A new image

Metabolic pathways in health and disease

New imaging technologies are providing a much clearer view of what happens to the food we eat. As well as rewriting the textbooks, such work could point the way to improved therapies for diseases such as diabetes.

While on sabbatical at Yale University in the early 1990s, Professor Roy Taylor had a bright idea. With a long-standing interest in human metabolism, he realised that the emerging technique of magnetic resonance imaging could offer an entirely new way of studying everyday metabolism in living subjects. Ten years on, not only has he helped move on both fields considerably, but his findings are also challenging long-held dogma and offering the prospects of significantly better treatments for type 2 or non-insulin-dependent diabetes (see box below).

Back in the UK, Professor Taylor, Professor of Medicine and Metabolism at the University of Newcastle upon Tyne, sought out Professor Peter Morris, one of the world’s leading authorities on magnetic resonance spectroscopy (MRS) at the University of Nottingham. MRS is a noninvasive technique allowing biochemical measurements on organs and tissues. It has a great many applications, from medicine to materials science. Indeed, Professor Morris may be one of the few researchers holding grants from both Rolls–Royce and the Wellcome Trust. The two hit it off and began what has become a highly successful cross-disciplinary collaboration.

For Professor Taylor, MRS offers a chance to monitor metabolism in real time – a great step forward. "Most of last-century research has been centred around what is going on in the blood, not what is going on in the tissues." This has major limitations. "Sampling the blood is a bit like trying to understand what is going on in London by examining the traffic on the M1: you’ll get quite a lot of information but you won’t understand London life." Information on tissues can be obtained by performing fat or muscle biopsies. However, this is not ideal. Biopsies involve the removal of tissue from fat or muscle usually under local anaesthesia, "which is not something one would volunteer for too many times," warns Professor Taylor. "You can only do that a few times to even the most resilient volunteers."

MRS overcomes both these problems: "MRS is a technique allowing us for the first time to measure the levels of biochemical substances in all organs of the body without having to stick needles in – and that is a wonderful advantage for our volunteers."

Food for thought

Oddly, given their importance, many aspects of metabolism remain incompletely understood. "We need to find out what happens when people have their Shredded Wheat in the morning," says Professor Taylor, "where that food stuff goes, how it is stored and how the body processes it. It might seem remarkable at this stage in history that we still do not quite understand what happens straight after we eat. We have the most vestigial understanding, even today."

It is generally assumed that, after a meal, the carbohydrate element is stored in the liver, and the fat component is stored in fat tissue. But using the MRS imaging technique, Professors Taylor and Morris have made a number of surprising discoveries – most notably that storage of metabolites was much more dynamic than previously thought. In normal people, carbohydrate turned up in relatively unexpected locations and behaved in unexpected ways: "The carbohydrate content of food was largely stored in muscle," explains Professor Taylor, "but there was a surprise. It didn’t just stay there until we needed to fuel the muscle in order to run for the bus; glucose actually went into the muscle glycogen stores and then came out again after four to five hours."

These findings triggered new ways of thinking about muscle, which is acting as a type of buffer, ensuring that the levels of glucose in the blood do not fluctuate too much. Professor Taylor’s latest work suggests that in normal subjects approximately 20–30 per cent of all carbohydrate entering the body is initially stored in skeletal muscle. This goes against the received wisdom: "We have a big problem to address, in that the muscle isn’t just doing what it ought to do – in terms of propelling people around – but it appears to be acting as a metabolic buffer to store glucose at the right time."

Professor Taylor has also noted that there are distinct patterns in the way the liver decreases production of new glucose after meals. These differences appear to be correlated to patients’ weight – the more they approached obesity, the less responsive their livers were. Understanding ‘baseline’ activities in ‘normal’ subjects is vital if we are to understand fully what is going on in metabolic diseases such as diabetes, and intervene effectively.

Implications for diabetes

As well as uncovering unsuspected metabolic pathways for carbohydrate in the normal body, Professors Taylor and Morris are also trying to find out how metabolism differs in diseases such as diabetes.

