THEO MURPHY (AUSTRALIA) HIGH FLYERS THINK TANK
Preventative health: Science and technology in the prevention and early detection of disease
University of Sydney (Eastern Avenue Complex), Thursday 6 November 2008
GROUP C: Metabolic syndrome
Chair: Professor Kerin O’Dea AO
Kerin O’Dea was appointed in 2006 as a professorial fellow at the University of Melbourne, Department of Medicine, St Vincent's Hospital, and the Baker Heart Research Institute. From 2000 to 2005 she was director of the Menzies School of Health Research in Darwin, Northern Territory. Kerin is a nutrition scientist and public health researcher who has made major contributions to understanding the relationship between diet and chronic diseases, particularly type 2 diabetes and related conditions. She is best known for her work on:
- the impact of diet and lifestyle change on risk of type 2 diabetes in Australian Aborigines, with a focus on the therapeutic and preventive implications;
- the epidemiology of diabetes and related conditions in Indigenous Australian populations;
- the role of diet in the aetiology, treatment and prevention of type 2 diabetes;
- factors affecting the metabolic responses to carbohydrates; and
- improving population health through improving the nutritional quality of the food supply.
Kerin's research group has a particular interest in diet and lifestyle interventions to reduce the risk of metabolic and vascular disease in relation primarily to type 2 diabetes and cardiovascular disease. The metabolic syndrome is a cluster of markers linked to insulin resistance and indicating increased risk of these conditions. Current studies include examining the impact of a traditional Mediterranean diet on non-alcoholic fatty liver disease and the metabolic syndrome, with particular emphasis on impact on regional patterns of fat distribution. Is it possible to move from 'metabolically unhealthy obesity' to 'metabolically healthy obesity' through dietary change and/or exercise.
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This is the scope of my presentation. I am going to be talking about the metabolic syndrome in the context of metabolically healthy obesity, briefly – everything is going to be brief – the role of diet and lifestyle; stress, psychosocial distress. To some extent I am going to concentrate on social disadvantage, using the indigenous Australians as a small case study there. Then I will finish by talking about the importance of the research agenda, better understanding the biological pathways, looking at influences across the life course and gene-environment interactions. I am particularly interested in the question of whether inflammation is one of the critical mediators. And I am going to finish on a rather pessimistic note of the challenge of interventions.
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I like this diagram because it shows that the obesity epidemic – and, clearly, the metabolic syndrome is very closely linked to that – is a really recent phenomenon. I think we have to better understand the social changes that took place in society that caused this quite sharp increase in obesity across the world and at relatively similar times in the early to mid-eighties – and I have a few ideas that I will share with you.
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There are several definitions of the metabolic syndrome. I am not going to go into them in detail and I am not even going to answer the question that people ask: does the metabolic syndrome exist? Certainly, there are clusters of conditions. They are related to central obesity, insulin resistance, high blood pressure and dyslipidemia.
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There are other factors that are probably very important to study: insulin resistance; fatty liver – non-alcoholic fatty liver disease is something that we have become very interested in recently; vascular dysfunction; a range of inflammatory markers, including acute phase reactants and adipokines; prothrombotic factors; and, of course, the hypothalamic pituitary adrenal [HPA] axis is intimately involved.
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The metabolic syndrome: is it fixed? Are we born with it? Are the differences purely genetic? Or is it possible to move fat from one depot to another? This is a really interesting question. I am going to discuss very briefly exercise and one dietary factor: fructose.
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This is a photo of a child and a Japanese Sumo wrestler.
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This is a CT scan of a young sumo wrestler who is consuming up to 9,000 calories, a day; but is very physically active though. He has very little intra-abdominal adipose tissue. He has a lot of muscle and a lot of subcutaneous adipose tissue.
