Exosomal MicroRNA-15a Transfer from the Pancreas Augments Diabetic Complications by Inducing Oxidative Stress

Tengku Ain Kamalden, Anne M. Macgregor-Das, Sangeetha Marimuthu Kannan, Brittany Dunkerly-Eyring, Nurliza Khaliddin, Zhenhua Xu, Anthony P. Fusco, Syatirah Abu Yazib, Rhuen Chiou Chow, Elia J. Duh, Marc K. Halushka, Charles Steenbergen, Samarjit Das

Research output: Contribution to journalArticlepeer-review

52 Scopus citations


Aims: MicroRNAs (miRNAs), one type of noncoding RNA, modulate post-transcriptional gene expression in various pathogenic pathways in type 2 diabetes (T2D). Currently, little is known about how miRNAs influence disease pathogenesis by targeting cells at a distance. The purpose of this study was to investigate the role of exosomal miRNAs during T2D. Results: We show that miR-15a is increased in the plasma of diabetic patients, correlating with disease severity. miR-15 plays an important role in insulin production in pancreatic β-cells. By culturing rat pancreatic β-cells (INS-1) cells in high-glucose media, we identified a source of increased miR-15a in the blood as exosomes secreted by pancreatic β-cells. We postulate that miR-15a, produced in pancreatic β-cells, can enter the bloodstream and contribute to retinal injury. miR-15a overexpression in Müller cells can be induced by exposing Müller cells to exosomes derived from INS-1 cells under high-glucose conditions and results in oxidative stress by targeting Akt3, which leads to apoptotic cell death. The in vivo relevance of these findings is supported by results from high-fat diet and pancreatic β-cell-specific miR-15a-/- mice. Innovation: This study highlights an important and underappreciated mechanism of remote cell-cell communication (exosomal transfer of miRNA) and its influence on the development of T2D complications. Conclusion: Our findings suggest that circulating miR-15a contributes to the pathogenesis of diabetes and supports the concept that miRNAs released by one cell type can travel through the circulation and play a role in disease progression via their transfer to different cell types, inducing oxidative stress and cell injury. Antioxid. Redox Signal. 27, 913-930.

Original languageEnglish (US)
Pages (from-to)913-930
Number of pages18
JournalAntioxidants and Redox Signaling
Issue number13
StatePublished - Nov 1 2017


  • Diabetic vasculopathy
  • Exosomes
  • MicroRNA
  • Oxidative stress
  • Pancreatic β-cells

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology


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