MiR-335 overexpression impairs insulin secretion through defective priming of insulin vesiclesVisa övriga samt affilieringar
2017 (Engelska)Ingår i: Physiological Reports, E-ISSN 2051-817X, Vol. 5, nr 21, artikel-id e13493Artikel i tidskrift (Refereegranskat) Published
Abstract [en]
MicroRNAs contribute to the maintenance of optimal cellular functions by fine-tuning protein expression levels. In the pancreatic beta-cells, imbalances in the exocytotic machinery components lead to impaired insulin secretion and type 2 diabetes (T2D). We hypothesize that dysregulated miRNA expression exacerbates beta-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 EndoC-beta H1 and in rat INS-1 832/13 cells (OE335) resulted in decreased glucose-stimulated insulin secretion, and OE335 cells showed concomitant reduction in three exocytotic proteins: SNAP25, Syntaxin-binding protein 1 (STXBP1), and synaptotagmin 11 (SYT11). 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.
Ort, förlag, år, upplaga, sidor
John Wiley & Sons, 2017. Vol. 5, nr 21, artikel-id e13493
Nyckelord [en]
Beta cell, exocytosis, insulin secretion, microRNA, patch-clamp, SNAP25, STXBP1, TIRF, Type 2 Diabetes
Nationell ämneskategori
Fysiologi
Identifikatorer
URN: urn:nbn:se:uu:diva-339717DOI: 10.14814/phy2.13493ISI: 000415351500008OAI: oai:DiVA.org:uu-339717DiVA, id: diva2:1177762
2018-01-262018-01-262018-01-26Bibliografiskt granskad