̽��ֱ�� of Cambridge - Graham Ladds

Surprise finding suggests diabetes drug could release rather than prevent blood sugar

Anonymous — Mon, 21 Sep 2015 10:26:18 +0000

Nearly all medications have some sort of side effects, some more unpleasant and dangerous than others. They may occur because a treatment affects the body in ways that weren’t previously anticipated, or simply because not every patient is identical.

This means there is a continual need for us to evaluate and study the medications we use. We discovered previously unidentified effects associated with a commonly prescribed diabetic medication. We found evidence that, in some cases, the treatment could actually promote the release of sugars into the blood – the opposite of what it’s designed to do. While our results, published in the Journal of Biological Chemistry, are very preliminary, they do point to a need for further investigations into how these medications work.

Diabetes affects around 347m people worldwide, a number that is growing in part due to rising levels of obesity. Type 2 or “adult-onset" diabetes occurs when cells in the body fail to respond to insulin, the chemical signal that regulates sugar and fat metabolism. This results in high sugar levels in the blood, which if untreated can damage blood vessels and nerves, leading to heart disease, strokes, kidney damage and loss of sight.

Exercise and diet changes can reduce the progression of diabetes if diagnosed early. Over time, however, most people require some form of medication. Treatments available today typically suppress sugar production and encourage the pancreas to release more insulin. This is because in a type 2 diabetes patient, the body often ignores the effects of naturally-produced insulin and, in response, produces more blood sugars, a process activated by the hormone glucagon.

New solution

Until recently, these medications were the only way to treat the disease before it had reached the stage when patients had to inject insulin themselves. In the past few years, however, a new treatment has emerged that both targets the effects of diabetes and promotes weight loss.

These therapies are based on a hormone known as glucagon-like peptide-1 or GLP-1. When you eat something, the intestine releases the hormone in order to promote insulin secretion. At the same time, it makes the stomach empty itself more slowly and makes us feel full – good news if you want a drug that can tackle obesity and diabetes at the same time.

Unfortunately, GLP-1 breaks down rapidly in the body. So in response, scientists created a number of artificial injectable versions that mimic its effects but last for much longer. While these GLP-1 mimetics have been approved for use and for treating diabetes, they are not without controversy and there is a continuous scientific and moral requirement for clinicians and scientists to evaluate and investigate their effectiveness and mechanism of action.

Our research, led by Cambridge ̽��ֱ��’s pharmacology department and Warwick ̽��ֱ��’s medical school, found that one such GLP-1 mimetic may, under specific conditions, activate the molecules in the body’s cells that recognise the signal from the hormone glucagon. Were this to happen in the liver, it could promote the release of sugars into the blood -– precisely the process that it is supposed to prevent.

It’s important to stress that these results are only initial findings and that more in-depth analysis is required. Our results, however, are likely to prove quite controversial. A limited number of published studies previously suggested that GLP-1 cannot bind to the glucagon receptor molecule at all, ruling out the possibility of this effect. Our research contradicts this.

̽��ֱ��key difference is that we studied how the treatment was affected by another molecule called RAMP2 that is found in varying amounts around the body. We found that without the presence of this molecule, the GLP-1 was able to bind with the glucagon receptor and so promote sugar release.

Ramping up the receptors

̽��ֱ��problem is that we know very little about RAMP2. Studies in mice have suggested that its levels vary in different tissues. Levels of RAMP2 appear to be lower in the liver than other areas of the body. This means there’s a chance GLP-1 mimetics could activate the glucagon receptors in liver tissue, promoting the release of sugars.

In our study, we found GLP-1 only has a limited ability to interact with glucagon receptors. But because the GLP-1 drugs are designed to reside in the body for much longer than the natural GLP-1 molecule, this may increase the chances of interaction. Another study earlier this year found that prolonged use (for more than 12 weeks) of the same GLP-1 mimetic in type 2 diabetes patients led to an increase in glucagon secretion, correlating with the results of our own study.

Our study in no way suggests that GLP-1 mimetics are at all dangerous for patients currently using them. Indeed, the beneficial effects for many patients currently outweigh the risks. But it does not mean that we should not continue to evaluate and investigate this treatment as new information about its interaction with the body emerges.

Graham Ladds, Lecturer in pharmacology, ̽��ֱ�� of Cambridge

This article was originally published on ̽��ֱ��Conversation. Read the original article.

Inset image: Diabetes (Jill Brown).

̽��ֱ��opinions expressed in this article are those of the individual author(s) and do not represent the views of the ̽��ֱ�� of Cambridge.

Graham Ladds, lecturer in pharmacology, discusses the controversy around a group of drugs used to treat Type 2 diabetes.

