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“An artificial pancreas given to pregnant women with diabetes could save mothers’ lives and improve the health of their babies,” BBC News has reported. The broadcaster said the device can keep sugar at normal levels for pregnant women with type 1 diabetes, for whom blood sugar control is quite difficult.

The device, which includes a small blood glucose sensor worn on the skin, was tested in a small study of 10 pregnant women with type 1 diabetes. The monitor’s ability to measure blood sugar and adjust insulin dosage accordingly was found to have a number of benefits for the women, with glucose levels being generally well-controlled.

However, this study did not compare this approach with other forms of intensive sugar control, such as manual blood sugar testing and insulin injections. Therefore the study’s results should be regarded as preliminary until further research directly compares the device against different methods. The researchers also said that, to ensure the best outcomes for the mother and baby, the mother’s glucose may need finer regulation than seen in this study.

 

Where did the story come from?

The study was carried out by researchers from the University of Cambridge, Cambridge University Hospitals NHS Foundation Trust, the Diabetes Centre at Ipswich Hospital NHS Trust and the Norfolk and Norwich University Hospital NHS Trust. It was funded by Diabetes UK, the National Institute for Health Research, the Juvenile Diabetes Research Foundation, Abbott Diabetes Care, the Medical Research Council, the Centre for Obesity and Related Metabolic Diseases, Cambridge Biomedical Research Centre and Addenbrooke’s Wellcome Trust Clinical Research Facility. The research was published in the peer-reviewed medical journal, Diabetes Care.

BBC News has reported this research and its context well, providing a balanced view of the treatment’s potential future. Describing the device as an “artificial pancreas” may incorrectly suggest that it is an implantable synthetic or mechanical organ. In fact this study was the first step in developing a system of continuous monitoring and dosing using a sensor that is taped to the arm or abdomen with a special adhesive, using a 5mm-long filament inserted under the skin to measure the level of glucose in the underlying tissue. The glucose readings from this sensor are then transmitted to a wireless receiver that can track blood sugar, and potentially control an automatic insulin delivery system that can administer adjusted insulin doses.

 

What kind of research was this?

This was a small observational study, without a comparison group, evaluating the effects of a technique known as “closed-loop insulin delivery” as a means of controlling blood sugar in pregnant women with type 1 diabetes. Type 1 diabetes occurs following the destruction of insulin-producing cells in the pancreas. This subsequently means the body is left without insulin, and is therefore unable to regulate the levels of glucose in the blood. The disease must be treated indefinitely with insulin, with a pancreatic transplant required in some extreme cases.

Pregnant women with type 1 diabetes find it particularly difficult to regulate their blood glucose because of pregnancy-related hormonal changes that affect the way insulin is metabolised, as well as changes in the baby’s weight and sugar requirements. Poor insulin control can lead to high sugar levels (hyperglycaemia), which in turn can lead to problems for the mother and baby.

The researchers were investigating the use of closed-loop insulin delivery for pregnant women both in the early and late stages of their pregnancy. This system continuously monitors the blood glucose of the patient and delivers insulin at the right dose when needed. The system has three important components, and  this study was investigating the appropriateness of a commercially available device (called the FreeStyle Navigator) for the first two of these:

• a way to continuously monitor the glucose levels
• an algorithm which can be used to convert the glucose reading into an appropriate insulin dose for delivery to the patient (this is called a model predictive algorithm)
• an insulin pump that can deliver the insulin.

Women were connected to an insulin pump in this study, but dosing was not automatic as the purpose of this research was to validate the algorithm that would determine the appropriate amount of insulin. Instead a nurse adjusted the insulin dose every 15 minutes using readings from the continuous monitoring and the algorithm.

 

What did the research involve?

Ten pregnant women, with an average age of 31 and with type 1 diabetes, were recruited to the study through three antenatal diabetes clinics in the UK. They were admitted to the research facility for 24-hour stays on two occasions; once early during their pregnancy (12 to 16 weeks) and again during later pregnancy (28 to 32 weeks). They were all receiving intensive insulin therapy either through the use of a pump or by repeated daily injections. All had a healthy pregnancy and in those with significant obesity, poor blood sugar control or other problems were not included.

The day before being admitted, the women had a FreeStyle Navigator sensor inserted into their upper arm and went through the device’s standard 10-hour calibration process to adjust it to their blood glucose levels. The women were then admitted to the research facility and had an insulin pump fitted to them. They were assessed following a standard evening meal and again after eating breakfast the next morning.

