., 1993). This can be an issue for children who do not want to be different from their peers and do not want to eat at times when there friends are playing. Toddlers can present a special problem as many do not eat regular meals but graze during the day.
Surprisingly, there has been little systematic study of the role of both quantity and quality of dietary components on the risk of hypoglycaemia. However, some studies of the prevalence of hypoglycaemia have found that a number of episodes can be attributed to missed meals (Daneman et al., 1989; Davis et al., 1997; Tupola et al., 1998b). The impact of dietary interventions in the avoidance of hypoglycaemia, mainly during sleep, have been examined, and this is discussed later in the section on hypoglycaemia prevention.
As early as 1926, it was found that exercise could potentiate the hypoglycaemic effect of insulin in patients with type 1 diabetes (Lawrence, 1926). During the first 5-10 minutes of exercising, muscle glycogen is used as the primary source of energy (Price et al., 1994). Subsequently, fuel is provided increasingly by circulating glucose, through gluconeogenesis and free fatty acids (FFAs), the release of which are under hormonal control and dependent predominantly on the portal glucagon: insulin ratio (Ahlborg et al., 1974). The acute effects of exercise are followed by restoration of the metabolic milieu. Muscle glucose uptake remains elevated as glycogen stores are replenished and although insulin sensitivity is enhanced in the period after exercise, increased glucose uptake by skeletal muscle can occur even in the absence of insulin (Cartee and Holloszy, 1990). The time taken to restore muscle glycogen to pre-exercise levels will depend on the intensity and duration of the exercise performed, and the timing and amount of dietary carbohydrate intake, but it can take several hours - typically 6-20 hours (Ivy and Holloszy, 1981; Richter, 1996).
Until recently there has been little systematic study of the impact of exercise in childhood on glucose homeostasis. One study used continuous glucose monitoring to study a standardised exercise protocol in a group of children who were using continuous subcutaneous insulin infusion (CSII). Glucose profiles were examined both during and after exercise on a cycle ergometer with the infusion pump either switched on or off (Admon et al., 2005). Hypoglycaemia was more common after exercise than during it, and this was true whether CSII was on or off. All subjects had one to three episodes of symptomatic hypoglycaemia within 2.5 to 12 hours after exercise and four subjects had asymptomatic hypoglycaemia during exercise, only one of whom had consumed extra carbohydrate because their pre-exercise blood glucose had been below 5.5mmol/l. Another study examined the impact of daytime exercise on overnight blood glucose profiles in 50 subjects aged 10-18 years on intensive insulin regimens (Tsalikian et al., 2005). On one occasion they were studied during a day of afternoon exercise, involving four periods of 15 minutes each on a treadmill at a heart rate estimated to be 55% of maximum effort for this age group, and on a separate occasion during a rest day. In this study, 22% of subjects developed hypoglycaemia during exercise; overnight hypoglycaemia was more common during the night after the afternoon exercise than during a night after the rest day (Tsalikian et al., 2005).
Studies of prevalence of hypoglycaemia have consistently found that younger children, especially those under the age of five years, are at increased risk of hypoglycaemia. This may be a consequence of increased insulin sensitivity, irregular eating patterns or impaired symptomatic awareness.
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