Not so sweet

Susan Swithers, professor of behavioural science at Purdue University, US, is piling up evidence that points to no-calorie sweeteners having an impact on our biochemistry. She also suspects that sweeteners are bad for us. ‘Artificial sweeteners don’t come into my house. My kids don’t consume diet sodas,’ she says, adding, ‘People may have been misled about what these products can actually accomplish.’

Indeed, much epidemiological data supports Swithers, with several large-scale trials indicating a correlation between artificial sweetener consumption and weight gain. For example, drinkers of artificially sweetened drinks were consistently found to have a higher body mass index in the San Antonio Heart Study, which followed over 3000 adults for at least seven years. The consensus from intervention studies indicates that artificial sweeteners do not help reduce weight when used alone (Q. Yang, Yale Journal of Biology and Medicine, 2010, 83, 101).

How could this be true if artificial sweeteners have little or no calories? Swithers suggests: ‘These sweeteners could be undermining the learned relationships that are important to regulate consumption. In a world without artificial sweeteners, one of the most reliable predictors of calories would be to taste something sweet,’ she says. A way to scramble that clear signal would be to introduce a sweet taste into the mouth and then not provide the expected calories.

Swithers has looked at the consequences of giving animals diets where sweet taste is a good predictor of calories, compared with diets where it is not. ‘The animals also have regular food to consume and what happens is the animals that get saccharin sweetened dietary supplements end up gaining more weight than the animals that get the sugar sweetened versions. This is partly because they over-eat their regular food and partly because they expend less energy,’ explains Swithers (Behavioral Neuroscience, doi: 10.1037/0735-7044.122.1.161). She recently outlined how frequent consumption of high-intensity sweeteners could be knocking the metabolism of people off kilter, leading to problems controlling blood sugar levels and energy balance (Trends in Endocrinology and Metabolism, 2013, 24(9), 431).

Similar effects – that is, weight gain – were seen when Swithers and her colleagues looked at the consequences of consuming acesulfame potassium in animal studies, which is one of the most popular sweeteners in use today (Behavioral Neuroscience, doi: 10.1037/a0016139).

Swithers believes that when sweeteners are tasted and they fail to deliver sugar to the blood, as anticipated, the body then produces an inhibitory response. The release of the hormone GLP-1 is impinged. GLP-1 works with insulin to regulate blood glucose but it also contributes to feelings of fullness. ‘Animals that have had experience with saccharin show lower release of GLP-1 in response to an oral glucose load than animals which had not had that experience,’ says Swithers.  

Recent research by a group at Washington University School of Medicine, Missouri, US, points to sweeteners turning the insulin volume up too. A study last year looked at 17 obese adults who did not have diabetes and did not use artificial sweeteners. They had an oral glucose tolerance test twice; they then consumed the sweetener sucralose or water 10 minutes before glucose. The sweetener was found to affect blood sugar and hormonal responses to the glucose adversely, suggesting that the sweetener has notable effects on the body (Diabetes Care, doi: 10.2337/dc12-2221). Commenting, Lustig says: ‘With the diet soda pre-treatment the insulin response was 20% higher, even though the glucose load was the same, so that is a bad sign. The brain is thinking sweet is coming, therefore sugar, so is releasing more insulin.’

It is this suspected swindle and the body’s reaction to it that are causing scientists to scrutinise artificial sweeteners. Obesity expert Carel le Roux at University College Dublin, Ireland, is convinced that sweeteners are not a benign sugar replacement. He says taste receptors in the mouth and receptors in the gut prepare the body for sugar influx when artificial sweeteners are consumed. When the body is conned, in the case of sweeteners, it may already have started processes and derail the proper handling of other food.

‘If you put something sweet in your body then you produce insulin. If you have a lot of insulin but no calories arrive, your blood sugar will fall. The next time you consume sugar it is pushed across the small bowel into the blood stream faster than it would have been. This is how you could end up eating more if you consume artificial sweeteners,’ explains le Roux. Insulin’s job is to clear the blood of sugar.

Swithers believes that because they suppress the effects of the gut hormone GLP-1, artificial sweeteners should be put in the dock while their long-term impacts are determined. ‘We are seeing evidence now from big epidemiological studies that people who drink diet sodas have an increased risk of not only Type 2 diabetes, but also of cardiovascular disease, high blood pressure and stroke,’ she says. If you do not have much GLP-1 you tend to eat more. Also, ‘essentially what we know from human studies and from animal studies is that GLP-1 really does seem to protect the cardiovascular system,’ says Swithers. So she is concerned that artificial sweeteners in diet drinks push down our GLP-1 levels, as she has reported for saccharin (Behavioral Brain Research, doi:10.1016/j.bbr.2012.04.024), which leaves us at increased risk of cardiovascular disease.

‘One diet soda a day is not very much, from one perspective, but the data suggest that one diet soda a day may be too much,’ she says. ‘It really does not take very much exposure to these sweeteners to produce increases in weight gain,’ she says. Industry, however, vehemently disagrees (see below).

