| 1. |
- Bacos, Karl, et al.
(författare)
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Type 2 diabetes candidate genes, including PAX5, cause impaired insulin secretion in human pancreatic islets
- 2023
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Ingår i: The Journal of clinical investigation. - 0021-9738 .- 1558-8238. ; 133:4
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes (T2D) is caused by insufficient insulin secretion from pancreatic β-cells. To identify candidates contributing to T2D pathophysiology, we studied human pancreatic islets from ~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 islet expression changes may predispose to diabetes, as they associated with HbA1c in individuals not previously diagnosed with T2D. Most DEGs were expressed in human β-cells based on single-cell RNA-sequencing data. Additionally, DEGs displayed alterations in open chromatin and associated with T2D-SNPs. Mouse knock-out strains demonstrated that T2D-associated candidates 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 identified molecular alterations in human pancreatic islets contributing to β-cell dysfunction in T2D pathophysiology.
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| 2. |
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| 3. |
- Karagiannopoulos, Alexandros, et al.
(författare)
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Glucocorticoid-mediated induction of ZBTB16 affects insulin secretion in human islets and EndoC-βH1 β-cells
- 2023
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Ingår i: iScience. - 2589-0042. ; 26:5, s. 1-23
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Tidskriftsartikel (refereegranskat)abstract
- Glucocorticoid use is associated with steroid-induced diabetes mellitus and impaired pancreatic β-cell insulin secretion. Here, the glucocorticoid-mediated transcriptomic changes in human pancreatic islets and the human insulin-secreting EndoC-βH1 cells were investigated to uncover genes involved in β-cell steroid stress-response processes. Bioinformatics analysis revealed glucocorticoids to exert their effects mainly on enhancer genomic regions in collaboration with auxiliary transcription factor families including AP-1, ETS/TEAD, and FOX. Remarkably, we identified the transcription factor ZBTB16 as a highly confident direct glucocorticoid target. Glucocorticoid-mediated induction of ZBTB16 was time- and dose-dependent. Manipulation of ZBTB16 expression in EndoC-βH1 cells combined with dexamethasone treatment demonstrated its protective role against glucocorticoid-induced reduction of insulin secretion and mitochondrial function impairment. In conclusion, we determine the molecular impact of glucocorticoids on human islets and insulin-secreting cells and investigate the effects of glucocorticoid targets on β-cell function. Our findings can pave the way for therapies against steroid-induced diabetes mellitus.
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| 4. |
- Karagiannopoulos, Alexandros, et al.
(författare)
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miRNAs in the beta cell - friends or foes?
- 2023
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 164:5
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Forskningsöversikt (refereegranskat)abstract
- Type-2 diabetes (T2D) develops due to insulin resistance and an inability of the pancreatic β-cells to increase secretion of insulin and reduce elevated blood glucose levels. Diminished β-cell function and mass have been implicated in impaired β-cell secretory capacity and several microRNAs (miRNAs) have been reported to be involved in regulating β-cell processes. We believe miRNAs are nodes in important miRNA-mRNA networks regulating β-cell function and that miRNAs therefore can be targets for the treatment of T2D. MiRNAs are short (≈19-23nt) endogenous non-coding RNAs which regulate gene expression by directly binding to the mRNA of their target genes. Under normal circumstances miRNAs act as rheostats to keep expression of their gene targets at optimal levels for different β-cell outputs. In T2D, levels of some miRNAs are altered as part of the compensatory mechanism to improve insulin secretion. Other miRNAs are differentially expressed as part of the process of T2D pathogenesis, which results in reduced insulin secretion and increased blood glucose. In this review we present recent findings concerning miRNAs in islets and in insulin-secreting cells, and their differential expression in diabetes, with a specific focus on miRNAs involved in β-cell apoptosis/proliferation and glucose-stimulated insulin secretion. We present thoughts around miRNA-mRNA networks, and miRNAs as both therapeutic targets to improve insulin secretion and as circulating biomarkers of diabetes. Overall, we hope to convince you that miRNAs in β-cells are essential for regulating their function and can in the future be of clinical use in treatment and/or prevention of diabetes.
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| 5. |
- Rönn, Tina, et al.
(författare)
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Genes with epigenetic alterations in human pancreatic islets impact mitochondrial function, insulin secretion, and type 2 diabetes
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Epigenetic dysregulation may influence disease progression. Here we explore whether epigenetic alterations in human pancreatic islets impact insulin secretion and type 2 diabetes (T2D). In islets, 5,584 DNA methylation sites exhibit alterations in T2D cases versus controls and are associated with HbA1c in individuals not diagnosed with T2D. T2D-associated methylation changes are found in enhancers and regions bound by β-cell-specific transcription factors and associated with reduced expression of e.g. CABLES1, FOXP1, GABRA2, GLR1A, RHOT1, and TBC1D4. We find RHOT1 (MIRO1) to be a key regulator of insulin secretion in human islets. Rhot1-deficiency in β-cells leads to reduced insulin secretion, ATP/ADP ratio, mitochondrial mass, Ca2+, and respiration. Regulators of mitochondrial dynamics and metabolites, including L-proline, glycine, GABA, and carnitines, are altered in Rhot1-deficient β-cells. Islets from diabetic GK rats present Rhot1-deficiency. Finally, RHOT1methylation in blood is associated with future T2D. Together, individuals with T2D exhibit epigenetic alterations linked to mitochondrial dysfunction in pancreatic islets.
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| 6. |
- Westholm, Efraim, et al.
(författare)
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Interleukin-4 reduces insulin secretion in human islets from healthy but not type-2 diabetic donors
- 2023
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Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 649, s. 87-92
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes (T2D) is associated with low-grade inflammation. Here we investigate if the anti-inflammatorycytokine interleukin-4 (IL-4) affects glucose-stimulated insulin secretion (GSIS) in human islets from nondiabetic(ND) and type-2 diabetic (T2D) donors. We first confirmed that GSIS is reduced in islets from T2Ddonors. Treatment with IL-4 for 48 h had no further effect on GSIS in these islets but significantly reduced secretionin ND islets. Acute treatment with IL-4 for 1 h had no effect on GSIS in ND islets which led us to suspect thatIL-4 affects a slow cellular mechanism such as gene transcription. IL-4 has been reported to regulate miR-378a-3pand, indeed, we found that this microRNA was increased with IL-4 treatment. However, overexpression of miR-378a-3p in the human beta cell line EndoC-βH1 did not affect GSIS. MiR-378a-3p is transcribed from the samegene as peroxisome proliferator-activated receptor gamma co-activator 1 beta (PCG-1β) and we found that IL-4treatment showed a clear tendency to increased gene expression of PCG-1β. PCG-1β is a co-activator of peroxisomeproliferator-activated receptor gamma (PPARγ) and, the gene expression of PPARγ was also increased withIL-4 treatment. Our data suggests that the protective role of IL-4 on beta cell survival comes at the cost of loweredinsulin secretion, presumably involving the PPARγ-pathway.
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