Our love affair with sugar may have provoked an alarming health crisis, but you might be surprised to learn where the most harmful sugars reside, as Clare Pain reveals.
IN 1980, DOCTORS FROM THE Mayo Clinic in the US reported on worrying “experiences with a hitherto unnamed disease”. Liver biopsies of 20 patients had revealed regions of dead cells, signs of inflammation, “striking fatty changes” and Mallory bodies – bright pink-staining structures that are a classic sign of alcoholic liver disease. Most of the biopsies revealed fibrosis (scarring that occurs after damage repair) and three had cirrhosis, both hallmarks of a repeatedly injured liver. To any doctor, the slide under the microscope gave clear evidence of a liver damaged by alcohol – ‘alcoholic hepatitis’. The problem was these patients did not drink, or if they did, only minimally.
The disease duly received a name – non-alcoholic steatohepatitis. Now, in 2012, it is the most common liver disease in the US and possibly throughout the developed world.
How is it that, in just over 30 years, a condition can go from unknown to the most common disease of a particular organ? Robert Lustig, a paediatric endocrinologist at the University of California, San Francisco, is convinced he knows the answer: excessive consumption of sugar, and one sugar in particular – fructose, the kind found in sweet fruit.
TODAY, ONLY A SMALL proportion of dietary fructose comes from fruit. In the US, a major source is high-fructose corn syrup (HFCS). This cheap sweetener, made from maize, contains a mixture of fructose (between 42% and 55%) and glucose, and is widely used in soft drinks.
Chemically, sugars are simple carbohydrates that taste sweet. Fructose is the sweetest, and its presence makes table sugar (sucrose, a mix of fructose and glucose) and HFCS considerably sweeter than glucose alone.
Extra sweetness is why the food industry adds sugar or HFCS to foods, says Kerin O’Dea, a professor of population health and nutrition at the University of South Australia in Adelaide. “Sugar is everywhere in the food supply. [Producers] add sugar because it sells more,” she says.
Sucrose is another major source. In the gut, sucrose molecules must be split into glucose and fructose before they can be absorbed and enter the bloodstream.
Lustig believes it’s fructose in the diet that is causing raised insulin resistance, fatty liver and the other symptoms of metabolic syndrome: a collection of symptoms that has escalated in populations in the past 30 years. Definitions differ, but a bulging waistline, high blood glucose concentration, high blood pressure, high levels of ‘bad fats’ in the blood, cardiovascular disease and fatty liver are often part of the picture.
People with metabolic syndrome are at risk of developing diabetes, heart disease and stroke. Depending on the definitions used, the proportion of affected adults in the US is between 15% and 34%.
One theory suggests that insulin resistance underlies these symptoms. Lustig fingers fructose as the culprit because of the way it’s dealt with in the liver. Unlike glucose, which – with the help of insulin – can be used by any body tissue as a major energy source, fructose is predominantly taken up by the liver – and there are differences in the way the liver processes glucose and fructose. Some fructose pathways lead to small increases in blood pressure and insulin resistance. Fructose is also more likely to be converted to fat, some of which is stored in the liver itself, while the remainder is exported in the bloodstream as triglycerides.
The picture fits neatly with the higher risks associated with metabolic syndrome: heart attacks and strokes become more likely with high blood pressure and raised triglyceride levels, and diabetes can result from insulin resistance.
O’Dea agrees that overconsumption of fructose causes problems. “High fructose in particular is associated with a fatty liver, whereas glucose isn’t. Fructose does seem to promote fat where it shouldn’t be – around the heart, in the pancreas and in the liver.
“Fatty liver is dangerous whether it is associated with alcohol or not,” she adds. Her group is researching whether the disease can be reversed by a change of diet. She points out that fructose has little effect on the hormones insulin and leptin, which tell the brain that we have eaten and are an important part of the satiety system, the mechanism by which we feel full. She also refers to an intriguing study in mice, which suggests that fructose might increase absorption of highly inflammatory ‘endotoxin’, a toxic substance derived from bacteria in the gut.
