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ludc web

Anna Wendt

Assistant researcher

ludc web

MiR-335 overexpression impairs insulin secretion through defective priming of insulin vesicles

Author

  • Vishal A. Salunkhe
  • Jones K. Ofori
  • Nikhil R. Gandasi
  • Sofia A. Salö
  • Sofia Hansson
  • Markus E. Andersson
  • Anna Wendt
  • Sebastian Barg
  • Jonathan L.S. Esguerra
  • Lena Eliasson

Summary, in English

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.

Department/s

  • Diabetes - Islet Cell Exocytosis
  • EXODIAB: Excellence of Diabetes Research in Sweden

Publishing year

2017-11-01

Language

English

Publication/Series

Physiological Reports

Volume

5

Issue

21

Document type

Journal article

Publisher

John Wiley & Sons Inc.

Topic

  • Cell and Molecular Biology
  • Endocrinology and Diabetes

Keywords

  • Beta cell
  • Exocytosis
  • Insulin secretion
  • MicroRNA
  • Patch-clamp
  • SNAP25
  • STXBP1
  • TIRF
  • Type 2 Diabetes

Status

Published

Research group

  • Diabetes - Islet Cell Exocytosis

ISBN/ISSN/Other

  • ISSN: 2051-817X