Journal Article

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

Krus, Ulrika, Lindqvist, Andreas, Ngara, Mtakai, Eliasson, Lena, Cowan, Elaine, Lagerstedt, Jens O., Wierup, Nils, Artner, Isabella, Mulder, Hindrik, Rönn, Tina, Esguerra, Jonathan L.S., Cataldo, Luis Rodrigo, Luan, Cheng, Ruhrmann, Sabrina, Bacos, Karl, Lyons, Claire L., Fex, Malin, Prasad, Rashmi B., Perfilyev, Alexander, Volkov, Petr, Ling, Charlotte, Ofori, Jones K., Karagiannopoulos, Alexandros, Bertonnier-Brouty, Ludivine, Gheibi, Sevda, Nilsson, Åsa, Barghouth, Mohammad

2023

Overview

Type 2 diabetes (T2D) is caused by insufficient insulin secretion from pancreatic β 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 β 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 β 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 β cell dysfunction in T2D pathophysiology.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Basic Medicine / Biochemistry, Molecular Biology / Biomedical research / Body composition / Causes of / Chromatin / Clinical Medicine / Development and progression / Diabetes / Diabetes mellitus (non-insulin dependent) / Diabetes Mellitus, Type 2 - genetics / Diabetes Mellitus, Type 2 - metabolism / DNA methylation / Endocrinology / Endocrinology and Diabetes / Endokrinologi och diabetes / Gene expression / Generalized linear models / Genes / Genetic aspects / Genetic research / Glycosylated hemoglobin / Health aspects / Homeostasis / Humans / Identification and classification / Insulin / Insulin - genetics / Insulin - metabolism / Insulin resistance / Insulin secretion / Insulin Secretion - genetics / Insulin-Secreting Cells - metabolism / Islets of Langerhans - metabolism / Klinisk medicin / Life Sciences / Medical and Health Sciences / Medical Genetics and Genomics (including Gene Therapy) / Medicin och hälsovetenskap / Medicinsk genetik och genomik (Här ingår: Genterapi) / Medicinska och farmaceutiska grundvetenskaper / Metabolism / Mice / Mitochondria / Mixed Function Oxygenases - metabolism / Molecular biology / Pancreas / Pancreatic beta cells / Pathophysiology / Pax5 protein / PAX5 Transcription Factor - metabolism / Physiological aspects / Proto-Oncogene Proteins - metabolism / RNA / RNA sequencing / Secretion / Single-nucleotide polymorphism / Type 2 diabetes