Lustig, for one, is certain that fructose is dangerous and is determined to do something about it. “Once we realised that fructose was a primary player in this story, it became clear that this was a public health problem that people could not control, because 80% of food products are laced with sugar ‘on purpose’ – because it makes them sell better. So it rose to a public health issue. That’s when I became fired up in terms of making a difference,” he says.
“Making a difference” has included co-authoring a commentary in the journal Nature in February 2012, in which Lustig argued that fructose is similar to alcohol in its toxic effects on the liver and suggested it should be taxed. A video of a lecture he gave called ‘Sugar: The Bitter Truth’ has had more than 2.5 million hits on YouTube.
NOT EVERYONE ACCEPTS that fructose is harmful, and some of the most vocal critics of the hypothesis are in Australia. Jennie Brand-Miller, a professor of biochemistry at the University of Sydney, is concerned that the fructose furore is taking attention away from what she believes is the key issue, the danger of over-rapid absorption of glucose in high glycaemic index (GI) foods. She acknowledges that fructose can cause increased levels of triglycerides but adds, “It’s important to say that this is the effect of excess fructose – not at all in the reasonable amounts that most people eat”.
Peter Clifton, head of the nutritional interventions lab at the Baker IDI Heart and Diabetes Institute in Melbourne, thinks experiments that demonstrate the effects of fructose have used unrealistically high levels.
“In America, some teenage kids may be having 30% of their energy supply as either sucrose or fructose. But that doesn’t apply to most of the adult population. I think that the energy excess is the most important thing – just eating too much rather than whether it’s a particular type of sugar.”
Meanwhile, Peter Havel, an endocrinologist at the University of California’s Davis campus, leads a team that is quietly chipping away at the fructose issue. Animal experiments have shown that high-fructose diets increase visceral fat (the fat around body organs that leads to a large waistline) and raise triglyceride levels in the blood. Havel thinks it is important to do these experiments in humans.
His team’s first step has been to find out what happens when people consume pure glucose or pure fructose. In a 2009 experiment on 32 overweight or obese people aged over 40, half spent 10 weeks drinking a glucose-sweetened beverage with each meal, while the other half had drinks sweetened with fructose. All up, the beverages provided 25% of their energy requirements.
Each group gained about 1.5kg in weight over the experiment, but the group drinking fructose beverages increased the amount of visceral fat by 14%, while those consuming glucose drinks put on 3% more visceral fat. Repeated measurements of blood triglycerides over 24 hours revealed that levels had nearly doubled in the people drinking fructose. In people on the glucose-sweetened drinks, on the other hand, dropped by about a third over 24 hours from values at the start of the experiment.
Blood glucose levels in the fructose group rose by 5%, their insulin levels rose by 10%, and their sensitivity to insulin decreased by 17% – all signs that insulin resistance was beginning to creep in. These effects were not seen in the glucose drinkers.
“I think we are at a point where we have some research that is suggestive,” says Havel. “I don’t think everything has been figured out yet.” He points to epidemiological studies looking for associations between sugar consumption and metabolic disease, but says it’s harder here to identify cause and effect. “That’s why we are looking at potential mechanisms with these interventional studies. We are looking not only at if it is happening, but also how.”
He admits they don’t yet have the research to make far-reaching conclusions. “The amount of sugar that produces significant adverse metabolic effects probably differs between genetic groups. It is likely to differ between populations … with age, obesity, activity level and general metabolic health all having an influence.”
This leads one to ask – just how much sugar are we all eating? In the US, data from the 2001–2004 National Health and Nutrition Examination Survey showed that Americans consumed 22 teaspoons of added sugar (that is, added during food processing) a day. That’s about 32kg per person per year.
THE OTHER HALF OF the sucrose molecule – glucose – has its own dark side. The primary product of photosynthesis, glucose is ubiquitous in nature as an energy source. We couldn’t live without it. But it is a two-edged sword, and is also damaging in excess.
