Category Archives: Science news

Can ketones lower blood sugar, and thus help diabetes?

By Jonathan Little (@DrJonLittle) and Étienne Myette-Côté, University of British Columbia

Low-carbohydrate, high-fat ketogenic diets are gaining popularity as a treatment option for type 2 diabetes because when someone eats less carbohydrates their blood sugar remain low. The diet is named after ketone bodies, compounds that the body produces when someone restricts their carbohydrate intake to very low levels.

Now, new ketone supplements that come in liquid or powder form claim to offer some of the benefits of a ketogenic diet without having to follow such a strict diet. Essentially, they allow you to drink ketones instead of relying on your body to produce them naturally. The appeal is obvious: lifestyle interventions like a ketogenic diet are hard to stick to over the long term. However, these supplements are also interesting for us physiologists because when someone eats a ketogenic diet, so many metabolic changes happen at the same time that it’s difficult to pinpoint which change caused which effect. Using ketone supplements can allow us to study the effects of ketones specifically.


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Unfortunately there is very little research on ketone supplements, particularly their impact on blood sugar or outcomes relevant to diabetes. To begin to fill this gap in knowledge, our recent research in The Journal of Physiology studied the effect of ketone supplements in healthy adults.

Introducing the ketone star: β-OHB

The most abundant and important ketone body produced by the liver during a ketogenic diet is called beta-hydroxybutyrate (β-OHB). β-OHB can be used as an alternative fuel to carbohydrates by some parts of the body including the brain, heart and muscles. In recent years, β-OHB has garnered substantial media and research attention: studies in cells and animals have shown that β-OHB has glucose lowering, anti-inflammatory, anti-oxidant, and even lifespan-extending effects (1, 2, 3, 4).

In humans, it is difficult to determine the effects of β-OHB itself due to the myriad of physiological and hormonal changes that occur when somebody follows a restrictive ketogenic diet. The first answers come from studies where researchers have infused ketones directly into the blood of participants – like with a drip feed. Several of these studies conducted over the last few decades have consistently observed that when you infuse β-OHB directly into the bloodstream of humans, their blood sugar drops (5, 6).

Although the infusion method provides insight, it lacks therapeutic application: it would be impractical to keep patients with diabetes on a ketone drip in an attempt to lower their glucose. With the blood sugar-lowering effects of β-OHB infusion having been consistently observed in the past, we became interested in studying whether the newly-developed ketone supplements might lower blood sugar levels in humans.


It would be impractical to keep patients with diabetes on a ketone drip.

Do ketone supplements lower blood sugar in humans?

Given that this was the first study (to our knowledge) to directly test this, we started by studying young healthy individuals. We recruited 20 healthy participants (10 males and 10 females, aged between 21 and 29 years) who underwent two oral glucose tolerance tests. This test involves drinking a large quantity of sugar (pure glucose) and measuring blood sugar at several time points afterwards to assess changes in blood sugar level. This test can also be used to diagnose diabetes.

One oral glucose tolerance test was performed 30 minutes following the consumption of the ketone supplement and one was performed after consuming a masked placebo. The order was random – some took the ketone supplement first and some the placebo first – and both the participants and study personnel performing the laboratory analyses were blinded, meaning that they did not know whether the participant had taken the ketone supplement or placebo.

The ketone supplement raised blood β-OHB to just over 3 mM within 30 min, levels normally seen after many weeks on a ketogenic diet or several days of fasting. This suggests that the supplements might be a good method to get β-OHB into the blood, without the hassle of a drip. When we then looked at the spike in blood sugar in response to the oral glucose tolerance test, it was much lower after drinking the ketone supplement compared to the placebo condition. Specifically, when plotted on a graph the area under the curve was decreased by ~16% when participants had the ketone supplement. Additional metabolic benefits of the ketone supplement were a reduction in levels of fatty acids circulating in the blood and an improvement in insulin sensitivity. Thus, consuming a ketone supplement was able to improve aspects of glucose regulation in healthy humans.

