Genetics: how the UKPDS contributed to determining the genetic landscape of Type 2 diabetes

The identification and functional characterisation of genetic variants that either cause or predispose to diabetes is a major focus of biomedical research. The molecular basis is now known for the majority of monogenic forms of diabetes arising from pancreatic beta-cell dysfunction; however finding the genetic variants underlying susceptibility to Type 2 diabetes (T2DM) has been a greater technical, statistical and biological challenge. The advent of biology-agnostic approaches made possible by the improved arsenal of research platforms and genetic tools available has increased the number of known T2DM genes dramatically and provided important insights into the pathophysiology of T2DM. Over the past 18 months, the list of T2DM susceptibility genes has grown from three to close to 20, illustrating the substantial progress which has been made. These recent milestones have not only illustrated the limited knowledge we have of the pancreatic beta-cell, but have also reinforced our belief in the involvement of common genetic variants in the genes involved in monogenic forms of diabetes in the susceptibility to T2DM and have clearly shown a primary role for pancreatic beta-cell dysfunction in T2DM. Both of these concepts were explored in the early work of the UK Prospective Diabetes Study (UKPDS) genetics research groups.