When that person stops exercising so much – I do not have a scan of this, unfortunately; I couldn't locate it for this talk – the fat actually moves into the abdomen, so there is less subcutaneous fat and there's much more intra-abdominal fat. This is fascinating. This does indicate that exercise is one of the governors – and we can discuss what the mechanism might be – of where fat goes in the body.
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So what about diet and body fat distribution? There is not very much data. There is some work that we did a number of years ago now. Quite unexpectedly we found that when we put people on two different diets using a randomised cross-over design, so each person went on both diets, that insulin resistant people with diabetes lost similar amounts of weight on the two different diets: a high fibre, high-carbohydrate, lowfat diet (which was the common diet then prescribed for type 2 diabetes), and a 'modified-fat diet', a Mediterranean style diet, in which the major fat was olive oil. The unexpected finding was that although they lost similar amounts of body fat, they lost fat in different places; in fact, fat seemed to move.
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This slide shows that, on the lowfat diet, they actually gained upper body fat – we could not tell whether it was intra-abdominal or not, because we were using DEXA [dual energy X-ray absorptiometry] – and lost a large amount of lower body fat from their thighs, which they didn't have very much of, as they were diabetic people. In contrast, with the modified fat diet, they lost more upper than lower body fat.
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Looking at the ratio, you can see that, with the lowfat, highcarbohydrate diet, they were really losing a lot of lower body fat; and, with the modified fat diet, they were actually losing it proportionately from both fat depots.
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This was a very, very interesting observation and we repeated it a number of times. But it wasn't always able to be demonstrated by others, although we were very pleased to see a recent study in Diabetes Care, again with people with type 2 diabetes and again showing that a high-carbohydrate but otherwise apparently healthy diet was associated with a redistribution of fat to the abdomen. So it was an adverse effect. Even though there was similar weight loss, it was happening in different places. It does seem to be that the effect is linked with insulin resistance. If you are not particularly insulin resistant to start with, then you don't seem to see this effect, as Peter Clifton and colleagues from CSIRO observed.
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Fructose: As many of you here will know, unlike glucose, fructose is taken up only by the liver and if it is not immediately needed as a source of energy, it is very efficiently converted into fatty acids and triglycerides. If you are overeating and over consuming sucrose [a disaccharide of glucose and fructose] in drinks and processed foods, it gets converted into fat. In animal models, it is an excellent way of producing insulin resistance. It produces fatty liver in association with increased inflammation and it produces central obesity. In human studies, it is linked to insulin resistance, elevated triglycerides, weight gain and hypertension. If you already have insulin resistance, you are more likely to experience these adverse effects of fructose: it exacerbates the metabolic syndrome.
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There are other issues with fructose that I do not have time to talk about in detail, but it is a fascinating possibility that it may get under the satiety radar. It doesn't stimulate insulin or leptin and is promoted because it has a low GI, and yet it may have little impact on central satiety mechanisms, particularly when you drink sucrose-containing drinks – of course, 50 per cent of that carbohydrate is fructose.
Recently I read a very interesting study of fructose feeding in mice. It led to a very efficient fat accumulation in the liver – I'll show you a diagram in a moment – but it was in association with increased portal levels of endotoxin, TNF alpha, and increased lipid peroxidation. These effects were significantly attenuated by concurrent antibiotic treatment. The authors suggested that fructose actually altered intestinal permeability and induced translocation of endotoxin from the intestine.
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Here's their data showing very clearly in the control [C] animals that antibiotics [C+AB] didn't do much at all to triglyceride accumulation; but, with fructose [F] feeding, the antibiotic treatment [F+AB] greatly reduced the very high levels of triglyceride accumulation. We are particularly interested in this because – as I'll talk in a moment – we are interested in whether there is a relationship between very low HDL [high-density lipoprotein] cholesterol levels (frequently observed in remote indigenous people) and burden of infectious disease.
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This is a very, very superficial look at the importance of the stress axis.
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There are certainly associations with altered feeding, altered food preferences, fat accumulation centrally, adverse steroid hormone profiles and increased risk of a number of other conditions that go beyond the metabolic syndrome.