This study in healthy humans raises the obvious question of whether the same effects could be seen in individuals with elevated blood sugar, such as individuals with type 2 diabetes, prediabetes, or obesity.

It is not clear if our results will carry over to people with these diseases. However, a major reason for high blood glucose in type 2 diabetes is that the liver is constantly “leaking” too much glucose into the circulation. If the ketone supplement prevents this, which is what we think happens, then ketone supplements might indeed be helpful for diabetes; it’s now up to future studies to build on our findings and hopefully find the answer!


  1. Madison, L. L., Mebane, D., Unger, R. H., & Lochner, A. (1964). The hypoglycemic action of ketones. II. Evidence for a stimulatory feedback of ketones on the pancreatic beta cells. The Journal of clinical investigation, 43(3), 408-415.
  2. Youm, Y. H., Nguyen, K. Y., Grant, R. W., Goldberg, E. L., Bodogai, M., Kim, D., … & Kang, S. (2015). The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome–mediated inflammatory disease. Nature medicine, 21(3), 263.
  3. Shimazu, T., Hirschey, M. D., Newman, J., He, W., Shirakawa, K., Le Moan, N., … & Newgard, C. B. (2013). Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science, 339(6116), 211-214.
  4. Edwards, C., Canfield, J., Copes, N., Rehan, M., Lipps, D., & Bradshaw, P. C. (2014). D-beta-hydroxybutyrate extends lifespan in C. elegans. Aging (Albany NY), 6(8), 621.
  5. Mikkelsen, K. H., Seifert, T., Secher, N. H., Grøndal, T., & van Hall, G. (2015). Systemic, cerebral and skeletal muscle ketone body and energy metabolism during acute hyper-D-β-hydroxybutyratemia in post-absorptive healthy males. The Journal of Clinical Endocrinology & Metabolism, 100(2), 636-643.
  6. Miles, J. M., HAYMOND, M. W., & GERICH, J. E. (1981). Suppression of glucose production and stimulation of insulin secretion by physiological concentrations of ketone bodies in man. The Journal of Clinical Endocrinology & Metabolism, 52(1), 34-37.
  7. Taggart, A. K., Kero, J., Gan, X., Cai, T. Q., Cheng, K., Ippolito, M., … & Jin, L. (2005). (D)-β-hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. Journal of Biological Chemistry, 280(29), 26649-26652.
  8. Reaven, G. M., Chang, H. E. L. E. N., Ho, H. E. L. E. N., Jeng, C. Y., & Hoffman, B. B. (1988). Lowering of plasma glucose in diabetic rats by antilipolytic agents. American Journal of Physiology-Endocrinology and Metabolism, 254(1), E23-E30.
  9. Ferrannini, E., Barrett, E. J., Bevilacqua, S., & DeFronzo, R. A. (1983). Effect of fatty acids on glucose production and utilization in man. The Journal of clinical investigation, 72(5), 1737-1747.
  10. Balasse, E. O., Ooms, H. A., & Lambilliotte, J. P. (1970). Evidence for a stimulatory effect of ketone bodies on insulin secretion in man. Hormone and Metabolic Research, 2(06), 371-372.
  11. Senior, B., & Loridan, L. (1968). Direct regulatory effect of ketones on lipolysis and on glucose concentrations in man. Nature, 219(5149), 83.


Why dieting is bad for you

By Simon Cork, Neurophysiologist, Imperial College London, @SimonCorkPhD

According to a 2016 survey of 2000 people in the UK, almost two thirds of us are on a diet at any one time. For most people, the typical diet consists of eating a salad for lunch, and cutting out desserts and snacks. NHS guidelines for weight loss recommend reducing calorie intake by around 600 calories each day. But is this advice right?

There is a theory among many scientists in the obesity field that body weight is fixed around a “set point”. That means that for the majority of people, body weight is typically static (unless drastic changes are made to exercise or diet). Any fluctuations in our body weight are compensated for by either increasing or decreasing energy input or output. You might feel this if you’re on a low calorie diet by feeling constantly tired and feeling like you just want to sit down. That’s your body’s way of trying to conserve energy.

