| 1. |
- Alonso, Lorena, et al.
(författare)
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TIGER : The gene expression regulatory variation landscape of human pancreatic islets
- 2021
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 37:2
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWASs) identified hundreds of signals associated with type 2 diabetes (T2D). To gain insight into their underlying molecular mechanisms, we have created the translational human pancreatic islet genotype tissue-expression resource (TIGER), aggregating >500 human islet genomic datasets from five cohorts in the Horizon 2020 consortium T2DSystems. We impute genotypes using four reference panels and meta-analyze cohorts to improve the coverage of expression quantitative trait loci (eQTL) and develop a method to combine allele-specific expression across samples (cASE). We identify >1 million islet eQTLs, 53 of which colocalize with T2D signals. Among them, a low-frequency allele that reduces T2D risk by half increases CCND2 expression. We identify eight cASE colocalizations, among which we found a T2D-associated SLC30A8 variant. We make all data available through the TIGER portal (http://tiger.bsc.es), which represents a comprehensive human islet genomic data resource to elucidate how genetic variation affects islet function and translates into therapeutic insight and precision medicine for T2D.
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| 2. |
- Atla, Goutham, et al.
(författare)
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Genetic regulation of RNA splicing in human pancreatic islets
- 2022
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1474-760X. ; 23, s. 1-28
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundNon-coding genetic variants that influence gene transcription in pancreatic islets play a major role in the susceptibility to type 2 diabetes (T2D), and likely also contribute to type 1 diabetes (T1D) risk. For many loci, however, the mechanisms through which non-coding variants influence diabetes susceptibility are unknown.ResultsWe examine splicing QTLs (sQTLs) in pancreatic islets from 399 human donors and observe that common genetic variation has a widespread influence on the splicing of genes with established roles in islet biology and diabetes. In parallel, we profile expression QTLs (eQTLs) and use transcriptome-wide association as well as genetic co-localization studies to assign islet sQTLs or eQTLs to T2D and T1D susceptibility signals, many of which lack candidate effector genes. This analysis reveals biologically plausible mechanisms, including the association of T2D with an sQTL that creates a nonsense isoform in ERO1B, a regulator of ER-stress and proinsulin biosynthesis. The expanded list of T2D risk effector genes reveals overrepresented pathways, including regulators of G-protein-mediated cAMP production. The analysis of sQTLs also reveals candidate effector genes for T1D susceptibility such as DCLRE1B, a senescence regulator, and lncRNA MEG3.ConclusionsThese data expose widespread effects of common genetic variants on RNA splicing in pancreatic islets. The results support a role for splicing variation in diabetes susceptibility, and offer a new set of genetic targets with potential therapeutic benefit.
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| 3. |
- Eliasson, Lena, et al.
(författare)
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MicroRNA networks in pancreatic islet cells : Normal function and type 2 diabetes
- 2020
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 69:5, s. 804-812
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Tidskriftsartikel (refereegranskat)abstract
- Impaired insulin secretion from the pancreatic β-cells is central in the pathogenesis of type 2 diabetes (T2D), and microRNAs (miRNAs) are fundamental regulatory factors in this process. Differential expression of miRNAs contributes to β-cell adaptation to compensate for increased insulin resistance, but deregulation of miRNA expression can also directly cause β-cell impairment during the development of T2D. miRNAs are small noncoding RNAs that posttranscriptionally reduce gene expression through translational inhibition or mRNA destabilization. The nature of miRNA targeting implies the presence of complex and large miRNA-mRNA regulatory networks in every cell, including the insulin-secreting β-cell. Here we exemplify one such network using our own data on differential miRNA expression in the islets of T2D Goto- Kakizaki rat model. Several biological processes are influenced by multiple miRNAs in the β-cell, but so far most studies have focused on dissecting the mechanism of action of individual miRNAs. In this Perspective we present key islet miRNA families involved in T2D pathogenesis including miR-200, miR-7, miR-184, miR-212/miR-132, and miR-130a/b/miR-152. Finally, we highlight four challenges and opportunities within islet miRNA research, ending with a discussion on how miRNAs can be utilized as therapeutic targets contributing to personalized T2D treatment strategies.
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| 4. |
- Esguerra, Jonathan L.S., et al.
