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 8

Schematic image presenting a model for how the T2D-associated changes may alter β cell function.

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Schematic image presenting a model for how the T2D-associated changes ma...
Our analysis showed that the islet expression of 395 genes is altered in T2D. These expression changes are enriched for genes affecting, e.g., insulin secretion, and functional analyses showed that the T2D-associated changes to OPRD1, PAX5, PCOLCE2, and SLC2A2 (encoding GLUT2) impair glucose-stimulated insulin secretion. In ND individuals, β cells highly express SLC2A2, leading to high levels of GLUT2 and efficient glucose uptake. This in turn, via glycolysis, the TCA cycle, and the electron transport chain (ETC) in well-functioning mitochondria, leads to ATP production, a higher cytosolic ATP/ADP ratio, and stimulation of insulin secretion. Simultaneously, our data suggest that signaling through OPRD1, an enkephalin receptor, stimulates insulin secretion. In T2D, there is dysregulation of PAX5, leading to greatly increased PAX5 mRNA and protein levels in β cells, as well as a severe reduction in SLC2A2 and OPRD1 expression. These changes lead to diminished insulin secretion, with PAX5 overexpression causing a strong reduction in mitochondrial activity. Simultaneously, PCOLCE2 is upregulated, which, through an unknown mechanism, also impairs insulin secretion. Importantly, elevated PAX5 may cause many of the other detrimental expression changes, including reduced SLC2A2 expression. Green arrows indicate stimulation, red arrows indicate inhibition, and dashed arrows indicate potential effects.