One method our body uses to keep its weight constant is a hormone called leptin, released by fat cells into our bloodstream. The more fat we have, the more leptin we have flowing through our blood. Normally, leptin acts in the brain to restrict appetite, effectively acting as the brake to restrict major changes in body weight. Minor increases in fat lead to increases in leptin, which reduces appetite. Loss of body fat causes decreases in leptin and thus increases in appetite to compensate. Leptin is therefore the body’s messenger to the brain, informing it of our weight.

The problem occurs when we override the effects of leptin, typically with respect to its appetite-restricting effects. More fat means more leptin, which should reduce our appetite, and thus reduce our body weight back to what our brains perceive as “normal”. However, if we override these effects (e.g. by ordering dessert after starters and a main, or eating large portions, thus eating past the point of feeling full), our brains eventually become resistant to leptin.

simon cork dieting

Leptin levels are directly correlated with body weight. Bronsky et al, 2007.

This leptin resistance effectively means that our brains are tricked into underestimating what our body weight truly is. Although a 150 kg person has more circulating leptin than a 70 kg person, the extra leptin doesn’t decrease appetite as it should because the brain has become resistant to leptin: it needs more leptin to have the same effect. The brain is therefore “tricked” into thinking the body has less fat than it really does.

This has significant consequences when people who want to lose weight go on low calorie diets. As we restrict food intake, we lose body fat. For reasons not fully understood, the levels of leptin fall at a greater rate than body fat. Our brains react by activating mechanisms to restrict any further loss of body fat and promote energy storage. One such reaction is lowering the resting metabolic rate – effectively the minimum amount of energy required to keep us alive.

You may remember a US TV series called “The Biggest Loser”. This show took overweight or obese people and subjected them to a gruelling exercise and diet regime. The contestant who lost the most weight by the end of the show won a significant cash prize. In 2016, the results of a study were released which followed the contestants after they finished the show. They found that almost all contestants regained their weight and found that some regained more weight than before they started.

And this is the crux of the matter. It has been found that people who go on crash diets significantly reduce their resting metabolic rate – effectively, they are using less energy just by being alive than before the diet. And this metabolic rate may never recover – even after stopping the diet.

This may explain why a number of contestants regained more weight after the show than they started with. Their bodies are constantly fighting against a famine. It may also be why most people who go on a diet fail to maintain their low body weight long term. This is the key issue that many people developing weight loss therapeutics are facing.

simon cork dieting 2

Calorie restriction (CR – blue line) results in significant decreases in resting metabolic rate (RMR) Davoodi et al, 2014

For many people, losing weight is relatively easy. Simply restricting calories and/or increasing the amount of energy we use, usually by exercising, will result in weight loss. Maintaining that weight loss is the key issue. Exercise is often the key to maintaining weight loss, but is difficult to maintain the necessary levels of exercise required to compensate for the decreases in energy use that occurs following dieting.

Scientists are currently investigating how to manipulate the body weight set point, by both re-sensitising the body to leptin (i.e. countering the leptin resistance), and/or by increasing the levels of naturally occurring hunger-suppressing hormones that our bodies release after eating.

If decades of dieting advice has told us anything, it’s that dieting doesn’t work to bring about long-term weight loss. But importantly, by permanently reducing the resting metabolic rate, dieting may actually be preventing our bodies ability to lose weight in the future.

Microbiome – fad or future?

By Simon Cork, Neurophysiologist, Imperial College London, @SimonCorkPhD

You may have heard many scientists and media types getting excited over the term “microbiome” recently. There was a series on BBC Radio 4 termed “The Second Genome” recently dedicated to it, and a succession of articles on the BBC News website 1 2. But what exactly is it, what does it do, and should we all be excited?

The microbiome is the term scientists give the community of bacteria that live in your guts (micro meaning small, and biome meaning biological community). People have been studying the microbiome for many years, and there is a remarkable amount of literature around the microbiome of insects. But recently, the microbiome of humans, and specifically the effects our microbiomes have on our overall health, has entered the spotlight.

