Type 2 diabetes candidate genes, including PAX5, cause impaired insulin secretion in human pancreatic islets
Karl Bacos, Alexander Perfilyev, Alexandros Karagiannopoulos, Elaine Cowan, Jones K. Ofori, Ludivine Bertonnier-Brouty, Tina Rönn, Andreas Lindqvist, Cheng Luan, Sabrina Ruhrmann, Mtakai Ngara, Åsa Nilsson, Sevda Gheibi, Claire L. Lyons, Jens O. Lagerstedt, Mohammad Barghouth, Jonathan L.S. Esguerra, Petr Volkov, Malin Fex, Hindrik Mulder, Nils Wierup, Ulrika Krus, Isabella Artner, Lena Eliasson, Rashmi B. Prasad, Luis Rodrigo Cataldo, Charlotte Ling
Karl Bacos, Alexander Perfilyev, Alexandros Karagiannopoulos, Elaine Cowan, Jones K. Ofori, Ludivine Bertonnier-Brouty, Tina Rönn, Andreas Lindqvist, Cheng Luan, Sabrina Ruhrmann, Mtakai Ngara, Åsa Nilsson, Sevda Gheibi, Claire L. Lyons, Jens O. Lagerstedt, Mohammad Barghouth, Jonathan L.S. Esguerra, Petr Volkov, Malin Fex, Hindrik Mulder, Nils Wierup, Ulrika Krus, Isabella Artner, Lena Eliasson, Rashmi B. Prasad, Luis Rodrigo Cataldo, Charlotte Ling
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Research Article Endocrinology Metabolism

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

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.

Authors

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

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Figure 6

Elevated Pax5 in INS1 β cells leads to cell loss and widespread transcriptomic changes affecting β cell function.

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Elevated Pax5 in INS1 β cells leads to cell loss and widespread transcri...
(A) Pax5 overexpression resulted in loss of INS1 β cells, as indicated by MTT assay (n = 4). (B and C) Pax5 overexpression in INS1 β cells increased caspase-3/-7 activity (n = 5) (B) and levels of cleaved (i.e., active) caspase-3 (n = 6, all samples were run on 1 gel) (C). (D) Pax5 overexpression reduced proliferation in INS1 β cells (n = 6). (E) mRNA expression of Btbd3, Faim2, Nab1, Pcolce2, Pde7b, Slc2a2, Socs1, and Tgm2 was altered in Pax5-overexpressing INS1 β cells (n = 8). (F) Enrichment of gene ontology terms among the genes with differential expression in Pax5-overexpressing INS1 β cells showed transcriptomic changes within pathways important for insulin secretion and cell numbers. *P < 0.05, **P < 0.01 ***P < 0.001, and ****P < 0.0001, by 2-tailed, paired t test (A–E). Box-and-whisker plots show the median, the 25th and 75th percentiles, and minimum and maximum values.