Reshma Ramracheya

After graduating with a degree in Applied Biology, I pursued a PhD at King's College London, where I researched the regulation of insulin secretion from pancreatic beta-cells by receptor-operated agonists. I then joined Patrik Rorsman's laboratory in Oxford as a postdoctoral researcher and played a leading role in characterising the secretory properties of human pancreatic alpha-, beta- and delta-cells. In 2012, I was awarded a Diabetes UK RD Lawrence Research Fellowship which has enabled me to establish myself as an independent researcher at the University of Oxford.  My research is aimed at dissecting the molecular mechanisms by which gut hormones, namely GLP-1 and PYY improve glucose-mediated insulin and glucagon secretion in pancreatic islets. Dysfunction of both secretory processes contributes to the onset of type 2 diabetes and represents the target of effective diabetes intervention.  GLP-1 can both enhance insulin secretion and inhibit glucagon release. However, the mechanism by which GLP-1 inhibits glucagon secretion is currently unknown. Recent data from our laboratory indicate that GLP-1 inhibits glucagon secretion from isolated islets by a direct effect not involving paracrine signals (for example insulin or somatostatin), but possibly mediated by a novel receptor that is expressed in alpha-cells but not in beta-cells. We are currently exploring the existence of a potential novel receptor for GLP-1 in human islets. Ultimately, this work may result in novel therapies that specifically target the hypersecretion of glucagon seen in diabetes.  In parallel, we are also investigating the impact of weight-loss surgery on pancreatic islet functions. We have recently demonstrated an important role of the much neglected gut hormone PYY on human pancreatic islet function and reversal of diabetes following gastric bypass surgery. The metabolic benefits of weight-loss surgery are so compelling that surgery is now being considered as a therapeutic option for type 2 diabetes in obese patients. However, this option is life-changing, risky and unsuitable for many patients. Thus, my lab is exploring the roles of GLP-1 and PYY, on human diabetes and their effects on islet physiology through the application of novel in-vitro methods (which cannot be done in humans) to investigate if the beneficial effects of surgery on glycaemia can be translated in man by non-surgical procedures. Like GLP-1, PYY is a substrate for the proteolytic enzyme dipeptidyl peptidase-IV (DDP-IV), which is highly expressed in the islets. We are also exploring whether  DPP-IV inhibition can influence PYY metabolism in islets and whether agents which enhance PYY release or its action can provide a novel, non-surgical therapy for type 2 diabetes.  Work in our laboratory involve an array of techniques including islet isolation, secretion studies with rodent and donor human islets, light microscopy and calcium imaging, cell culture, gene knockdown and biochemical assays.