In insects and other animals, the bacteria that live in and around them have remarkable effects not only on their heath but on their development. For many insects and animals, interactions with bacteria are a requirement for their survival. One particularly powerful example of the influence of bacteria on a host’s behaviour is in the fruit fly.

Feeding fruit flies different diets (and thus altering their gut microbiome composition) causes them to preferentially mate with flies fed on the same diet. When given antibiotics, which wipe out their bacteria, this preference disappears.

In humans, we are only just beginning to understand (or perhaps recognise) the importance that the microbiome has on our health. We are also beginning to understand how changes in our microbiome predispose, or even cause, certain diseases.


Less bacteria, more weight?

Take obesity for example. Worldwide, over 2.1 billion people are overweight or obese. The causes of obesity vary from person to person, but one common factor found in obese individuals is the lack of diversity of their gut bacteria. In a lean individual, the gut bacteria will contain a variety of different strains and species of bacteria. However, in individuals with obesity, this diversity is significantly reduced (with an increase in the ratio of the Firmicutes and a decrease in the Bacteoridates species).

We also know that babies who are born via caesarean section are at a higher risk of developing a number of health conditions in later life, one of which is obesity. The reasons why are not completely understood, but we know that C-section babies do not get the full complement of bacteria that babies born naturally get.

Essentially, in the first few months of life, a baby born via C-section has a gut bacterial population that more closely resembles that found on the skin, as this is often the first bacteria that they come into contact with.

Quite astonishingly, it may be possible that gut bacterial populations that predispose to disease act as a form of non-genetic inheritance of disease. For example, an obese mother, who likely has a bacterial population with a low diversity, may pass this low diversity to her child during delivery, thus predisposing them to obesity in later life.

So what does this mean? Well, the honest answer is we don’t quite know. At the moment, these observations are simply that, observations. We can predict whether or not a person will be obese or lean with 90% accuracy simply by studying the diversity of their microbiome, but what we don’t fully understand is how the bacteria are contributing to weight gain.


What’s in it for them: bacteria causing obesity? And other diseases?

One theory is that certain bacteria have the ability to harvest energy from our diets more effectively than others. Couple this with a sedentary lifestyle and you have the recipe for weight gain.

Another theory is that the bacteria are interfering with our brain chemistry. We know that many species of bacteria can secrete molecules that are either the same or have very similar chemistry to many of the molecules found in our brain, and we know that bacteria are able to secrete these chemicals in response to certain foods.

Could it be then, that our bacteria are driving our food choices? Imagine a population of gut bacteria that have a penchant for sugar; they use this as their main source of energy and want to make sure that it keeps coming. Is it possible that in response to their host eating a sugary meal, the bacteria release chemicals that tells their brain to eat more? This may sound far-fetched, but there’s increasing evidence that this may actually be happening.

There’s also increasing evidence that our gut bacteria may be driving a number of other conditions, including asthma, depression and anxiety, possibly through chemicals they release which interfere with our normal brain chemistry.

To each their own: individual differences and possible ways to shift them

So what can we do about this? Well, the bad news is this area of research is still very much in its infancy.

There are a few things we do know.

Our gut bacterial populations vary considerably from person to person, which makes a one-size fits all approach to fixing a dysfunctional microbiome tricky (although the microbiomes of people living in the same house are more similar than they are to the rest of the population).

The difficulty now is figuring out how we can shift this composition in later life. Unfortunately, downing a yoghurty probiotic drink containing a single strain of bacteria doesn’t really have much of an effect on the overall composition of the community in our guts. Many of the bacteria found in these drinks are not normally found in the guts of anyone – in fact they’re chosen largely because they can survive both the hostile journey from mouth to gut, and through the factory.

Our diets play a large role in the composition of our microbiome. And our microbiome populations become fixed during our early life. Differences in how we were delivered, whether we are breast fed or bottle fed, which country we grow up in and whether we share our house with pets, all affect the composition of our microbiome.

