Robert Semple Research Group (Affiliate)

Human Genetic Disorders of Insulin Action

Research in a Nutshell 

Reduced ability of insulin to lower blood glucose is known as insulin resistance. This is common, is closely associated with obesity, and is believed to drive numerous major diseases. We aim to understand how it occurs and how it is linked to diabetes, fatty liver, high blood fat levels, reduced fertility and cancer. To do this we focus on rare and severe disorders caused by changes in individual genes, including severe insulin resistance, low blood glucose, and/or excess tissue growth. We study people with known genetic changes, look for new genetic changes in studies of people and populations, and investigate the changes we find in mice and cells. Specific interests include:

Defects of insulin signalling: We use these to test which diseases are caused by lack of insulin action, and which by compensatory increased insulin action. We are systematically studying all possible insulin receptor mutations, and are investigating anti-receptor antibodies as potential treatments for extreme insulin receptor defects.

Mutations increasing insulin-like signalling:  Activating mutations, especially in the  PIK3CA gene, usually occur after conception, are found patchily in the body, and often lead to devastating tissue overgrowth.  We are studying human stem cells to address fundamental disease mechanisms.

Genetic disorders disrupting fat cell energy generation and/or DNA damage repair that cause insulin resistance:  We use these to understand lifecourse resilience of human fat tissue, which is crucial for metabolic health. 

Contact

r.semple@ed.ac.uk

Collaborations

• Grzegorz Kudla, University of Edinburgh
• Pleasantine Mill, University of Edinburgh
• Elizabeth Patton, University of Edinburgh
• Antonella Fidanza, University of Edinburgh
• Cataline Vallejos, University of Edinburgh
• Ruth Loos, University of Copenhagen
• Stephen O’Rahilly, University of Cambridge
• David Savage, University of Cambridge
• Julian Sale, MRC LMB, Cambridge
• Gemma Brierley, Anglia Ruskin University, Cambridge

Partners and Funders

• Wellcome Trust
• British Heart Foundation
• CLOVES Syndrome Community