Tackling obesity and diabetes: Institute of Metabolic Science

According to data from the latest Health Survey for England, 60% of men, 50% of women and 25% of children will be obese by 2050 if no action is taken. The International Diabetes Federation estimates that more than 285 million people worldwide currently have diabetes and that this will increase to 438 million by 2030.

‘There is little doubt that modern-day lifestyles, which promote excessive food intake and discourage physical activity, have been driving the rapid increase in these disorders,’ explained Professor Nick Wareham, co-Director of the Institute of Metabolic Science (IMS) with Professor Steve O’Rahilly. ‘But not everyone exposed to an obesogenic environment is obese, and some overweight people don’t suffer adverse conditions like type 2 diabetes. It’s our genetic make-up that determines the effect of our lifestyle.’

It is this complex interplay between genes and environment, and how the scales can be tipped towards better health, which interests researchers at the IMS. ‘Work in these areas has been flourishing for some time in Cambridge and unprecedented scientific opportunities to understand these disorders have been emerging locally and internationally,’ said Professor O’Rahilly. ‘By creating the IMS, we have been able to focus the multidisciplinary research and to link it directly with patient care.’

The IMS is a tri-institutional partnership between the University of Cambridge, the Cambridge University Hospitals NHS Foundation Trust and the Medical Research Council (MRC). Opened in 2008, the £20 million building has within it: the MRC Epidemiology Unit, led by Professor Wareham; the University of Cambridge’s cross-departmental Metabolic Research Laboratories (MRL), led by Professor O’Rahilly, which includes the MRC Centre for Obesity and Related Metabolic Diseases; and the Clinical Care Centre, incorporating the Wolfson Diabetes and Endocrine Clinic and the Weston Centre for Childhood and Adolescent Diabetes and Endocrinology. The Wolfson Foundation, Garfield Weston Foundation and The Atlantic Philanthropies were major benefactors.

Finding the ‘fat’ genes

The MRL houses the research groups of around 20 Principal Investigators (PIs), whose expertise ranges from genetics and biochemistry, to cell biology and physiology. In addition to undertaking basic research into processes such as insulin action and the control of energy balance, these investigators provide the expertise that is critical for improved understanding of why particular genetic defects lead to human obesity and/or diabetes. They are also working increasingly closely with basic and clinical neuroscientists to understand the biological underpinnings of appetite and how this can be disturbed by genetic and environmental factors. The Wellcome Trust (WT) has played a particularly important role in fostering the development of the MRL through its generous support of many of its PIs and through additional strategic support.

A breakthrough in the understanding of obesity came in the 1990s when Cambridge researchers discovered an underlying genetic predisposition to gain weight. ‘It was a rare, severe form of the condition that led us to identify the broken gene,’ explained Professor O’Rahilly who, together with Dr Sadaf Farooqi, was the first to describe patients who lacked leptin, which normally controls food-seeking behaviour. They were able to reverse the life-threatening obesity by giving patients daily injections of synthetic leptin. Since then, the Cambridge team and others have discovered eight genes that, when broken or missing, cause devastating consequences in those affected. The most recent discovery, published in Nature in February 2010, showed that some morbidly obese children are missing an entire region of chromosome 16.

Gene defects as strong as these affect more than a million people worldwide. Could there also be gene variants that produce a strong drive to eat in an even greater proportion of the population? One floor down from the MRL is the MRC Epidemiology Unit, which carries out studies at the population level to look for associations with disease. In a recent international collaborative study, the genomes of 32,000 individuals were scanned to uncover genetic associations with higher body mass index. This resulted in the discovery of six variants that affect a large proportion of the population. It turns out that several of the common variants occur in and around the very same genes that the researchers in the MRL had found to be the cause of severe forms of obesity.

The influence of lifestyle

Genes are only part of the story. Many large-scale investigations on the influence of lifestyle are under way in the MRC Epidemiology Unit to find out why some people are more susceptible than others to developing diabetes or obesity, and how this might be prevented.

To do this, a large number of people need to be studied for long periods of time. The InterAct study, for instance, is a major international consortium led by Cambridge that is analysing more than 10 years of follow-up data for 500,000 people in nine European countries and India who provided information on diet and physical activity at baseline. By analysing the genetic profile of the 12,500 people who have developed type 2 diabetes, and a similar number who have remained diabetes free, the team aims to pinpoint how genes and lifestyles interact. To balance this large-scale approach, the Fenland Study, which has just recruited its 5,000th volunteer, is collecting much more in-depth information about the links between these disorders and diet, lifestyle and genetic factors for individuals in the Cambridge region.

Several research groups are investigating how to translate knowledge gained from epidemiological studies into preventive action, by assessing diet and physical activity in adults and children, and testing interventions. Better measurement of notoriously difficult-to-measure behaviours like physical activity is a key part of this translational process. The MRC Epidemiology Unit has pioneered new methods for assessing physical activity and energy expenditure, including combined heart rate and movement sensors and waveform accelerometry.

Linking basic and clinical science

Many of the scientists at the IMS are also clinicians who treat patients in the Clinical Care Centre, on the ground floor of the building, or monitor their progress at the Cambridge WT Clinical Research Facility close by. This is a vital component of the success of the IMS: ‘The clinical problems presented by patients inform the research, which in turn helps us to build the clinical expertise needed to assess and handle their care,’ explained Professor O’Rahilly. Indeed, IMS scientists have discovered several previously unrecognised forms of diabetes and obesity in patients referred to the Centre as part of a national referral programme.

Recently published research shows how far the practical help for patients has progressed. Dr Roman Hovorka, based in the MRL, has developed an ‘artificial’ pancreas for patients with type 1 diabetes that can help them to control their blood sugar levels while asleep. The recent study was carried out during overnight stays for children and teenagers with type 1 diabetes at the WT Clinical Research Facility and is a stepping stone for the next stage of testing the system at home.

Other exemplars of the link between basic and clinical science include the work of Professor David Ron, Wellcome Trust Principal Research Fellow in the MRL, who is an international authority on cellular stress, a process of great relevance to the development and progression of obesity and diabetes; and Dr Susan Ozanne, British Heart Foundation Senior Fellow in the MRL, who investigates the mechanisms whereby nutrition early in life can influence later risks of obesity and diabetes.

Future choices

Researchers at the IMS are keen to maximise the impact of their work by informing steps to reduce and prevent obesity and metabolic disorders. Key to this vision is the Institute’s connection to the Centre for Diet and Activity Research, which promotes excellence in public health research, and is directed by Professor Wareham at Cambridge’s Institute of Public Health. Professor Wareham explained: ‘This connection is important for translating a better fundamental understanding of these conditions, gained through research at the IMS, into helping people to make the right choices to stay healthy.’

For more information about research at the IMS, please visit www.ims.cam.ac.uk/