Metabolism, Endocrinology & Bone

Professor Sir Stephen O'Rahilly

Stephen O'RahillyWelcome to the Metabolism, Endocrinology & Bone theme. Our research is helping to translate basic scientific research into real advances in understanding, treatment and prevention of human metabolic, endocrine and musculoskeletal diseases.

It involves conditions such as obesity and diabetes, which are common and responsible for widespread, major health problems, as well diseases such as lysosomal storage disorders, extreme insulin resistance and congenital hypothyroidism. Whilst the latter are rare they can have devastating consequences for patients and their families. Musculoskeletal diseases include arthritis, osteoporosis, back and joint pain and are the main cause of work related illness in the UK.

Obesity: One of the main links between obesity and ill health is a significant increase in the likelihood of developing type 2 diabetes, insulin resistance and cardiovascular disease (together known as the metabolic syndrome), as well as some cancers and osteoarthritis. Our investigators have identified several genetic causes of obesity, 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. 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.

People with Type 2 diabetes and insulin resistance are unable to respond normally to insulin. Our theme has world-leading strengths in the genetics of both common and rare forms of insulin resistance. Lipodystrophy (lack of fat) is studied as a model of insulin resistance and the metabolic syndrome. In addition to identifying genetic causes of insulin resistance, 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.

In Type 1 diabetes the pancreas is unable to produce insulin. Our team is 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. In collaboration with industry partners, the group has developed the first prototype system that will be tested by patients in their own homes.

Musculoskeletal disorders, a group of over 200 conditions including osteoporosis, arthritis, back pain and damage to joints, muscles and tendons, are the most common cause of work-related illness in the UK.  Support from Cambridge BRC is enabling research into musculoskeletal disorders to lead world-class translational research in three areas including:

  • Osteoporosis which affects 1 in 2 women and 1 in 5 men over the age of 50 years in the UK - the resulting fractures cost an estimated £1.8 billion annually.
  • Arthritis which causes long term health problems in more than 7 million adults in the UK leading to a loss of 206 million working days annually.
  • Aseptic loosening or osteolysis is associated with failure of hip prostheses within 10-15 years of hip replacement; a substantial concern for the 44,000 UK patients undergoing hip replacements annually.

Lysosomal storage disorders Tay-Sachs and Sandhoff diseases (GM2 gangliosidosis) are rare, recessive disorders, resulting in severe mental retardation and early death. As yet, there are no effective treatments. Members of the theme, with European collaborators, are developing novel forms of gene therapy for these conditions.

Professor Sir Stephen O'Rahilly
January 2013