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MiR-335 overexpression impairs insulin secretion through defective priming of insulin vesicles
Lund Univ, Lund Univ Diabet Ctr, Dept Clin Sci Malmo, Islet Cell Exocytosis, CRC 91-11,SUS Malmo,Box 50332, S-20213 Malmo, Sweden..
Lund Univ, Lund Univ Diabet Ctr, Dept Clin Sci Malmo, Islet Cell Exocytosis, CRC 91-11,SUS Malmo,Box 50332, S-20213 Malmo, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Lund Univ, Lund Univ Diabet Ctr, Dept Clin Sci Malmo, Islet Cell Exocytosis, CRC 91-11,SUS Malmo,Box 50332, S-20213 Malmo, Sweden..
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2017 (English)In: Physiological Reports, E-ISSN 2051-817X, Vol. 5, no 21, article id e13493Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
John Wiley & Sons, 2017. Vol. 5, no 21, article id e13493
Keywords [en]
Beta cell, exocytosis, insulin secretion, microRNA, patch-clamp, SNAP25, STXBP1, TIRF, Type 2 Diabetes
National Category
Physiology
Identifiers
URN: urn:nbn:se:uu:diva-339717DOI: 10.14814/phy2.13493ISI: 000415351500008OAI: oai:DiVA.org:uu-339717DiVA, id: diva2:1177762
Available from: 2018-01-26 Created: 2018-01-26 Last updated: 2018-01-26Bibliographically approved

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