To see the effects of too much glucose, you only have to look at the complications of diabetes, where chronic high blood glucose concentrations damage some particularly sensitive tissues. “High glucose levels in cells are actually harmful,” says Brand-Miller. “That’s why people with diabetes develop complications like blindness and nerve damage and kidney failure.
If the glucose level in the blood is high, the tissues that take up the glucose at the same level are compromised as well. They become dysfunctional over time.”
One well-understood mechanism by which glucose damages the body is oxidation, in which high glucose concentrations in cells leads to formation of reactive oxygen species (ROS), which can leave a trail of damage in their wake.
Vincent Monnier, an experimental pathologist at Case Western Reserve University in Ohio, is probing another way glucose wreaks havoc. For the past 30 years, he has been interested in molecules called advanced glycation end products – or AGEs for short. And it turns out the acronym is very apt.
Glucose reacts with some proteins in a process called glycation. In particular, it binds to the amino acid lysine (found in many proteins) in the so-called Maillard reaction. This reaction is often known as the ‘browning reaction’ and is important in cooking. It’s the Maillard reaction that makes bread crusts brown, caramelises onions and puts the tasty ‘burnt’ coating on a steak.
It isn’t just cooking that invokes the Maillard reaction. In the body, this browning reaction occurs (albeit slowly) as glucose encounters proteins containing lysine, eventually yielding a series of altered proteins – the AGEs. Of course, proteins need to be exactly the right shape for them to work properly. A protein that has become an AGE is unlikely to function as normal.
Fructose also reacts with proteins in the Mallaird reaction – far more readily than glucose. It reacts about seven times faster, causing even more AGEs (perhaps more properly called advanced fructation end products). It’s worth remembering that when doctors measure ‘blood sugar’, they are measuring glucose levels. The level of fructose in the blood isn’t measured.
One AGE precursor, discovered in the lab that Monnier joined in the 1970s, has become a key marker in diabetes. The protein haemoglobin reacts with glucose, forming a glycation product known as HbA1c. At any one time, only a small proportion of the haemoglobin in the blood is present as HbA1c, but the higher the blood glucose concentration, the higher the HbA1c levels. This marker is now followed routinely in patients with diabetes to give an indication of their average blood glucose levels over time.
HbA1c gradually gets replaced, but in longer-lived proteins like collagen, the glycation products eventually become harmful AGEs. Monnier has pictures showing human cartilage (which, like skin and many other tissues, contains collagen) browning with time. In patients with diabetes, the higher exposure to glucose means that the browning happens much faster. “A person with type 1 diabetes aged 37 will probably have collagen looking more like that of a 76-year-old’s,” he says.
IN 2005, MONNIER’S TEAM showed that levels of two AGEs predicted the long-term risk of developing diabetic complications. “The next question is – are these AGEs responsible for the diabetic complications?” he asks.
Much of the problem seems to be with proteins in the extracellular matrix – the tissue that surrounds cells and provides structural support. “If, for example, one tries to grow cells in AGE-rich collagen, the cells behave poorly: they secrete inflammatory factors and attach poorly and die. And AGEs have been shown to damage the endothelial cells that line blood vessels.” He adds that many experiments have shown that AGEs can cause the dysfunctions seen in diabetic kidney disease and nerve damage.
HbA1c occurs in all of us to some degree, not just people with diabetes. It serves as a marker of our exposure to the harmful effects of blood glucose. Monnier points to studies showing that the higher the levels of HbA1c, the higher the mortality and morbidity. He sees diabetes as an accelerated ageing process, with the ageing caused by high blood glucose levels.
He isn’t the only person who thinks that glucose ages us. Cynthia Kenyon, an expert on ageing at the University of California, San Francisco, studies a tiny nematode worm, Caenorhabditis elegans. Nematodes have a lifespan of only a few weeks, and so are ideal for ageing research. Kenyon has unravelled much of their ageing process, and believes that similar mechanisms occur in other animals, including humans.
