Background: Non-coding genetic variants that influence gene transcription in pancreatic islets play a major role in the susceptibility to type 2 diabetes (T2D), and likely also contribute to type 1... Show moreBackground: Non-coding genetic variants that influence gene transcription in pancreatic islets play a major role in the susceptibility to type 2 diabetes (T2D), and likely also contribute to type 1 diabetes (T1D) risk. For many loci, however, the mechanisms through which non-coding variants influence diabetes susceptibility are unknown. Results: We examine splicing QTLs (sQTLs) in pancreatic islets from 399 human donors and observe that common genetic variation has a widespread influence on the splicing of genes with established roles in islet biology and diabetes. In parallel, we profile expression QTLs (eQTLs) and use transcriptome-wide association as well as genetic co-localization studies to assign islet sQTLs or eQTLs to T2D and T1D susceptibility signals, many of which lack candidate effector genes. This analysis reveals biologically plausible mechanisms, including the association of T2D with an sQTL that creates a nonsense isoform in ERO1B, a regulator of ER-stress and proinsulin biosynthesis. The expanded list of T2D risk effector genes reveals overrepresented pathways, including regulators of G-protein-mediated cAMP production. The analysis of sQTLs also reveals candidate effector genes for T1D susceptibility such as DCLRE1B, a senescence regulator, and lncRNA MEG3. Conclusions: These data expose widespread effects of common genetic variants on RNA splicing in pancreatic islets. The results support a role for splicing variation in diabetes susceptibility, and offer a new set of genetic targets with potential therapeutic benefit. Show less
Pancreatic islet transplantation by a new method is introduced here : the isolation of islets in an organ preservation solution, the University of Wisconsin solution. A new concept allowing for the... Show morePancreatic islet transplantation by a new method is introduced here : the isolation of islets in an organ preservation solution, the University of Wisconsin solution. A new concept allowing for the first time large-scale isolation and transplantation of consistently near 100% pure islets of Langerhans in a preclinical dog model with fasting normoglycemia up to 3 years posttransplant. Detailed metabolic studies demonstrated normal insulin levels after meals with preservation of gut hormone action stimulating insulin secretion at the mild hyperglycemia after meals. The introduction of the University of Wisconsin solution organ preservation solution for islet isolation at the start of these studies in 1989 is a new concept … and has been shown by now in 2022 , world-wide , to make the future of islet isolation and transplantation methods for insulin-dependent diabetes mellitus (IDDM). Show less
