| 1. |
- Salunkhe, V.A., et al.
(författare)
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MiR-335 regulates exocytotic proteins and affects glucose-stimulated insulin secretion through decreased Ca2+-dependent exocytosis in beta cells
- 2015
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 58:Suppl. 1, s. 128-128
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Konferensbidrag (refereegranskat)abstract
- Background and aims: Ca2+-induced exocytosis is essential for insulin to be secreted from beta-cells, and in islets from type-2 diabetic (T2D) donors the expression of several genes coding for exocytotic proteins is reduced. Largely this phenomenon cannot be explained by polymorphism; rather it is likely due to epigenetic factors like microRNAs (miRNAs). Indeed, previous studies have identified a number of miRNAs with differential expression in the islets from T2D donors and the Goto- Kakizaki (GK) rat. One of the upregulatedmiRNAs in the GK rat is miR- 335, predicted to target several exocytotic genes amongst those Stxbp1 is a validated target. Here we aim to investigate whether miR-335 regulates the expression of exocytotic genes and affects insulin secretion and exocytosis in beta-cells. Materials and methods: Insulin secretion was measured by radio immuno assay. Exocytosis and docking of insulin granules was studied by capacitance measurements using the patch-clamp technique and by TIRF microscopy. Rat miR-335 was overexpressed using chemicallymodified mature microRNA mimic in INS-1 832/13 beta-cells by transfection. Gene knockdown was performed with RNAi. Protein and mRNA levels were analysed with Western Blot and RT-qPCR, respectively. Results: Overexpression of miR-335 (OE335) in INS-1 832/13 cells reduced insulin secretion at 16.7 mM glucose compared to control cells (SCR) (n=3; p
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| 2. |
- Axelsson, Annika, et al.
(författare)
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Sox5 regulates beta-cell phenotype and is reduced in type 2 diabetes
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes (T2D) is characterized by insulin resistance and impaired insulin secretion, but the mechanisms underlying insulin secretion failure are not completely understood. Here, we show that a set of co-expressed genes, which is enriched for genes with islet-selective open chromatin, is associated with T2D. These genes are perturbed in T2D and have a similar expression pattern to that of dedifferentiated islets. We identify Sox5 as a regulator of the module. Sox5 knockdown induces gene expression changes similar to those observed in T2D and diabetic animals and has profound effects on insulin secretion, including reduced depolarization-evoked Ca 2+-influx and β-cell exocytosis. SOX5 overexpression reverses the expression perturbations observed in a mouse model of T2D, increases the expression of key β-cell genes and improves glucose-stimulated insulin secretion in human islets from donors with T2D. We suggest that human islets in T2D display changes reminiscent of dedifferentiation and highlight SOX5 as a regulator of β-cell phenotype and function.
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| 3. |
- Omling, E., et al.
(författare)
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Nationwide study of appendicitis in children
- 2019
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Ingår i: British Journal of Surgery. - : Oxford University Press (OUP). - 0007-1323 .- 1365-2168. ; 106:12, s. 1623-1631
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Tidskriftsartikel (refereegranskat)abstract
- Background: Paediatric surgical care is increasingly being centralized away from low-volume centres, and prehospital delay is considered a risk factor for more complicated appendicitis. The aim of this study was to determine the incidence of paediatric appendicitis in Sweden, and to assess whether distance to the hospital was a risk factor for complicated disease. Methods: A nationwide cohort study of all paediatric appendicitis cases in Sweden, 2001–2014, was undertaken, including incidence of disease in different population strata, with trends over time. The risk of complicated disease was determined by regression methods, with travel time as the primary exposure and individual-level socioeconomic determinants as independent variables. Results: Some 38 939 children with appendicitis were identified. Of these, 16·8 per cent had complicated disease, and the estimated risk of paediatric appendicitis by age 18 years was 2·5 per cent. Travel time to the treating hospital was not associated with complicated disease (adjusted odds ratio (OR) 1·00 (95 per cent c.i. 0·96 to 1·05) per 30-min increase; P = 0·934). Level of education (P = 0·177) and family income (P = 0·120) were not independently associated with increased risk of complicated disease. Parental unemployment (adjusted OR 1·17, 95 per cent c.i. 1·05 to 1·32; P = 0·006) and having parents born outside Sweden (1 parent born in Sweden: adjusted OR 1·12, 1·01 to 1·25; both parents born outside Sweden: adjusted OR 1·32, 1·18 to 1·47; P < 0·001) were associated with an increased risk of complicated appendicitis. Conclusion: Every sixth child diagnosed with appendicitis in Sweden has a more complicated course of disease. Geographical distance to the surgical facility was not a risk factor for complicated appendicitis.
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| 4. |
- Salunkhe, Vishal A., et al.
(författare)
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MiR-335 overexpression impairs insulin secretion through defective priming of insulin vesicles
- 2017
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Ingår i: Physiological Reports. - : Wiley. - 2051-817X. ; 5:21
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Tidskriftsartikel (refereegranskat)abstract
- MicroRNAs contribute to the maintenance of optimal cellular functions by fine-tuning protein expression levels. In the pancreatic β-cells, imbalances in the exocytotic machinery components lead to impaired insulin secretion and type 2 diabetes (T2D). We hypothesize that dysregulated miRNA expression exacerbates β-cell dysfunction, and have earlier shown that islets from the diabetic GK-rat model have increased expression of miRNAs, including miR-335- 5p (miR-335). Here, we aim to determine the specific role of miR-335 during development of T2D, and the influence of this miRNA on glucose-stimulated insulin secretion and Ca2+-dependent exocytosis. We found that the expression of miR-335 negatively correlated with secretion index in human islets of individuals with prediabetes. Overexpression of miR-335 in human KndoC- (βH\ and in rat INS-1 832/13 cells (OE335) resulted in decreased glucose-sti- mulated insulin secretion, and OE335 cells showed concomitant reduction in three exocytotic proteins: SNAP25, Syntaxin-binding protein 1 (STXBPl), and synaptotagmin 11 (SYTll). Single-cell capacitance measurements, complemented with TIRF microscopy of the granule marker NPY-mEGFP demonstrated a significant reduction in exocytosis in OE335 cells. The reduction was not associated with defective docking or decreased Ca2+ current More likely, it is a direct consequence of impaired priming of already docked granules. Earlier reports have proposed reduced granular priming as the cause of reduced first-phase insulin secretion during prediabetes. Here, we show a specific role of miR-335 in regulating insulin secretion during this transition period. Moreover, we can conclude that miR-335 has the capacity to modulate insulin secretion and Ca2+-dependent exocytosis through effects on granular priming.
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