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Possible knowledge gap over diabetes drug side effects

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A potential gap in scientific knowledge about a class of drugs that are used to treat type 2 diabetes has been highlighted in a new study by UK researchers.

The researchers said that while their findings were speculative at this stage, they suggested a lack of complete information about the potential impact of GLP-1 agonists, or incretin mimetics.

“What we have shown is that we need a more complete understanding of how anti-diabetic drugs interact with receptors in different parts of our bodies”

Graham Ladds

They found that one of the treatments had the previously unrecognised potential to activate receptor sites for the hormone, glucagon, which can promote the release of sugars into the blood – a process that GLP-1 agonists are supposed to prevent.

The study authors, from Cambridge and Warwick universities, stressed that more in-depth research will be needed before “definitive conclusions can be drawn” based on their initial findings.

They highlighted that there was no evidence that existing GLP-1 agonists were in any way dangerous for patients, but they do call for a more comprehensive approach to testing any new drugs from the class before they were launched.

Dr Graham Ladds, from St John’s College in Cambridge, said: “What we have shown is that we need a more complete understanding of how anti-diabetic drugs interact with receptors in different parts of our bodies.

“GLP-1 agonists clearly benefit many patients with type 2 diabetes and there is no reason to presume that our findings outweigh those benefits. Nevertheless, we clearly lack a full picture of their potential impact,” he said.

GLP-1 agonists, such as exenatide and liraglutide, are a group of injectable drugs normally prescribed as a second line treatment to patient with poorly controlled diabetes.

They imitate the effects of a naturally-occurring hormone, called a glucagon-like peptide, which regulates blood glucose levels both by stimulating the release of insulin and inhibiting glucagon.

Like other peptides, GLP-1 takes effect by binding to specific receptor sites in cells. GLP-1 agonists are synthetic molecules which are designed to bind to these receptors in the same way.

The new study, published in the Journal of Biological Chemistry, investigated the possibility that instead of activating these receptors, GLP-1, or treatments that mimic it, might bind to the receptor for glucagon instead.

This belongs to the same general “family” of receptors, but activating it could cause an unwanted side-effect for people with diabetes, because it can potentially enable the release of more sugar into the bloodstream.

The researchers discovered that in certain conditions GLP-1 could bind to the glucagon receptor. Their initial experiments, carried out on yeast containing the receptor, found that it was activated not only by GLP-1, but also by a GLP-1 agonist, which was among three such drugs that the group tested.

Further experiments were then carried out in a mammalian cell culture, with similar results.

“The work shows that, contrary to our previous assumptions, glucagon receptors can potentially be activated by anti-diabetic treatments,” said Dr Ladds.

“The study shows that there is a critical need to take this into account when designing new therapeutics,” he added.

“GLP-1 receptor agonists continue to be investigated in clinical trials with careful safety monitoring by manufacturers and regulatory authorities around the world”

Novo Nordisk

A spokeswoman for Novo Nordisk, which makes liraglutide, highlighted that GLP-1 receptor agonists had been used to treat diabetes for almost a decade.

“GLP-1 receptor agonists continue to be investigated in clinical trials with careful safety monitoring by manufacturers and regulatory authorities,” she said.

“While this paper looks to be very interesting basic research, the  particular laboratory tests employing yeast is somewhat unusual,” she said.

“Numerous other publications on glucagon and GLP-1 do not support its findings, and therefore it is difficult if not impossible to extrapolate to clinical impact,” she added.

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Readers' comments (1)

  • I was diagnosed with type 2 Diabetes and put on Metformin on June 26th, 2014. I started the ADA diet and followed it 100% for a few weeks and could not get my blood sugar to go below 140. Finally i began to panic and called my doctor, he told me to get used to it. He said I would be on metformin my whole life and eventually insulin. At that point i knew something wasn't right and began to do a lot of research. On April 13th I found this book on I read the book from end to end that night because everything the writer was saying made absolute sense. I started the diet that day and the next morning my blood sugar was down to 100, the next day was in the 90's and now i have a fasting blood sugar between Mid 70's and the 80's. My doctor took me off the metformin after just one week of being on this lifestyle change. I have lost over 30 pounds in a month. I now work out twice a day and still have tons of energy. I have lost 6+ inches around my waist and I am off my high blood pressure medication too. I have about 20 more pounds to go till my body finds its ideal weight. The great news is, this is a lifestyle I can live with, it makes sense and it works. God Bless the writer. I wish the ADA would stop enabling consumers and tell them the truth. You can get off the drugs, you can help yourself, but you have to have a correct lifestyle and diet. No more processed foods.

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