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More information on individual studies within DIRECT

Prediabetes Glycaemic Deterioration (WP 2.1)

We know that some people are at a higher risk of developing diabetes than other people. We know some of the reasons why this is so. For example, risk is increased if people are overweight or if they have a family history of diabetes. However, there is still a lot we don’t know about why people get diabetes. We want to identify biomarkers that will help us find out which patient’s blood sugar levels will get worse over time and which patient’s blood sugar levels will remain the same. This will help us develop the best ways to stop and treat diabetes.

Studying people who are more likely to get diabetes, (in the “pre-diabetes” stage), may give us new information on how diabetes develops. It will also help us to work out the people who are most likely to get the disease and those who will not. It is important to remember is that many people with pre-diabetes remain at this stage for a long time and some will never get the disease.

The Patient Information Sheets provided to participants in their native language are available on request.

  • Dutch
  • Danish
  • Swedish
  • Finnish

NB. There is no English version as the Prediabetes (WP2.1) study was not conducted at any UK centres.

Type 2 diabetes progression study (WP2.2)

The level of blood sugar control changes over time in Type 2 diabetes. This is different for different patients. For example, some people manage on just diet control or one type of tablet for many years and their diabetes does not get worse. Other people cannot control their blood sugars with diet control alone or diet control plus tablets; they get worse very quickly and need to add more treatment over time to keep their blood sugar levels under control. At the early stage of diabetes, it is not possible to know how it will progress. The DIRECT studies are designed to help us understand this better and to find new tests that can predict who will get worse very quickly and who will not. This in turn will enable us to plan diabetes treatment on an individual basis.

We believe that changes in the way the beta-cells in the pancreas release insulin are a major factor in determining the changes in blood sugar levels over time. This project will work out how well the pancreas produces insulin after someone has had a meal. We believe that the amount of fat in the liver and pancreas might also affect this. Therefore the study includes magnetic resonance imaging (MRI) scan of the liver and pancreas at the start of the study.

Studying people who have early stage Type 2 diabetes (i.e. they have been diagnosed with diabetes within the last 2 years) is important. We believe that we will get the clearest picture of the changes in pancreatic beta-cell function at an early stage of the condition. This is also the time when doctors and patients attempt to plan longer term management of the diabetes and try to decide which treatments are best for individual patients.

The Patient Information Sheets provided to participants in their native language are available on request.

  • English
  • Danish
  • Swedish
  • Dutch

Extreme glycaemic response to metformin and sulfonylureas (WP 3.1)

The drug Metformin is one of the best treatments for Type 2 diabetes. It works really well for some patients but it does not work very well for others. We looked to see if there is anything special in the urine or blood of patients who respond to Metformin differently. We were particularly interested in the patients who respond exceptionally well to this treatment and those who respond poorly. By comparing these two groups of people we can attempt to work out why some people don’t respond well (and also why some do respond well!).

The Patient Information Sheets provided to participants in their native language are available on request.

  • English
  • German

Metformin intolerance study (WP3.2)

On the Patient Information Leaflet provided with the packaging of the drug Metformin it says that gastrointestinal problems such as nausea, vomiting, diarrhoea, stomach pain or loss of appetite are very common side effects of metformin (affecting more than 1 in 10 people). These side effects are more marked for some people than for others.

We wanted to understand why some patients with diabetes develop severe gut related side effects to metformin, whereas other people can take it in high doses without any side effects at all. We believe that studying people who have had severe gut related side effects to metformin in the past will help to give us a clearer understanding of why some people develop side effects and others don’t.

GLP-1R analogues (WP3.3)

Some patients are started on an injection to help treat their diabetes. These injections are a type of drug called a GLP-1 Receptor Analogue (GLP-1RA), and currently there are three available types of this drug. They are called Exenatide (Byetta or Bydureon), Liraglutide (Victoza) and Lixisenatide (Lyxumia). This type of treatment has been used around the world for the last few years and can have some dramatic results both in terms of stabilising blood sugar levels and helping with weight loss. This is why this treatment can be popular with patients and their doctors. However, some patients’ blood sugar levels do not improve very much with these injections. Other patients do really well, and may end up reducing the dose of some of the other drugs they use or indeed stopping some other drugs altogether.

This study tried to find out why people respond differently to treatment with GLP-1RA. This research may show that we can predict in advance that someone is not likely to respond to treatment. This would mean that they would not have to inject the treatment for at least 6 months and put up with any side effects. On the other hand, if we find out why some people respond very well to this sort of drug, we may be able to develop better drugs that work in more people.

Acute beta-cell secretagogues (WP3.4)

This study combines two existing sets of study data from Copenhagen, Denmark and Leiden, The Netherlands.

In the Danish study, two studies called the “family study” and the “UNG92” study had been performed previously quite a long time ago. All the participants were given an intravenous glucose tolerance test followed by a glucose infusion and tolbutamide (sulphonylurea) infusion. The purpose of the tests (or stimuli) was to cause the production of insulin to see how well the beta cells in the pancreas were working. Some of the patients were studied again after many years had passed, allowing the comparison between their samples from the different visits to see how age had affected the function of the beta cells in the pancreas. In the UNG92 study, at the time of the second test all the participants were young individuals aged 18-32 years. They were not diabetics. In the family study though, the participants were diabetics. Their children and wives/husbands were studied as well. Some of the children had diabetes and some did not. This allowed the researchers to look at what genes might influence whether or not the children developed diabetes.

In the Dutch study, called the “hyperglycaemic clamp study”, the participants were firstly given an infusion of glucose to stabilise the level of blood sugars and then given an infusion of an enzyme called GLP-1 followed by an infusion of arginine. Again, the purpose of the tests was to stimulate the production of insulin. The GLP-1 is a hormone released from the stomach after eating that tells the pancreas to produce insulin. Since it is released into the blood from the stomach (i.e. secreted), it is called a “secretagogue”. The arginine response is a measure of near maximal insulin secretion so it measures what the pancreas in that person is capable of if it was working at its absolute hardest. The participants included different types of twins (identical and non-identical twins) and also their brothers and sisters. The majority of the participants showed no signs of diabetes at the time they were tested.

The DNA from the participants in both these studies has been examined to see if there are any particular genes that might influence insulin response to the stimuli that were used, as well as to study the inheritance of diabetes.

Also the blood from the participants was studied to see if any biomarkers could be found that either predicted the response to stimuli or were changed after the stimuli were added.

By combining the data from these 2 studies we have been able to ask a number of important questions and to study why some people’s beta cells in their pancreas work very well and others do not. We have also been able to study why diabetes passes down in families between parent and child.

The Patient Information Sheets provided to participants in their native language are available on request.

Early remission of diabetes following metabolic surgery (WP 3.5)

It is well known that patients with obesity who undergo bariatric surgery to reduce the size of their stomach sometimes have remission of diabetes i.e. their diabetes gets significantly better and sometimes goes away. As a result of the surgery the patients lose a lot of weight afterwards but interestingly their diabetes improves before they have lost significant weight. This suggests that the removal of a part of the stomach might have a lot to do with the diabetes going away. The stomach releases many different hormones when it receives a meal. These tell our brains that we are full and need to stop eating and they also tell our pancreas to work, since as the meal is absorbed and the blood sugars rise, insulin is needed to control the blood sugar level. This close coordination is vital to keep the body working properly.

This study attempts to find out how stomach reduction surgery leads to remission of diabetes. In particular we are looking to find new drug targets that might be present in the stomach, that influence diabetes. We are also seeking biomarkers of successful diabetes remission.