No More Nightmares

For many young people and their parents, nocturnal (night-time) hypoglycaemia (low blood sugar) is perhaps the most feared short-term complication of diabetes. Intensive diabetes control is beneficial for all people with the condition – maintaining good blood glucose control overnight is critical in reducing the body’s exposure to high glucose. But it increases the risk of a dangerous drop in blood glucose levels while people are asleep.
 
After an evening meal, person’s blood glucose levels are maintained throughout the period of overnight fasting by the production of glucose in the liver. This is regulated by insulin. In people with diabetes, if no insulin is taken overnight, their blood glucose at normal levels.
 
Due to other hormonal changes which occur in the body overnight, insulin requirement are not constant, and are usually higher towards the end of the night. This is why people on a fixed dose of insulin overnight may experience a rise in blood glucose levels towards the morning – the so called ‘dawn phenomenon’ – while remaining at risk of hypoglycaemia between around 2am to 4am. Insulin requirements may not be the same from one night to the next.

There are other variables: the insulin requirements of adults and children may vary according:
• To the rate at which they metabolise their evening meal
• The amount of exercise they take – exercising in the evening affects night time blood glucose
• Their age – age and puberty-related changes affect a young person’s insulin requirements.

Nocturnal hypoglycaemia arises largely through a mismatch of insulin delivery to insulin requirements, which, importantly, might not be the same from one night to the next.

Scale of the problem
The extent of the problem in nocturnal hypoglycaemia in children and adolescences has become clearer over the past few years, with the development of continuous glucose monitoring systems – up to 50% of children and adolescents will have very low blood glucose levels for long periods over-night.

This is the case for young people who inject insulin twice or three time a day, and even those on multiple(three or more) injection or insulin pump therapy.
The episodes tend to be asymptomatic (show no symptoms): the children do not wake up or become aware of the low levels. This might be explained by the weakening during sleep of the normal counter-regulatory mechanisms, which should come into play to push blood glucose up when these become low.

Walking on thin ice
Fortunately, studies to date do not show any adverse effects in terms of intellectual functioning the day after an episode of nocturnal. However, there is a suggestion that night-time lows may affect mood: children may wake up somewhat irritable. The concern is that these young people are ‘walking on thin ice’ overnight.
Any further change in their insulin dose, eating habits or level of physical activity in the evening could lead to a severe ‘hypo’. It also suggested that low overnight blood glucose levels might make people less aware of having low glucose during the day. Such ‘hypoglycaemic unawareness’ puts young people at high risk of sudden, unexpected and disabling hypoglycaemia.

Reducing the risks
Our ability to monitor changes in glucose levels from one minute to the next over periods of up to three days using continuous blood glucose sensors has revealed the extent of the problem of nocturnal hypoglycaemia. It also provides us with a useful tool for evaluating modifications in insulin therapy which could reduce the risks.
We now know that dividing the daytime insulin dosage into three to four injections and using new short – and long-acting insulin analogues – taking the long-acting insulin last thing at night can reduce the risk of nocturnal hypoglycaemia
Furthermore, continuous glucose sensors can be used by children with diabetes as well as their parents or other cares to predict episodes of nocturnal hypoglycaemia and take appropriate evasive action.
As a general rule, if blood glucose levels are low the morning around 8am to 9am, this usually indicates that they were much lower during the ight – between 2 am and 4 am. This problem can be avoided, in part at least, through the use of insulin analogues or a pump.
The analogues reduce the high levels of insulin that are typical between 2am and 4am; pumps can be programmed to deliver smaller amounts of insulin early in the night compared with the later period.

Closed-loop solutions
The risk of nocturnal hypoglycaemia will be almost entirely eradicated if the future development of so-called ‘closed-loop’ system is successful.
In a ‘closed-loop’ system:
• A continuous glucose sensor informs an insulin pump as to the best amount of insulin.
• If this dose leads to a fall in glucose levels, the pump receives a signal to reduce the amount of insulin.
• If blood glucose continues rising quickly, the pump is instructed to deliver a larger dose.
Given that we already have the technology for glucose sensing and insulin pump delivery, developing such a closed loop system might appear quite straight forward. However, the solutions are actually very complicated.
A key problem is the long interval that might occur between sensing blood glucose concentrations and delivering the appropriate amounts of insulin. Here, the skills of metabolic modellers are essential. They derive an algorithm (formula) that can reliably predict the outcome, whether a young person continues with a given rate of insulin delivery or makes minor changes.
Fortunately, such mathematical expertise has been developed, and closed-loop systems are at last being clinically evaluated. Nocturnal hypoglycaemia will be eradicated if the development of ‘closed loop’ system is successful.
The path to closed-loop control is clearly marked. Clinical testing will be preceded by the development of prototypes which use approved glucose sensors and insulin pumps, and establish wireless communication between the components.
Collaboration and academia is likely to give rise to successful results most quickly – as demonstrated by the two-year ‘Artificial Pancreas Project’, which was established in 2006 by the Juvenile Diabetes Research Foundation.
Private companies provide the continuous glucose sensors and insulin pumps while academics develop dosing algorithms, integrate the components, and carry out clinical studies.

Hope for the Future
The doubt remains as to whether or not the existing continuous glucose sensors are sufficiently accurate and reliable to drive insulin delivery in a closed-loop fashion. Once demonstrated – there appears to be solid support for a positive answer – the next challenge will be to take the testing of closed-loop systems out of the controlled laboratory environment and into the community.
The ongoing discussions between researchers, industry and regulatory bodies are ensuring that the necessary regulatory framework will be ready within about two years.
Clinical testing will establish the ability of closed-loop systems to improve glucose control and reduce the risk of nocturnal hypoglycaemia. It is hoped that the first generation of commercial closed-loop systems will be available in a few years.
However, these systems are unlikely to be fully autonomous. They might remind us of the first generation of mobile phones, bulky and with limited functionality, but should provide firm foundations for the technology to mature while progressively reducing, and possibly entirely eliminating, the nightmare of nocturnal hypoglycaemia.

 

APP/KOL/AC 01/08/2007


Shelia O’Kelly Editor, Diabetes Ireland