TY - JOUR
T1 - Type 2 diabetes candidate genes, including PAX5, cause impaired insulin secretion in human pancreatic islets
AU - Bacos, Karl
AU - Perfilyev, Alexander
AU - Karagiannopoulos, Alexandros
AU - Cowan, Elaine
AU - Ofori, Jones K.
AU - Bertonnier-Brouty, Ludivine
AU - Rönn, Tina
AU - Lindqvist, Andreas
AU - Luan, Cheng
AU - Ruhrmann, Sabrina
AU - Ngara, Mtakai
AU - Nilsson, Åsa
AU - Gheibi, Sevda
AU - Lyons, Claire L.
AU - Lagerstedt, Jens O.
AU - Barghouth, Mohammad
AU - Esguerra, Jonathan L.S.
AU - Volkov, Petr
AU - Fex, Malin
AU - Mulder, Hindrik
AU - Wierup, Nils
AU - Krus, Ulrika
AU - Artner, Isabella
AU - Eliasson, Lena
AU - Prasad, Rashmi B.
AU - Cataldo, Luis Rodrigo
AU - Ling, Charlotte
N1 - 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.
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
U2 - 10.1172/JCI163612
DO - 10.1172/JCI163612
M3 - Journal article
C2 - 36656641
AN - SCOPUS:85148113921
VL - 133
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 4
M1 - e163612
ER -