There is some evidence that the brain responds differently to sugars and artificial sweeteners, depending on whether or not people have consumed sweeteners. According to Swithers, people who do not drink diet drinks can distinguish between real sugar and the mock sugar, whereas people who do drink them are less able to do that, citing a study that suggested sweeteners rewire the brain’s reward circuitry (Physiology & Behavior, doi: 10.1016/j.physbeh.2012.05.006).

However, there is also evidence that the mammalian brain can tell when it is consuming calories, which fogs the picture. Hungry rats prefer sugar solution over saccharin solution, even when the flavour is heavily masked (A. Sclafani and K. Ackroff, Physiology & Behavior, 1994, 56, 399).

Ivan E. de Araujo at the John Pierce Laboratory in New Haven, Connecticut, US, is exploring how the brain senses artificial sweeteners and sugar, and his studies suggest that the brain can learn to tell the two apart. He has shown that mice made blind to sugar taste develop a strong preference for sugar solutions based only on calorie content (Neuron, 2008, 57, 930). The results suggest that calories, not just sweetness, influence the brain reward circuits that control our desire for food. 

‘In animal studies, it is clear. Initially, they like artificial sweeteners but eventually they figure out they are not gaining much in consuming it. ‘If you give them a choice then, they will consume sugar. So the brain figures it out,’ says de Araujo. He believes that dopamine-secreting cells respond to the metabolic consequences of ingesting foods – they are sensing higher energy intake. ‘We have found that the energy content of sugars is a strong stimulator of dopamine-releasing cells. These cells are sensitive to energy content.’
Dopamine is a neurotransmitter, a chemical messenger released by nerve cells and a reward hormone. So its release signals to the brain that the food is full of the good stuff – calories. When you instead eat low- or no-calorie sweeteners while trying to lose weight – effectively starving your body – your body may fight back by craving sugar all the more, Araujo contends.

Dopamine is known to be involved in addictive behaviour. In his influential book, Fat chance, Lustig noted that sweeteners affect dopamine receptors in the brain and that they could prove equally as addictive as sugars. He also wrote about the possibility that sweeteners might change the composition of intestinal bacteria, which may generate inflammation and lead to increased stomach fat. 

Others argue that sweetness without calories only partly triggers the food reward pathway. When no calories hit the brain, this may fuel food-seeking behaviour, which is something Araujo and Swithers both say there is evidence for. Araujo believes it may be a better strategy to take even a small amount of sugar with sweeteners, just to deliver a small reward hit.  But he emphasises that he is conducting basic research, using animals, and that complex human behaviour and environment are part of any outcome in people.

Many scientists, who are sceptical that sweeteners offer a way to lose weight, do not, however, advocate a return to sugary alternatives. ‘It is certainly not the case that we should be encouraging people to stop drinking diet soda and go back to drinking regular soda,’ says Swithers. ‘Is it better or worse to drink a diet soda a day? That is the wrong question. The question is: why should we tell anyone that it is okay to drink a soda a day?’

Swithers is encouraged that more attention is being made on positive and negative outcomes but says showing cause and effect is a tough ask. ‘Also many of these effects don’t show up for five, 10, maybe 20 years, and it is very difficult for regulators to tease out what exactly is contributing to risk,’ she says. Regulators interrogate ingredients for safety, but do not check combinations of ingredients or dietary repercussions of eating them.  

Lustig views the knowledge vacuum as the ‘elephant in the room’ with regards to sweeteners.  ‘We know what happens to sweeteners when they get into the body because regulators had to determine this to approve them; what we don’t know enough about is how the various diet sweeteners influence our long-term food intake, weight, body fat or metabolic status. But what is known does give rise for concern: sweeteners are not devoid of meaning for the body,’ he says.

Lustig concludes: ‘There may be a role for diet sweeteners possibly as a weaning mechanism, in the same way methadone was developed for heroin addiction. But people tend to stay on methadone because they don’t want to be weaned off. It may be that diet sweeteners may be the methadone of sugar. It may help. But we don’t know yet.’

The American Beverage Association, which represents the non-alcoholic refreshment beverage industry, describes diet drinks as an effective tool as part of ‘an overall weight management plan’, and says studies have repeatedly shown their benefits in helping reduce calorie intake. Reacting to a study in January 2014 that found overweight people drink more diet drinks (American Journal of Public Health, doi: 10.2105/AJPH.2013.301556), the Association said that this should come as no surprise, since overweight people try to reduce calorie intake. ‘Losing or maintaining weight comes down to balancing the total calories consumed with those burned through physical activity,’ it said in a statement.
The Association also pointed out to the American Diabetes Association (ADA) that swapping sweeteners for added sugars has the potential to help curb cravings for something sweet. The ADA added, in a statement on sweeteners in July 2012, that substituting artificial sweeteners for sugar may help people reach and maintain a healthy body weight ‘as long as the substitution doesn’t lead to eating additional calories later as ‘compensation’.’ The ADA described the scientific evidence as ‘inconclusive’ with respect to whether the strategy is effective in the long term for reducing intake of sugars and calories.