Type 2 diabetes candidate genes, including PAX5, cause impaired insulin secretion in human pancreatic islets.

Type 2 diabetes (T2D) is caused by insufficient insulin secretion from pancreatic ß cells. To identify candidate genes contributing to T2D pathophysiology, we studied human pancreatic islets from approximately 300 individuals. We found 395 differentially expressed genes (DEGs) in islets from individuals with T2D, including, to our knowledge, novel (OPRD1, PAX5, TET1) and previously identified (CHL1, GLRA1, IAPP) candidates. A third of the identified expression changes in islets may predispose to diabetes, as expression of these genes associated with HbA1c in individuals not previously diagnosed with T2D. Most DEGs were expressed in human ß cells, based on single-cell RNA-Seq data. Additionally, DEGs displayed alterations in open chromatin and associated with T2D SNPs. Mouse KO strains demonstrated that the identified T2D-associated candidate genes regulate glucose homeostasis and body composition in vivo. Functional validation showed that mimicking T2D-associated changes for OPRD1, PAX5, and SLC2A2 impaired insulin secretion. Impairments in Pax5-overexpressing ß cells were due to severe mitochondrial dysfunction. Finally, we discovered PAX5 as a potential transcriptional regulator of many T2D-associated DEGs in human islets. Overall, we have identified molecular alterations in human pancreatic islets that contribute to ß cell dysfunction in T2D pathophysiology.

Islet microRNAs in health and type-2 diabetes.

Failure of the ß-cell to secrete enough insulin is a major contributing factor in the pathogenesis of type-2 diabetes (T2D). MicroRNAs provide an extra layer in the regulation of protein expression, and are thus involved in ß-cell compensation during development of the disease. In this review, we discuss how microRNAs can regulate their target protein expression and phenotypic output, present the status of nutritional regulation of microRNA expression, and summarize work on microRNA expression in human islets. In conclusion, current data lend support to microRNAs being essential regulators of insulin secretion. Future work will describe microRNAs in α-cell function, details of the microRNA-mRNA network, and possibilities to use microRNAs as biomarkers and in therapeutic treatment of T2D and complications.