The researchers used the women’s weight, basic insulin requirements and total insulin dose in the preceding three days to adjust the algorithm to calculate how much insulin was required in relation to their blood glucose levels. At each session, the researchers determined the blood glucose levels and how much time the women had spent in their target glucose ranges. The researchers recorded any episodes of high blood sugar (hyperglycaemia) or low blood sugar (hypoglycaemia). They assessed overnight glucose control and glucose control around meal times (by measuring prandial insulin levels). They also determined how accurate the FreeStyle Navigator sensor was at detecting blood glucose by comparing it to independent measures of plasma glucose.

 

What were the basic results?

When assessing overnight glucose control, women in early pregnancy spent 84% of their time in the target range of blood glucose, and women in late pregnancy scored 100%. The women were hyperglycaemic for 7% of the night in early pregnancy but not at all during late pregnancy. No women were hypoglycaemic during the night in this study.

Around mealtimes, results were similar between early and late pregnancy, with women spending 68% to 77% of their time within the appropriate blood glucose target ranges after a large evening meal. Glucose control after the breakfast meal was achieved less well, with more women outside their target ranges compared with after the evening meals.

The FreeStyle Navigator sensor performed with no episodes of unsafe control and was deemed to be clinically acceptable about 94% of the time. There were no episodes of low blood sugar with symptoms. There was one unexplained episode of a woman in early pregnancy experiencing hypoglycaemia during the early hours of the morning.

 

How did the researchers interpret the results?

The researchers conclude that they have demonstrated the acceptability of the FreeStyle Navigator monitoring and algorithm system in women with type 1 diabetes during pregnancy. They said that the use of this system was associated with almost-normal blood glucose overnight in both early and late pregnancy, and that this indicates that the algorithm can adjust the need for insulin as necessary over the course of pregnancy.

 

Conclusion

This small “proof of concept study” has found that a system of continuous blood sugar monitoring and automatic dose calculation appears effective and safe for women with type 1 diabetes, both early and late in their gestation. The researchers found that while using the device, none of the women had symptoms of hypoglycaemia (low blood) sugar) at night. The researchers compare the results of their small study to other findings that suggest that pregnant women with type 1 diabetes spend on average 16.2% (about 1.3 hours) of the night in a state of hypoglycaemia.

The study authors also said that their system reduced the time women were hyperglycaemic (had high blood sugar) in the night. Their study found that women had blood sugar over the ideal limit 7% of the time, compared with about 36% seen in other studies.

Importantly this is not a full product that includes continuous monitoring and automatic dosing in one device. A nurse was involved in delivering the insulin according to the continuous readings fed into the algorithm every 15 minutes. It is premature to refer to the this as an artificial pancreas as it doesn’t replace its function.

The researchers said that on the basis of these findings they are planning a randomised controlled study of closed-loop insulin delivery with tighter blood glucose targets, alongside a comparison group that will be treated with other intensive control methods. This will first take place in a hospital setting and will then be extended into the home environment. In the meantime, they said that the results from this study pave the way for future research to refine the system in pregnancy.

This is well-conducted research in an important area of medicine but it is still a small, preliminary study and the results will need to be replicated in larger studies that further explore the safety and feasibility of this system for pregnant women with type 1 diabetes. Ultimately, the purpose is to reduce death and miscarriage rates in diabetic mothers and their babies, and large, long-term studies will need to assess whether this approach to glucose control can consistently deliver such benefits: better glucose control and fewer adverse outcomes.

Links To The Headlines

Extra pancreas hope for pregnancy. BBC News, January 31 2011

Links To Science

Murphy HR, Elleri D, Allen JM et al. Closed-Loop Insulin Delivery During Pregnancy Complicated by Type 1 Diabetes. [Published online before print] January 7 2011

“Chain smokers battling in vain to quit may be able to blame it on their miswired brains,” reported The Sun. It said that scientists have revealed that the problem lies in a gene within the brain that normally “squashes” the urge for more nicotine when intake reaches a critical level.

This news story is based on a study in rats and mice, so the relevance to humans is uncertain. Importantly, it is yet to be established whether humans carry this gene, and this theory of addiction has not been tested outside the lab. However, early laboratory research such as this is important and valuable, and the results suggest a future direction for research into human addictions. It will be some time before these findings translate into addiction treatment or prevention.

 

Where did the story come from?

The study was carried out by researchers from the Scripps Research Institute in Florida and the University of Colorado in the USA. It was funded by the National Institute on Drug Abuse and the James and Esther King Biomedical Research Programme at the Florida Department of Health. The research paper was published in the peer-reviewed medical journal Nature.

This is a study in genetically modified mice and rats, and the findings may not be applicable to humans. Therefore The Sun’s interpretation that “chain smokers battling in vain to quit may be able to blame it on their miswired brains” is premature.