Perhaps the easiest way of shifting our microbiome is related to how much fibre we eat. Our bodies can’t digest dietary fibre on its own, and most of the fibre we eat makes its way to the end of our digestive tracts. This is where it feeds the bacteria in our guts, who in response not only increase their diversity (fibre feeds a lot of different kinds of bacterial species, who can all grow in its presence), but also release chemicals which are beneficial to our bodies’ health.


Poop pills: what do we know about this surprising possible obesity treatment?

However, there is another way we can shift our microbial population – faecal transplants. If we take an obese mouse, and feed its droppings to a lean mouse (thus transplanting its bacteria), that lean mouse will become obese – regardless of what it eats. The same is true if you take the gut bacteria from an obese human and transplant it into the gut of a lean mouse. That in itself is amazing.

But is the same true for humans? Well, faecal transplant (or FT) has been used clinically to treat C. difficile (or C-diff as it’s commonly known) infection. This nasty hospital-acquired infection is difficult to treat with standard antibiotics and, left unchecked, can be fatal. However, FT is an effective treatment for C-diff and is a cure for many people.

On the other hand, the literature surrounding its effectiveness for treating obesity in humans is controversial, and also risky. A lack of proper clinical trials means we don’t fully know whether it works or to what extent. Furthermore, FT has the potential to transmit a number of diseases, and given the increasing number of conditions that are being attributed to gut bacteria, the risk might just be too great given our level of understanding.

The bottom line: the future looks promising

So what’s the take home message? The microbiome is an exciting area of research, and undoubtedly will lead to treatments for a number of diseases in the future.

As it stands, our understanding is largely based on observational data – a case of correlation, rather than causation. But many people are confident causation is there, we just need the definitive proof.

In the meantime, the best thing we can do to feed our hungry bugs is to increase the amount of fibre in our diets and reduce unnecessary antibiotic use. The good news is that a lot of people are getting excited, and the gut microbiome is no longer the playground of just the microbiologists. Gut scientists, lung scientists and neuroscientists are all getting in on the action, and these collaborations are rapidly increasingly our knowledge of how the bacteria in our bowels are affecting our health. The time for the microbiome to really show its potential grows ever closer.




Guardians of the brain under pressure

By Sevda Boyanova, @boyanova_sand Hao Wang, @olivia_hao, King’s College London, UK

In England, more than 1 in 4 adults are affected by high blood pressure, making it the third most common cause of premature death, after smoking and poor diet. Globally, 1.5 billion people are expected to have high blood pressure by 2025. This ‘silent killer’ usually occurs without symptoms, and contributes to more than half of heart attacks and strokes.


Recently, scientists have revealed a connection between high blood pressure and the disruption of the gateway to the brain’s blood circulation, called the blood-brain barrier. These disruptions might lead to problems in the part of our nervous system involved in heart rate and blood pressure regulation (called the autonomic nervous system), thus contributing to high blood pressure.

So, how exactly does the blood-brain barrier work? The blood-brain barrier is the boundary between the blood flow that is circulating around our body, and the brain. Its function is two-fold: it regulates the balance of molecules flowing in and out of the brain, and also protects the brain from toxic substances. It’s formed by the cells that make up the walls of capillaries, tiny blood vessels in the brain. These cells, called endothelial cells, are joined together tightly so that blood contents cannot cross into the brain like they do in other parts of the body. The cells of the brain capillaries also contain transporters which move specific molecules across the walls of the capillaries. Surrounding the capillaries are three types of cells – astrocytes, pericytes and microglia – which work together with them to maintain a stable blood composition, allowing the brain to function properly. Scientists have implicated three players in the link between the blood-brain barrier and high blood pressure.

Blood Brain Barrier

This cake, submitted to our #BioBakes competition, represents the blood-brain barrier, with the cells of the blood vessel wall (blue) tightly joined by adhesive molecules (green squares) so that potentially harmful components in the blood cannot cross.

The first is a molecule involved in increasing blood pressure by constricting blood vessels (called angiotensin II). Angiotensin II can make the blood-brain barrier more porous which may affect the nervous system’s control of blood pressure. However, at the moment it is not clear if blood-brain barrier disruptions happen prior to or as a result of high blood pressure.