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Social disadvantage: I will just remind you what the diet and lifestyle was of Aborigines when they lived as hunter-gatherers.
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It was a remarkably healthy diet derived from non-domesticated animals, marine foods and uncultivated plant foods. It's the diet that we really need to look to ourselves to know what humans probably should eat. It had a very low ratio of omega-6 to omega-3 polyunsaturated fats, whereas we have a high one. It was a rich source of bioavailable phytochemicals from uncultivated plant foods. So it was very high nutrient quality, and it was anti-oxidant and anti-inflammatory. It was also a bulky diet, so it was hard to overeat. Non-domesticated animals are very lean and they are actually quite omega-3 rich as well, even if they are not seafood.
In addition to the diet, physical activity was built into daily routines. You had to exercise to survive; you wouldn't eat if you didn't exercise. There was no evidence of substance abuse and there was a very high level of social cohesion. So it was an extremely different environment than people are living in today.
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We don't have metabolic data from people living as traditional hunter-gatherers; but the nearest we could get to it was in 1985, when we looked at a traditionally-oriented group on a remote outstation in Arnhem Land. They were living mostly off the land, but not entirely so they did have some Western foods. These are their parameters. I just want to point out how lean they were. The young woman who had a BMI of 19 looked positively plump in this group. They had the healthiest biochemical profile of nutritional status that I had ever seen: very healthy red cell folate levels, good haematocrit but – perhaps unexpectedly – higher than expected insulin and triglyceride levels, suggestive of insulin resistance, even under those circumstances; we don't know whether acquired or genetic, but probably a combination of both.
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This is what people looked like when they lived a traditionally oriented lifestyle. This is a recent photo – I have permission to show this – of a man in Arnhem Land. He is around 60 and he has a fantastic physique. The body build of Aboriginal people as hunter-gatherers was what we call a linear body build: narrower across the shoulders and hips, relatively short torso, long limbs. It is an ideal body build to maximise heat loss in hot environments. But, when you have that body build, you have a greater percentage body fat for a given BMI. So we don't think that European BMI cut-offs are appropriate for many indigenous people.
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When people gain weight, they gain it exclusively centrally and remain often slim in the legs and arms. This central pattern of fat distribution in both men and women is associated strongly with dyslipidemia and insulin resistance.
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This slide summarises the very heavy burden of metabolic disorders and vascular disorders in Aboriginal people. We are particularly interested in whether a heavy burden of infectious disease amplifies this risk. I won't have much time to talk about that today, but it is a very interesting question.
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This just shows the very high rates of metabolic syndrome. Sorry, Paul [Zimmet], we used the NCEP [National Cholesterol Education Program] definition here of the metabolic syndrome; it probably is less sensitive than the IDF [International Diabetes Federation] definition. You can see that it is highly prevalent and that many people have the metabolic syndrome.
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This slide illustrates the very low HDL cholesterol levels in Aboriginal populations. In the AusDiab study, 5.5 per cent of women and 14.5 per cent of men had HDL cholesterol levels below 1 mmol/L; in the Central Australia Aboriginal population, it was between 70 and 80 per cent of men and women. There was essentially no difference between men and women.
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Karen Walker, a colleague of mine, has researched international data on HDL cholesterol levels. The middle-class Indians from Mumbai had a HDL cholesterol profile very similar to people in the US and probably people in Australia – higher HDL cholesterol in women than men. But people in Andhra Pradesh, a very poor, very impoverished part of India, had profiles as close as we had ever seen to indigenous people in Central Australia. So we are interested in how poverty might mediate these effects.
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We think that social disadvantage, poor quality diet, high burden of psychosocial distress and high burden of infectious disease all interact to exacerbate the oxidative and inflammatory burden of the metabolic environment.