Her research on this tiny worm has led to the discovery that a gene for an insulin receptor called DAF-2 plays a key role in the regulation of the ageing process. If the DAF-2 gene is altered, leading to defective receptors, the worm lives twice as long. So it seems that higher insulin levels has a life-shortening effect.
In another experiment, Kenyon grew the worms in a medium containing a 2% solution of glucose. The adult worm’s lifespans were shortened by 20%.
Kenyon herself eats a diet very low in carbohydrates. This is because carbohydrates such as potatoes, rice, bread and pasta are sugars in disguise: starches formed from glucose molecules chained together. The digestive system rapidly snips the chains, releasing glucose into the bloodstream.
Another advocate of eating as few carbs as possible is Ron Rosedale, a physician based in Boulder, Colorado. One of the first people to recognise the damage caused by insulin resistance, he has been treating patients with type 2 diabetes, obesity and cardiovascular disease in a very unorthodox way for over 20 years. He removes insulin-increasing medications and puts patients on a diet very low in carbohydrates, with carefully controlled amounts of protein and high levels of healthy fats.
Rosedale co-authored a study that looked at changes in the blood profiles of 31 patients after three months on his diet. Their insulin levels dropped by 40%, and other laboratory parameters paralleled those seen in calorie-restricted animals. (Some studies have suggested that calorie restriction is a way to extend lifespan). Rosedale describes it as a “diet designed to reduce ageing”.
“There’s no good sugar to eat,” says Rosedale. “It’s a non-essential nutrient. Our body can make all the glucose it needs without us needing to eat it. The question is, is it better to eat glucose or to let the body make it? I believe it’s much better to let the body make the glucose it requires at the time.”
IT SEEMS CLEAR THAT at least some aspects of sugar are harmful. Are we further ensnared by it being addictive? Surprisingly, despite the current obesity epidemic, the science of food addiction is still in its infancy. But the early research heralds a warning.
Nicole Avena, of the University of Florida in the US, is a pioneer in the field. “When I started this work with Bart Hoebel 12 years ago, doing my PhD at Princeton, no one else was studying it. At first the work was not well received at scientific meetings. Over the past five years there’s been a lot more interest and people are starting to think, ‘maybe food could be addictive’. Now work from other labs is starting to validate our early research.”
Avena has been coaxing rats to binge on sugar to see whether they show attributes of addiction. The rats are allowed access to water sweetened with 10% sucrose for 12 hours a day, starting four hours into their nocturnal activity period. Having intermittent access to sugar seems to be important in eliciting bingeing behaviour, as rats with constant access to the sugar water do not binge. Waiting for four hours for their sugary treat is “the equivalent of skipping breakfast in humans,” says Avena. The rats also have access to their normal food, known as chow.
As the days go by the rats gradually drink more sugar water and eat less chow, doubling their sucrose intake by three weeks. If just chow is available over the same 12-hour periods, there is no tendency for the rats to gradually eat more.
Avena has looked for, and found, the classic signs of addiction in her sugar-bingeing rats. One sign is withdrawal symptoms. Opioid drugs, such as morphine or heroin, work by activating opioid receptors in the brain. If you give naloxone (which blocks the opioid receptors) to an opioid addict, they will experience withdrawal symptoms. Naloxone has no effect on people who are not opioid addicts, so it’s a good indicator of addiction.
When Avena gave naloxone to her rats, their teeth began chattering, their forepaws trembled and they showed increased anxiety: all withdrawal symptoms. She has also demonstrated evidence of craving. Rather than acting on the opioid receptor itself, Avena says sugar is causing the release of endogenous opioids (morphine-like substances that occur naturally within the brain). “Their addiction is less in magnitude with sugar than with drugs like morphine and heroin,” she says, “but the fact that we see the same brain areas involved suggests it is a similar mechanism.”
We associate sugar with instant pleasure, but evidence is accumulating that excess consumption brings longer-term pain. That little molecule is certainly sweet, but probably not innocent.