We should continue to evaluate and investigate this treatment as new information about its interaction with the body emerges

Graham Ladds

Dennis Skley

Diabetes 2/4

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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Study highlights possible knowledge gap over effects of some diabetes drugs

tdk25 — Fri, 18 Sep 2015 04:05:31 +0000

A gap in scientific knowledge about a family of drugs that are used to treat Type 2 diabetes has been highlighted in a new study.

Researchers behind the study say that while their results are speculative at this stage, they point to a lack of complete information about the potential impact of a group of treatments known as GLP-1 agonists, or incretin mimetics.

In particular, their survey found that one such treatment has the hitherto unrecognised potential to activate receptor sites for the hormone, glucagon. This can promote the release of sugars into the blood, which is a process that GLP-1 agonists are supposed to prevent.

̽��ֱ��paper, which is published in ̽��ֱ��Journal Of Biological Chemistry, stresses that these are only initial findings, and that more in-depth research will be needed before “definitive conclusions can be drawn” about the existing results.

̽��ֱ��researchers also say that there is no evidence that existing GLP-1 agonists are in any way dangerous for patients, but they do call for a more comprehensive approach to testing new drugs of this type, before they are released on to the market.

̽��ֱ��work was carried out by a team of researchers, led by academics from the ̽��ֱ�� of Cambridge and the ̽��ֱ�� of Warwick. Dr Graham Ladds, from the Department of Pharmacology and St John’s College, ̽��ֱ�� of 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. Understanding that picture, and being able to consider all the components of target cells for such treatments, is vital if we want to design drugs that have therapeutic benefits for diabetes patients, without any unwanted side effects.”

People affected by diabetes suffer from excessively high blood sugar levels and resulting complications, caused by the fact that their body does not produce enough insulin – the hormone that enables the uptake of sugar from food. According to the World Health Organisation, about 347 million people worldwide have diabetes and it is likely to become the seventh leading cause of death in the world by the year 2030. Among adults, Type 2 diabetes accounts for the vast majority of cases.

GLP-1 agonists are a group of injectable drugs which are normally prescribed to patients who have not been able to bring their condition under control through lifestyle changes or with first-stage, tablet treatments.

They work by imitating the effects of a naturally-occurring hormone, called a Glucagon-like peptide (GLP-1). This regulates blood sugar levels both by stimulating the release of insulin, and also by inhibiting glucagon, another hormone which allows the liver to release stored sugar into the bloodstream.

In addition, both GLP-1 and GLP-1 agonists have a number of other potentially beneficial effects. These include telling the brain when a person is full, and clinical trials have shown that some GLP-1 agonists can promote weight loss.

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

Building on previous research, however, the new study investigated the possibility that instead of activating these receptors, GLP-1, or treatments which 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.

Although a limited number of previous studies had suggested that this was not possible, the team’s lab-based tests discovered that in certain conditions, GLP-1 can 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.

̽��ֱ��researchers found that the decisive element was another protein called a receptor activity-modifying protein (RAMP2). When RAMP2 was present, it prevented the peptides – including the diabetes treatments – from binding to the glucagon receptors. In its absence, however, binding became possible.

Little is currently known about RAMP2. Tests in mice have, however, shown that its levels vary in different parts of the body. In the liver, where glucagon receptors stimulate the release of sugar into the blood, levels of RAMP2 appear to be lower than in other parts of the body. As a result, it is possible that some GLP-1 agonists could activate these receptors and, potentially, promote the effects of glucagon, which they are supposed to inhibit.

“ ̽��ֱ��work shows that, contrary to our previous assumptions, glucagon receptors can potentially be activated by anti-diabetic treatments,” Dr Ladds added. “To date, very little work has been done on RAMPs, but they clearly play an important part in the process of regulating blood sugar, which is core to helping people with diabetes. ̽��ֱ��study shows that there is a critical need to take this into account when designing new therapeutics.”

̽��ֱ��study was funded by the Biotechnology and Biological Sciences Research Council (BBSRC - Grant numbers: BB/G01227X/1 and BB/M000176/1).

Reference:
Weston, Cathryn et. al. 'Modulation of Glucagon Receptor Pharmacology by Receptor Activity-modifying Protein-2 (RAMP2).' Journal of Biological Chemistry (2015). DOI: 10.1074/jbc.M114.624601.

Scientists have found that some drugs from a group of anti-diabetic treatments may, in certain circumstances, act on glucagon receptors in the body, meaning that they could also potentially enable the release of sugar into the bloodstream.

̽��ֱ��work shows that, contrary to our previous assumptions, glucagon receptors can potentially be activated by anti-diabetic treatments

Graham Ladds

Steven Depolo via Flickr

GLP-1 Agonists are injectable drugs that regulate blood sugar levels and have also been shown to promote weight loss, making them an attractive form of treatment for Type 2 diabetes, which is often linked to obesity.

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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