Professor Steve O’Rahilly
Diabetes, Endocrinology and Metabolic Medicine
Metabolic diseases include common conditions such as obesity and diabetes, which, with nearly a quarter of all adults and one in five children in England currently classed as obese (http://healthsurvey.hscic.gov.uk/support-guidance/public-health/health-survey-for-england/adult%E2%80%99s-obesity-and-bmi.aspx), are responsible for some of the most pressing public health issues of our time. Other metabolic diseases such as lysosomal storage disorders, extreme insulin resistance and congenital hypothyroidism are extremely rare, but have devastating consequences for patients and their families.
The University of Cambridge has identified metabolic disease as one of its major strategic priorities. In 2008, in partnership with the MRC and Cambridge University Hospitals NHS Foundation Trust, the University formally opened the Institute of Metabolic Science (IMS), a purpose-built institute on the Cambridge Biomedical Campus. The IMS is dedicated to understanding the causes and adverse health consequences of obesity and translating this knowledge into novel, effective approaches to prevent and treat metabolic disease. A major goal of the IMS is to facilitate cross-disciplinary interactions between basic and clinical scientists, epidemiologists and clinicians to maximise the impact of research and improve the quality of patient care. Clinical research in metabolic disease in Cambridge also benefits greatly from the Metabolism, Endocrinology, Bone and Biomaterials theme of the NIHR BRC. In 2013, the MRC and Wellcome Trust increased their commitment in this disease area in Cambridge with the award of £24m to establish the Wellcome Trust–MRC IMS, including creating the MRC Metabolic Diseases Unit, construction of clinical research facilities devoted to metabolic disease, and funding to enhance core lab facilities and support collaborative work with the Cambridge Institute for Medical Research (CIMR) and the Sanger Institute.
Basic experimental research encompasses scientists from Departments such as Clinical Biochemistry, Medicine, Clinical Neuroscience, Obs & Gynae, Paediatrics and Public Health, who work across the full spectrum of experimental approaches including biochemistry, cell biology, genetics, functional genomics, neuroscience, electrophysiology, animal models, basic and human neuroscience, experimental medicine, epidemiology and public health. There are strong links with other Research Themes within the Clinical School, including Neurosciences and Mental Health, Genetics and Genetic Medicine, Stem Cells and Regenerative Medicine, Cardiovascular Medicine, Epidemiology and Public Health and Women’s Health. Close collaborations with groups in other Departments and related Institutes in the Cambridge area are also fostered by the Metabolic Network, a university-funded strategic initiative that brings together researchers with related interests from across the University and surrounding Institutes, and by the 4-year Wellcome Trust PhD programme in Metabolic and Cardiovascular Disease, which is run in conjunction with colleagues in the Cardiovascular Medicine Theme.
Particular areas of expertise include the genetics of metabolic diseases, such as obesity, insulin resistance and inherited endocrine disease. In obesity, the study of extreme human phenotypes and, several genetic causes, including defects in leptin, the melanocortin 4 receptor (MC4R) and several other genes which normally act in the brain to control appetite and energy balance. MC4R defects occur in 5-6% of severely obese children, making this the most common monogenic cause of extreme obesity identified to date. Researchers in the MRC Epidemiology Unit, sited in the IMS, have made major advances in the understanding of genetic factors influencing human growth and body composition in the general population Together with advances in behavioural neuroscience, including functional imaging, these studies highlight the crucial role of the hypothalamus in regulating appetite and satiety, and indicate the value of targeting central pathways to develop new obesity treatments. Several novel genetic disorders have recently been discovered using whole exome sequencing, including identification of the first rare copy number variants associated with severe early-onset obesity. In addition, the theme has world-leading strengths in the genetics of both common and rare forms of insulin resistance and in inherited endocrine disease, including conditions resulting from disruption of nuclear hormone receptors. As well as identifying underlying genetic causes, detailed physiological studies in humans are helping understand why these genetic changes lead to disease, which is essential for developing preventative strategies and therapeutic opportunities.
A particular strength in all these studies is the ability to identify relevant genetic variation and to explore the biological and pathophysiological impact on molecular and cellular function and in vitro as well as in model organisms and humans. This is greatly facilitated by the strength in basic biochemistry and cell biology within the IMS and in closely affiliated institutes such as CIMR, our long-standing, wide-ranging expertise in studying human physiology, and our growing expertise in the generation and evaluation of animal models.
Other recent basic experimental discoveries include: that the effects of thyroid hormones on brown fat are mediated via the hypothalamus, a region of the brain that also controls food intake; insights into the mechanisms linking obesity and mishandling of lipid species that might lead to insulin resistance and diabetes; novel discoveries concerning epigenetic changes that link poor diet during pregnancy with an increased risk of the offspring developing Type 2 diabetes in later life; paradigm shifting observations of circadian regulation in red blood cells that overturn the long held belief that circadian rhythms require changes in gene expression; increasing insight into the relationship between endoplasmic reticulum stress and metabolic disease; and research into the function and dysfunction of the endocrine cells of the gastro-intestinal tract, including how they are regulated and how they might be best manipulated to achieve therapeutic benefit in obesity and diabetes.
Lysosomal storage disorders are a group of rare, recessive metabolic diseases. Research in the therapy of these conditions involves improving outcomes in Gaucher disease through disease stratification, and building on successful trials in animal models to develop a clinical trial of gene therapy for Tay-Sachs and Sandhoff diseases (GM2 gangliosidosis), both of which result in severe mental retardation and early death. As yet, there are no effective treatments.
In Type 1 diabetes the pancreas is unable to produce insulin. Research in this area is focused on aetiology and early intervention based on immune mechanisms. In addition, there is a strong programme of research pioneering the development and use of the ‘artificial pancreas’, which replaces the missing insulin in exactly the amount required to control glucose levels. Key findings include improved control of overnight glucose concentrations and reduced risk of night-time hypoglycaemia in both children and adults, including pregnant women. In collaboration with industry partners, the group has developed the first prototype system to be tested by patients in their own homes.
