UC San Diego

The dysregulation of elevated blood glucose levels, which characterizes a group of diseases under the umbrella of diabetes, poses a serious health burden to millions of people worldwide. Cell types in the human pancreas, particularly those in the hormone-producing pancreatic islets, have been strongly implicated in the development of most forms of diabetes. Efforts to map the genetic risk associated with developing diabetes have mainly identified variants in non-coding regions of the genome. These variants likely regulate expression of target genes, which then lead to the cellular changes that underlie disease. However, previous efforts to connect these risk variants to mechanisms have been limited and had minimal integration with known phenotypic risk of diabetes. Additionally, previous work has primarily been focused on the most common forms of diabetes, leading our understanding of rarer forms of the disease severely lacking. In this dissertation I analyze the results of multiple single cell multimodal sequencing assays to understand pancreatic gene regulation and its relation to diabetes risk. First, I establish baseline gene regulatory networks in a cohort of non-diabetic individuals and compare these to changes with phenotypes and genotypes associated with diabetes risk, including age, BMI, and genetic risk variants. Using these networks, I identify multiple novel mechanisms of type 1 and type 2 diabetes risk in pancreatic islet cell types. Second, I focus on a rare form of diabetes, cystic fibrosis-related diabetes (CFRD), where exocrine destruction of the pancreas precedes eventual development of hyperglycemia, often by decades. I map gene regulatory networks altered in pancreatic cell types from individuals with cystic fibrosis and integrate these findings with spatial information on cell-cell interactions and tissue environment. I characterize specific cellular interactions and tissue features associated with cellular dysfunction and nominate multiple signaling pathways that may facilitate these interactions. In total, the research contained in this thesis represents important advances in our understanding of how gene regulation governs cell types in the human pancreas, and how this facilitates risk of both common and rare forms of diabetes.