The second is molecules involved in the immune response. High blood pressure is related to low levels of inflammation (the first response when a threat to the body is detected), which is enough to activate the immune system. This activation leads to more inflammatory cells and molecules in the blood. These molecules can affect the structure of the blood-brain barrier, weakening it. Researchers have shown an increase in molecules that take part in the inflammatory response and in the production of white blood cells, during high blood pressure and heart failure. Therefore, these factors may play a part in the initial dysfunction in the blood-brain barrier, and may work alongside angiotensin II to worsen the disease.

The final player comes from the brain itself, in the form of cells that mediate inflammation. These are some of the brain cells that aren’t neurons, called astrocytes and microglia. These cells are normally involved in maintenance, surveillance and repair of the brain. However, researchers have found that microglia might be responsible for sustaining high blood pressure and astrocytes might work together with the microglia to release inflammatory molecules in response to infection by bacteria or viruses. Therefore, glial cells might have an effect on the blood-brain barrier’s ability to keep harmful molecules out. Also, there is evidence that glia could influence the activity of the autonomic nervous system (involved in heart rate and blood pressure regulation); in animal models, increased glial activation happens in brain regions important for the control of blood pressure.

The growing area of research on the link between the blood-brain barrier and high blood pressure is exciting because the blood-brain barrier is a very important target for new therapeutics. Further investigation of the mechanisms involved in maintaining the integrity of the blood-brain barrier will be useful for developing interventions targeted at treating or limiting the progression of conditions such as high blood pressure.


Setiadi, A. et al., 2017. The role of the blood-brain barrier in hypertension. Experimental Physiology.

How loud is loud: the physiology of ear ringing

by Thomas Tagoe, Accra College of Medicine, @Tom_DAT

Benedicta took in the sweet smell of flowers in the field as she felt the chill of a cool breeze blowing over her. She could hear the sound of rushing waters from the stream nearby as she lay in the grass biting into a freshly baked doughnut and marvelling at the birds flying high over-head.

In the space of a few seconds, Benedicta had all her five main senses stimulated, providing her with information about the world outside her body. Each of these senses is specialised to a specific part of the body; nose to smell and skin to touch, eyes to sight, ears to hearing, and tongue to taste. Although each of these senses is assigned to a specialised part of the body, it is all interpreted by one part of the body: the brain.


The five organs respond to different stimuli and convert it all into one type of signal, electricity, which the brain can understand. Light, sound, touch, and odours are all converted to electrical signals which the brain interprets to let us see beauty, hear melodies, and experience the world. This is part of why the brain uses 25% of the body’s energy although it makes up only 2% of the body weight.

Of all the organs and systems which convert a given sense to electrical signals, the auditory system is one of the most impressive. It converts vibrations in the air, better known as sound, into an electrical signal for the brain. Like any finely tuned machine, the auditory system can start to fall apart if abused, such as through exposure to prolonged periods of loud sound. To understand how this can happen, it is best to appreciate how the system works under normal conditions.


The outer part of the ear, known as the pinna, funnels sound in the air towards the ear canal. This is the reason cupping your hands behind your ears makes hearing better. Once the sound is channelled into the ear canal, it vibrates the ear drum which is connected to three small bones known as the malleus, incus and stapes. These three continue the chain of vibrations which ends in the cochlea, a spiral-looking organ where specialised hair cells are attached to a surface which is tuned like a guitar string. Different frequencies of sound cause vibrations in various sections to bend these hair cells; high frequency sounds like that of a whistle vibrate the bottom end while low frequency sounds like a bass drum vibrate the top end.

These hair cells are the pivotal point in the whole auditory system. Each one that bends from vibrations sends a unique electrical signal. The louder the sound, the more they bend, sending a stronger electrical signal to the brain. Once the electrical signal is in the brain, various bits of information are teased out of it to help us identify language, music, tones and much more.

