Abstract
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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | e163612 |
| Tidsskrift | Journal of Clinical Investigation |
| Vol/bind | 133 |
| Udgave nummer | 4 |
| Antal sider | 17 |
| ISSN | 0021-9738 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:We acknowledge Leif Groop for laying the foundation for LUDC and this work, the BEA Core Facility at the Karolinska Institute for transcriptomic analysis of INS1 β cells, as well as Anna-Maria Ramsay and Monika Dudenhöffer-Pfeifer for technical assistance. We thank Olle Korsgren and the Nordic Network for Clinical Islet Transplantation (Juvenile Diabetes Research Foundation [JDRF] award 31-2008-413) and the tissue isolation teams and Human Tissue Laboratory within EXODIAB/LUDC. Elements of Figure 2I and the graphical abstract come from Servier Medical templates, which are licensed under a Creative Commons Attribution 3.0 Unported License (https://smart.servier.com). This work was funded by the Hjelt Foundation, the Crafoord Foundation, and the Påhlsson Foundation (to KB); the JKO: Royal Physiographic Society through the Birgit and Hellmuth Hertz Foundation (to JKO); the Swedish Research Council (2020-02179) and the Novo Nordisk Foundation (NNF19OC0057339) (to JOL); the Swedish Research Council (2021-01777) and the Novo Nordisk Foundation (18OC0034238) (to HM); the Swedish Research Council (2020-01017, 2017-00862 and 521-2012-2119), the Region Skåne-ALF, Diabetes Wellness Research Foundation Sweden, EFSD, the Hjelt Foundation, the Novo Nordisk Foundation, and the Swedish Diabetes Foundation (to NW); the Swedish Research Council (2020-04461), the Novo Nordisk Foundation (NNF20OC0063485), and the Påhlsson Foundation (to IA); the Swedish Research Council (2019-01406), the Region Skåne-ALF (ALFSKANE-450661), and the Swedish Diabetes Foundation (DIA2019-454) (to LE); the Swedish Research Council (2021-02623) (to RBP); and the Swedish Research Council (2018-02567 and 2021-00628), the Region Skåne-ALF, Strategic Research Area Exodiab (2009-1039), the Novo Nordisk Foundation (NNF19OC0057415 and NNF21OC0067294), the Swedish Foundation for Strategic Research (IRC15-0067), the European Research Council (ERC-Paintbox), and the Swedish Diabetes Foundation (to CL).
Funding Information:
Human islets. Human islets of Langerhans were obtained from the Human Tissue Laboratory, which is funded by the Excellence of Diabetes Research in Sweden (EXODIAB) network (www.exodiab.se/home) in collaboration with the Nordic Network for Clinical Islet Transplantation Program (www.nordicislets.org). Islets from cadaver donors were prepared by enzymatic digestion and density gradient separation. Islet preparation purity and counts were determined as described previously (69). Details on islet purity, measured by dithizone staining of individual islet preparations, are presented in Supplemental Table 14.
Publisher Copyright:
Copyright: © 2023, Bacos et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.