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, abnormal adipose tissue function and/or excess tissue growth. We study people with known genetic changes, looking for new causal genetic changes, investigating the changes we find in mice and cells, and undertaking experimental medicine studies and clinical trials in patients.. More recently such forward genetic approaches to severe phenotypes have been complemented by reverse genetic approaches, interrogating genes of interest in the rich and growing population-wide genetic datasets available nationally and internationally.