Their research has also called into question some long-standing beliefs about metabolic diseases such as type 2 diabetes. A drop in responsiveness to insulin in diabetes has been put down to a defect in the internal signalling pathways inside cells triggered by the hormone, whereas in fact it may be linked to the way fatty molecules (such as fatty acids) are metabolised by the body. They have also discovered that much less carbohydrate – only about 15 per cent – finds its way into the muscle in diabetic subjects after a meal.

The major challenge now is to gain a more detailed picture of the destination of metabolites after meals, to find out what exactly the role of the liver is and the newly identified buffer in the muscle. A key question is how processing of one type of biochemical substance, say carbohydrate, is affected by mechanisms affecting other classes of metabolite such as fatty acids. And, of course, to discover how these processes go wrong in disease.

These kinds of issues are so important medically, because there is still much room for improvement in the treatment of diabetes. "We know we can use insulin in type 2 diabetes to remove malaise and tiredness, but we don’t have the means to employ it effectively to minimise long-term complications. In older people – say 70–80s – it may be that this standard form of treatment is acceptable, but if the patients are much younger – 30–40s – then we know they have a poorer outlook than older people and we would like to look at how to utilise the insulin better. Using MRS in conjunction with new insulin analogues may ultimately aid the effectiveness of treatment of these patients."

In the future this research could provide patients with their own treatment profile. The term diabetes actually covers a collection of disease processes that may have quite different underlying causes. Rather than ‘type 2 diabetes’, says Professor Taylor, it should be ‘type 57 diabetes’ – "Just like the Heinz varieties, but all the tins have lost their labels. Researchers as yet don’t actually understand all the different subtypes of type 2 diabetes. A few pure genetic disorders have been worked out, but this is a tiny proportion of all the type 2 conditions. However, it is highly likely that there are a few common subtypes." By classifying the different types of response using MRS, these subtypes could be diagnosed and patients delivered a more specific therapy. As Professor Taylor says, "I think we are at the start of a voyage of discovery."

Type 2 diabetes: Causes and treatment

If you are over 40, and have begun to notice you are more thirsty and need to urinate during the night, there is a reasonable chance you may have type 2 diabetes. Other symptoms include tiredness and increased susceptibility to infections. Type 2 or non-insulin-dependent diabetes currently affects around 2 per cent of the UK population and about 10 per cent of those over 60.

What is type 2 diabetes?
Two mechanisms are at work. On the one hand, beta cells in the pancreas produce less insulin, the hormone that enables the body to maintain glucose levels in the blood. Superimposed upon this, liver, muscle and fat become less sensitive to the actions of insulin.

As a result, the body doesn’t produce enough insulin in response to meals and nor does it respond adequately to that which is produced. Too much glucose ends up in the blood and not enough gets stored.

How can it be treated?
Currently, the basic treatment for type 2 diabetes is dietary control, such as avoiding sweet food. Patients are also advised to avoid fatty foods and take more exercise.

Unfortunately these approaches are only effective over a certain window in the development of type 2 diabetes, after which patients have to begin medication. There are two commonly used forms of therapy – one stimulates the production of insulin in the pancreas and the other inhibits the production of glucose in the liver. In recent years a third class of compounds have been developed that increase the level of tissue sensitivity to insulin. However, as the pancreas is deteriorating throughout the course of the disease, patients usually have to begin taking insulin after a period of years.

As well as the immediate problems caused by impaired glucose control, people with diabetes are susceptible to serious long-term complications, resulting from the blockage or narrowing of large arteries or small blood vessels. Blockage of the larger arteries supplying the brain, heart and lower limbs increases the likelihood of stroke or heart attack, whereas the effects on the smaller vessels can cause blindness, kidney failure or nerve damage.

External links

Professor Roy Taylor at the University of Newcastle: Research interests
Professor Peter Morris at the University of Nottingham: Research interests

A new image

Metabolic pathways in health and disease

Food for thought

Implications for diabetes

External links

Further reading