Ear hair cells

So how can the whole system go wrong? Imagine the difference between beating a drum with open palms and pounding on it with clenched fists; that’s the difference between the effects of normal and loud sound. Loud sounds cause strong vibrations which can eventually destroy the hair cells. This primarily leads to hearing loss but can also lead to tinnitus, the perception of sound in the absence of an external stimulus, typically experienced as a “ringing in the ears”.

Tinnitus is an interesting condition because it suggests that somewhere in the brain, a false signal is being generated in response to a sound which does not exist in the outside world. There are a number of researchers working to understand how this occurs. Their findings suggest that after exposure to loud sound, some of the cells in the brain area called the dorsal cochlear nucleus become easily stimulated, making them respond inappropriately to signals. This and other findings could be traced back to the hair cells in the cochlea, suggesting that once these hair cells get damaged, irrevocable changes follow in the brain.

How loud is loud

The dangers posed by prolonged exposure to loud sound have been known for a while now. So much so that many countries require by law that people who work under conditions of loud sound wear ear protection. Now isn’t it quite curious that as one group of people are required by law to wear ear protectors, while another group willingly expose themselves to the same dangerous levels of sound. Think of the last time you were at a concert, on a night out, or better yet, turned up the volume in your head phones while travelling home.  The short or long-term damage caused by prolonged exposure to loud sound, whether from headphones or planes remains the same: hearing loss and tinnitus.

How do pain meds lose their effect?

By Julia Turan, Communications Manager

You know something’s not right when more Americans are dying from pain medications than illegal drugs. This opioid crisis is filling headlines, and rightly so. However, for patients with chronic pain, tolerance to opioids such as morphine, not addiction, is the real issue. Tolerance is not usually a problem for acute pain after injuries or surgery, but for chronic pain, the patients need the drug to work over a long period.

Most studies have focused on how tolerance affects individual brains cells (neurons). New research from The Journal of Physiology clarifies a piece of the puzzle of how opioid tolerance changes the communication between neurons. This brings us one small step closer to one day developing pain therapies that avoid the development of opioid tolerance.


Tolerance to a drug means that larger and larger amounts are required to achieve the desired effect. Patients can become tolerant regardless of whether or not they are addicted. Tolerance does not result from abusing the drug, but rather, it can occur even when the patients follow their course of treatment as required.

The research, led by Adrianne Wilson-Poe and Chris Vaughan at The University of Sydney looked at rat brain slices after giving the animals a low dose treatment of morphine that produces tolerance. To study this, the researchers used a technique that records electrical activity in an area called the midbrain that plays an important role in the pain-relieving effects of opioids. Rather than examine individual neurons they measured how neurons talk to each because this communication is how the brain works.


To understand their findings, we need to understand a bit about how our neurons talk to each other. To send a signal, molecules travel from the sender brain cell to the receiver across a gap called the synapse. The synapse has two sides, the pre-synapse and the post-synapse. The pre-synapse is part of the brain cell sending the message, and the post-synapse is part of the receiving cell.

One of the molecules sent between neurons is called GABA. Opioids normally decrease the release of GABA. After chronic treatment with opioids, the researchers found that their dampened effect was due to fewer molecules of GABA being available on the sending side. Consequently, opioids had less of an effect on GABA release from the sending side, as there were fewer molecules around. This reduced communication between neurons is likely to contribute to reduced effectiveness of opioids after chronic treatment.

Diet, exercise or drugs – how do we cure obesity?

by Simon Cork, Imperial College London, @simon_c_c

October 11th is officially “World Obesity Day”, a day observed internationally to promote practical solutions to end the obesity crisis. The term “obesity crisis” or “obesity epidemic” is often repeated by the media, but how big is the problem? Today, over 1.9 billion adults worldwide are overweight or obese. By 2025, this is projected to increase to 2.7 billion with an estimated annual cost of 1.2 trillion USD. Of particular concern is that 124 million children and adolescents worldwide are overweight or obese. In the UK, this equates to 1 in 10 children and adolescents and is projected to increase to 3.8 million by 2025. We know that obesity significantly raises the risk of developing 11 different types of cancer, stroke, type 2 diabetes, heart disease and non-alcoholic fatty liver disease, but worryingly, we now know that once someone becomes obese, physiological changes to the body’s metabolism make long-term weight loss challenging.