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The research agenda: it is important to highlight that we can't assume with a population like Aboriginal Australians that differences in disease risks and health outcomes are necessarily primarily genetic. We have to drill down and really look at how the environment could be influencing that – 'deep phenomics' as people in the nutrigenomics field emphasise. We have to look at influences across the life course: what are the critical periods; the importance of the intrauterine environment? Epigenetics is obviously important and is a fascinating area for research.
Organ development: it is possible for example that under-nutrition in utero, maternal smoking, and other insults lead to an under-endowment of nephrons, that might predispose Aboriginal people to renal failure as they age.
Under- and overnutrition: undernutrition in utero is associated with maternal smoking and poor nutrition; while overnutrition can be secondary to diabetes in pregnancy, which is increasingly common. A mother's perceived stress: smoking and alcohol abuse are all important. I think that one of the great challenges in this field is to better tease out the roles of these life course and environmental factors in unmasking genetic susceptibility.
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Diet as a modulator of gene expression: fructose inhibits SHBG [sex hormone-binding globulin] production by the liver, for example. Lipids are very important in terms of inflammatory and anti-inflammatory processes, particularly the long chain polyunsaturated fatty acids of both omega-3 and omega-6 classes.
Fatty acids themselves activate nuclear receptors and individual fatty acids differ markedly in their effects. For example, oleic acid (a monounsaturated fatty acid) tends to stimulate fat oxidation, whereas stearic acid (a saturated fatty acid) tends to stimulate triglyceride synthesis and fat deposition.
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This is one of my favourite slides. This is a slide of two eggs, one from a Greek village and the other from a US supermarket. When you first look at them, they look pretty similar, until you get to the omega-3 fatty acids. When you look at the ratio, the Greek village egg has a ratio of just over one and the egg from the American supermarket – which is probably like most of the eggs we buy from battery farms – has a ratio of almost 20. When I showed this slide once up in Darwin, one of the paediatricians there said to me, 'Would it be the same in humans?' and I said, 'I've never thought about that; it could be.' Omega-3 fats are now recognised to be critically important in the development of neural tissue. A slide like this illustrates how complex our food supply is, and how it can be changed in major ways by different agricultural and animal husbandry practices.
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This slide shows some of the key questions. I think inflammation is a critical mediator of many of the adverse outcomes of metabolic syndrome, which unfortunately I have not had time to talk about. There is the interaction or interplay between infectious disease, particularly chronic infectious disease, and vascular disease risk. What are the causes of the very low HDL cholesterol levels in very disadvantaged populations? We suspect it is linked to infection – but we do not know. And how important is diet and exercise?
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Time is running out - I have two more slides which I will summarise very quickly. The challenge of interventions: we think we know what to do in relation to this, but we don't know how to achieve it. The very sections of the population that we are most interested in – the most disadvantaged – are often the hardest to reach. We have to ask all these questions, many of which are similar to those Paul Zimmet asked. I think this is really important: what is our best buy in this area? That is one of our big challenges. Relying primarily on education might have the unintended consequence of increasing these social gradient and differentials.
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This is my last slide. So we have to have a population approach. Healthy choices have to become easy choices. When we look at the food supply, we can learn a lot from what has been done with tobacco – taxation and other legislative changes, and urban planning. But it is going to take a lot of political will, and do we have it? We need our transformational political leader here. I'm not sure that Obama is going to do this in the United States – but that's what we need now, because these are very, very big challenges. Thank you.
Discussion
Question: Natkunam Ketheesan, James Cook University. You showed the link between fatty acid uptake from the liver when you have a lot of fructose in your diet, but then you said that we should have a large fruit diet.
Kerin O'Dea - No, I didn't say fruit, but that is a very important point. There is a slide that I did not have time to put in. Fruit is different. When you have fructose in fruit, it is diluted. It is present with a whole lot of bioactive phytochemicals. It has fibre. Really, when you give fructose as part of fruit, you don't get any inflammatory response; when you give it in a soft drink, you do get it.