(författare)
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Glucocorticoid induces human beta cell dysfunction by involving riborepressor GAS5 LincRNA
- 2020
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Ingår i: Molecular Metabolism. - : Elsevier BV. - 2212-8778. ; 32, s. 160-167
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Tidskriftsartikel (refereegranskat)abstract
- Objective: A widely recognized metabolic side effect of glucocorticoid (GC) therapy is steroid-induced diabetes mellitus (DM). However, studies on the molecular basis of GC-induced pancreatic beta cell dysfunction in human beta cells are lacking. The significance of non-coding RNAs in various cellular processes is emerging. In this study, we aimed to show the direct negative impact of GC on beta cell function and elucidate the role of riborepressor GAS5 lincRNA in the GC signaling pathway in human pancreatic beta cells. Methods: Patients undergoing two weeks of high-dose prednisolone therapy were monitored for C-peptide levels. Human pancreatic islets and the human beta cell line EndoC-βH1 were incubated in pharmacological concentrations of dexamethasone. The GAS5 level was modulated using anti-sense LNA gapmeR or short oligonucleotides with GAS5 HREM (hormone response element motif). Immunoblotting and/or real-time PCR were used to assess changes in protein and RNA expression, respectively. Functional characterization included glucose-stimulated insulin secretion and apoptosis assays. Correlation analysis was performed on RNAseq data of human pancreatic islets. Results: We found reduced C-peptide levels in patients undergoing high-dose GC therapy. Human islets and the human beta cell line EndoC-βH1 exposed to GC exhibited reduced insulin secretion and increased apoptosis. Concomitantly, reduced expression of important beta cell transcription factors, PDX1 and NKX6-1, as well as exocytotic protein SYT13 were observed. The expression of the glucocorticoid receptor was decreased, while that of serum and glucocorticoid-regulated kinase 1 (SGK1) was elevated. The expression of these genes was found to significantly correlate with GAS5 in human islet transcriptomics data. Increasing GAS5 levels using GAS5 HREM alleviated the inhibitory effects of dexamethasone on insulin secretion. Conclusions: The direct adverse effect of glucocorticoid in human beta cell function is mediated via important beta cell proteins and components of the GC signaling pathway in an intricate interplay with GAS5 lincRNA, a potentially novel therapeutic target to counter GC-mediated beta cell dysfunction.
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| 5. |
- 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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| 6. |
- Nagao, Mototsugu, et al.
(författare)
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Diagnostic potential of miR-483 family for IGF-II producing non-islet cell tumor hypoglycemia
- 2021
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Ingår i: European Journal of Endocrinology. - 1479-683X. ; 184:1, s. 41-49
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Tidskriftsartikel (refereegranskat)abstract
- Objective: In insulin-like growth factor II (IGF-II) producing non-islet cell tumor hypoglycemia (NICTH), high molecular weight forms of IGF-II (big IGF-II) are produced as a cause of spontaneous hypoglycemia. MicroRNA (miRNA)-483 family, encoded in an intron lesion of IGF2 gene, is suggested to be co-expressed with IGF-II. Here, we tested whether serum miR-483-5p and -3p levels are associated with the presence of big IGF-II in NICTH. Design: Serum samples from patients who were suspected to have IGF-II producing NICTH (n = 42) were tested. MiR-483-5p and -3p levels were evaluated using quantitative PCR. IGF-II level was analyzed using ELISA. The presence of big IGF-II was identified by Western blotting. Results: Big IGF-II was detected in the sera of 32 patients. MiR-483-5p (P = 0.0015) and -3p (P = 0.027) levels were significantly higher in sera with big IGF-II (n = 32) than in those without (n = 10), whereas serum IGF-II level (P = 0.055) was not significantly different between the groups. The median serum concentration of miR-483-5p was ~10 times higher than that of miR-483-3p. Although a strong correlation was observed between the two miRNAs (r = 0.844, P < 0.0001), but neither of which was correlated with serum IGF-II level. The areas under the receiver operating characteristic curves of miR-483-5p (0.853) and -3p (0.722) were higher than that of IGF-II (0.694) for detecting the presence of big IGF-II. Conclusion: The associations of serum miR-483-5p and -3p levels with the presence of big IGF-II suggest the diagnostic potential of these miRNAs for IGF-II producing NICTH.
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| 7. |
- Nagao, Mototsugu, et al.
(författare)
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Potential Protection Against Type 2 Diabetes in Obesity Through Lower CD36 Expression and Improved Exocytosis in β-Cells
- 2020
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 69:6, s. 1193-1205
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is a risk factor for type 2 diabetes (T2D); however, not all obese individuals develop the disease. In this study, we aimed to investigate the cause of differential insulin secretion capacity of pancreatic islets from donors with T2D and non-T2D (ND), especially obese donors (BMI ≥30 kg/m2). Islets from obese donors with T2D had reduced insulin secretion, decreased β-cell exocytosis, and higher expression of fatty acid translocase CD36. We tested the hypothesis that CD36 is a key molecule in the reduced insulin secretion capacity. Indeed, CD36 overexpression led to decreased insulin secretion, impaired exocytosis, and reduced granule docking. This was accompanied by reduced expression of the exocytotic proteins SNAP25, STXBP1, and VAMP2, likely because CD36 induced downregulation of the insulin receptor substrate (IRS) proteins, suppressed the insulin-signaling phosphatidylinositol 3-kinase/AKT pathway, and increased nuclear localization of the transcription factor FoxO1. CD36 antibody treatment of the human β-cell line EndoC-βH1 increased IRS1 and exocytotic protein levels, improved granule docking, and enhanced insulin secretion. Our results demonstrate that β-cells from obese donors with T2D have dysfunctional exocytosis likely due to an abnormal lipid handling represented by differential CD36 expression. Hence, CD36 could be a key molecule to limit β-cell function in T2D associated with obesity.
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