Our understanding of the physiology of food intake and metabolism and the pathophysiology of obesity has grown considerably over the past few decades. Obesity was seen, and often still is seen, as a social problem, rather than a medical issue: a lack of self-control and willpower. We now know that physiological changes occur in how our bodies respond to food intake. For example, hormones which are released from the gut following food intake and signal to the brain via the vagus nerve normally reduce food intake. However, in obesity, the secretion of these hormones is reduced, as is the sensitivity of the vagus nerve. The consequence of this is a reduced sensation of feeling full.


Imaging of the hypothalamus (a key region for keeping food intake at a balanced level) shows a reduction in activity following food intake in lean men, an effect which was absent in obesity. This effect may relate to a reduction in the body’s responses observed following food intake in obesity, such as balancing blood sugar and signalling that you are full. Furthermore, numerous studies have shown that obese individuals have a reduced availability of dopamine receptors, the structures on cells that respond to the pleasure chemical dopamine, in key brain regions associated with reward. Whether the reduction in dopamine receptor availability is a cause or consequence of obesity remains to be fully explored, but it is likely to be a combination of both of these factors. Individuals with a gene called the Taq1 A1, associated with a decreased availability of dopamine receptors, are more likely to become obese, suggesting that decreased responsiveness to high calorie foods leads to increased consumption in order to achieve the same level of reward. (Interestingly, this same gene is also associated with an increased risk of drug addiction). However, much like drug addiction, hyper-stimulation of the dopamine system (i.e. by consuming large quantities of dopamine-secreting, high calorie foods) can in turn lead to a reduction in dopamine receptor levels, thus creating a situation where more high calorie foods are required to stimulate the same level of reward.

It is therefore clear that obesity is not simply a manifestation of choice, but underpinned by complex changes in physiology which promote a surplus of food consumption, called positive energy balance. From an evolutionary standpoint, this makes sense, as maintaining a positive energy balance in times of abundant food would protect an individual in times of famine. However, evolution has failed to keep up with modern society, where 24-hour access to high calorie foods removes the threat of starvation. The good news is that we know that weight loss as small as 5% can yield significant improvements in health, and can often be managed without significant modification to lifestyle.



Presently, treatment options for obesity are limited. The first line treatment is still diet and exercise; but as the above examples of how our physiology changes show, maintaining long term weight loss through self-control alone is almost always impossible. However, the future does look bright, with new classes of drugs either recently licenced, or in production. Saxenda (a once-daily injectable drug which mimics the gut hormone GLP-1 made by Novo Nordisk) has recently been licenced for weight loss in patients with a BMI greater than 30. However, after 56 weeks treatment, average weight loss was a modest 8kg. Likewise Orlistat (which inhibits absorption of dietary fat, made by Roche) has been on the market for a number of years and shows average weight loss of around 10%. However, it is associated with unpleasant side effects, such as flatulence and oily stools. Presently, bariatric surgery is the only treatment that shows significant, long term weight loss (around 30%, depending on the surgical method used) and is also associated with long-term increases in gut hormone secretion and vagus nerve sensitivity.  Research is currently underway to assess whether the profile of gut hormones observed post-surgery can be mimicked pharmacologically. Studies have shown that administering select gut hormones in combination results in a reduction in body weight and food intake greater than the sum of either hormone when administered in isolation. This observed synergy between gut hormones will undoubtedly form the basis for future pharmacotherapies with improved efficacy, with various combinations currently in both clinical and pre-clinical trials.

For healthcare policy makers, the future obesity landscape does not make for happy reading. A combination of better therapies and improved public health messages are undoubtedly needed to stem the rising tide. However, both policy makers and society as a whole should be mindful that changes in ones physiology mean maintaining long-term weight loss through diet and exercise alone are unlikely to be the whole answer.