Abstract

Beta cells found in pancreatic islets secrete insulin in order to regulate blood glucose after a meal. Dysfunction of these cells results in an impaired ability to secrete insulin in response to glucose and is an underlying contributor to common forms of diabetes. In Type 1 diabetes lower baseline secretion can exist prior to autoimmunity. In Type 2 diabetes a multifaceted relationship between impaired secretion and reduced ability to uptake glucose leads to dysglycemia. Genome-wide association studies have identified over a thousand regions of the genome which modulate risk of developing diabetes, but progress in linking genetic elements to their molecular mechanisms has been slow. Whilst previous studies have linked genetic variation to glycemic traits such as blood glucose and insulin levels, a lack of human donor tissue has limited our ability to directly characterize the genetic and molecular determinants of human islet function genome wide. Through years of collaborative efforts, we have amassed the largest collection of human islet donor tissue, with comprehensive measurements of islet function, such as amount of insulin secreted in response to glucose stimulation in a dish. Furthermore, we have profiled gene expression, chromatin accessibility and protein abundance to link genetic elements to islet tissue-specific molecular pathways. My research will perform the first Genome wide association study uncovering genetic variants, proteins and pathways which alter diabetes risk through islet and beta cell dysfunction. Under this novel framework, I will use genetic evidence to assess safety and efficacy for therapeutic perturbation.