Genetic and nutritional control of pancreatic beta cell identity.

Diabetes mellitus affects more than 20 m Europeans and 400 m individuals worldwide. The complications of the disease, including blindness, kidney failure, cardiovascular disease and cancer, drastically reduce quality of life, and consume almost 10 % of health care costs in most westernised nations. These figures are expected to increase further in coming years. The most common form, Type 2 diabetes (T2D), has both genetic and environmental causes, and is particularly prevalent in those affected by over-nutrition and obesity. Therapeutic approaches towards T2D have relied in the past on enhancing the actions of insulin, responsible for lowering blood glucose levels, and on stimulating insulin secretion. However, none of the existing therapies reverse the progressive loss of normal beta cell identity and function and hence the gradual worsening of disease symptoms. "Genome wide association studies" (GWAS) for T2D have now identified numerous genetic variants whose inheritance is associated with an increased risk of diabetes. The identification of these genes, most of which influence insulin production, provides both improved powers of prediction and, just as excitingly, potential new molecular targets for drug treatment. More than 100 hundred genetic loci have now been identified which collectively harbour almost 500 genes. Our work seeks firstly to determine which of the genes in selected loci are responsible for increased disease risk. This involves both genetic studies in man, and functional analyses based on studying the impact of deleting a particular gene from the disease relevant tissue - usually the pancreatic beta cell. We have shown that a changes in the expression of a gene termed STARD10, which is able to bind fat molecules (lipids) within the cell and carry them between discrete intracellular locations, is responsible for the increased diabetes risk observed in carriers with a specific set of genetic variants on chromosome 11. At present, however, we have very little idea how this gene affects the cell's metabolism to impair the release of insulin. Understanding this question is important since it may provide new ways in which to improve the production of the hormone in those individuals (more than 80 % of the population) who are at increased risk of diabetes thanks to carrying the risk variant of this gene. We will therefore perform cellular analyses using human islets, human-derived beta and beta-like cells, the latter produced in the test tube from embryonic stem cells, to determine the impact of deleting STARD10, and to understand how the variants associated with disease risk alter the expression of this gene. The second Aim of our studies is to understand how two gene products, LKB1 and AMPK, are able to regulate pancreatic beta cell function. We know that deleting either gene in the mouse beta cell leads to a change in cellular identity, leading to the up-regulation of other genes which are not normally expressed in the islet but present at high levels in nerve and liver cells. AMPK, which is itself regulated by LKB1, is of particular interest since this enzyme is controlled by nutrients including glucose. We will determine whether changes in the activity of either enzyme affect gene expression by prompting changes in the structure (opening or closing) of nuclear DNA. We will also determine the impact of small molecule AMPK activators, which hold therapeutic promise in diabetes, on beta cell function. Our final Aim is to determine whether the role of STARD10 in controlling beta cell function may be altered in the absence of LKB1, a phenomenon we have recently described for another GWAS gene, TCF7L2, or by changes in nutritional status. We will use novel and powerful technologies including genome editing, directed differentiation of human embryonic stem cells, mouse genetics, photopharmacology and imaging of the islet after engraftment within the mouse eye, to answer our questions.