 

What kind of research was this?

This laboratory study in rats and mice investigated the role of a certain type of receptor found in the walls of nerve cells. Nicotine is able to bind to some of the receptors in the nerve cells leading to changes that are responsible for the key feelings a smoker may describe, including heightened activity, improved reaction time and a sense of reward and satisfaction. The receptors that nicotine can bind to are called nicotinic acetylcholine receptors (nAChRs) and they are each made up of five subunits.

Previous research has found an association between tobacco addiction and mutations in the genes that are responsible for how these molecular subunits are formed. In particular, mutations in the gene that is responsible for a subunit called ‘alpha 5′ have been linked to lung cancer and COPD in smokers.

The researchers wanted to understand better the role that these receptors and genes have in the processing of nicotine in the body. They also wanted to see how important they are for the functioning of the receptor molecules.

 

What did the research involve?

The study included normal rats and mice and those that had been genetically modified not to have the gene responsible for the formation of the alpha 5 subunit. Normal mice and these mutant mice were exposed to a system where they could self-administer nicotine by pressing on a lever that would result in an hourly delivery of an intravenous dose, during a one-hour session, seven days a week. The researchers assessed whether the presence or absence of the gene had any effect on how much nicotine the mice took in and their behaviour in seeking out nicotine. In separate experiments they also increased the dose of nicotine available to the mice so that they could determine whether the mice moderated their nicotine intake themselves accordingly.

The alpha 5 subunit occurs in many different cells in the brain, but seems concentrated in a group of areas collectively known as “the habenulo”. The researchers investigated where this region was responsible for regulating nicotine intake by injecting this region of rats’ brains with a virus that carried a working copy of the gene. They then tested whether this restored the expected regulation of nicotine intake in the rats, particularly with regards to limiting intake at high doses.

In a separate set of experiments, the researchers investigated whether normal and mutant rats differed in their reward-seeking and how nicotine fulfilled this. They implanted electrodes into the brain, which rats could self-stimulate. These induced a pleasurable stimulation and the researchers measured whether the rats modified their seeking of this type of pleasure depending on their nicotine exposure.

 

What were the basic results?

Normal mice appeared to moderate their intake of nicotine so that they were consuming about 1.5mg/kg per session, while those with the mutation took in greater quantities. The mutant mice also appeared to be more motivated to seek and obtain nicotine at high doses. Mutant and normal mice were not affected differently by nicotine itself and the researchers said that a deficiency in the functioning of the alpha 5 subunit actually seemed to prevent the negative feedback that may limit the intake of nicotine. The injection of functioning genes for the alpha 5 subunit into the habenulo regions restored the functioning of the subunit.

Rats and mice with mutations in the alpha 5 subunit did not demonstrate the same limits in reward from high doses of nicotine that normal mice did.

 

How did the researchers interpret the results?

The researchers said that genetically modified mice have a reduced ability to regulate their intake of nicotine, particularly at higher doses, and that “these findings are highly consistent with the increased vulnerability to tobacco addiction in human smokers” with mutations in these genes.

They said that they have found that mutations resulting in deficiencies in the functioning of the alpha 5 subunit leads to a relative insensitivity to the inhibitory effects of nicotine on reward pathways.

 

Conclusion

These findings are an important early step in investigating the biological causes of addiction in humans. Both newspapers and the researchers have applied these findings to human health. The researchers said that their findings have important implications for understanding the high incidence of lung cancer and COPD in individuals who have variations in the gene responsible for the functioning of the nicotinic receptors in nerve cells, particularly in shaping the alpha 5 subunit.

However, this is early research and it is too soon to say that the cause of addiction has been found and that it is due to a “faulty brain”. Given the complexities of human behaviour, it is highly unlikely that a mutation in a single gene is the reason why some people are addicted to nicotine. There may be many biological and environmental reasons why someone may start smoking and why they find it difficult to stop.

It will be some time before these findings can translate into approaches to treatment or prevention of addiction. Researchers treated rats mice in this study by injecting a virus into their brains. This virus carried a functioning gene that was able to restore the role played by the alpha 5 subunit and recover the nicotine self-regulation in mutant animals. Whether such a technology could work safely in humans is not known at present.

Links To The Headlines

Fancy a smoke? You have a faulty brain. The Sun, January 31, 2011

Smoking habit linked to brain pain defect. Daily Express, January 31 2011

Links To Science

Fowler CD, Lu Q, Johnson OM, et al. Habenular a5 nicotinic receptor subunit signalling controls nicotine intake. Nature 2011