Exosomal miRNAs and isomiRs: potential biomarkers for type 2 diabetes mellitus

Yong Ling Sou,1 William M. Chilian,2 Wickneswari Ratnam,3 Shamsul Mohd Zain,4 Sharifah Zamiah Syed Abdul Kadir,4 Yan Pan,1 Yuh-Fen Pung 1,*

Division of Biomedical Science, Faculty of Science and Engineering, University of Nottingham Malaysia , 43500 Semenyih, Selangor, Malaysia
Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272 USA
Department of Biological Sciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Bangi, Selangor 43600, Malaysia
Department of Pharmacology, University of Malaya, Kuala Lumpur 50603, Malaysia

Type 2 diabetes mellitus (T2DM) is a metabolic disease that is characterized by chronic hyperglycaemia. MicroRNAs (miRNAs) are single-stranded, small non-coding RNAs that play important roles in post-transcriptional gene regulation. They are negative regulators of their target messenger RNAs (mRNAs), in which they bind either to inhibit mRNA translation, or to induce mRNA decay. Similar to proteins, miRNAs exist in different isoforms (isomiRs). miRNAs and isomiRs are selectively loaded into small extracellular vesicles, such as the exosomes, to protect them from RNase degradation. In T2DM, exosomal miRNAs produced by different cell types are transported among the primary sites of insulin action. These interorgan crosstalk regulate various T2DM-associated pathways such as adipocyte inflammation, insulin signalling, and β cells dysfunction among many others. In this review, we first focus on the mechanism of exosome biogenesis, followed by miRNA biogenesis and isomiR formation. Next, we discuss the roles of exosomal miRNAs and isomiRs in the development of T2DM and provide evidence from clinical studies to support their potential roles as T2DM biomarkers. Lastly, we highlight the use of exosomal miRNAs and isomiRs in personalized medicine, as well as addressing the current challenges and future opportunities in this field. This review summarizes how research on exosomal miRNAs and isomiRs has developed from the very basic to clinical applications, with the goal of advancing towards the era of personalized medicine.

Figure 1. The biogenesis and release of exosomes. Exosome biogenesis can be summarized in four steps: (1) The inward budding of the plasma membrane to form early endosomes; (2) Early endosomes mature into multivesicular bodies (MVBs) (also known as late endosomes); (3) The invagination of MVBs membrane to form intraluminal vesicles (ILVs) by the ESCRT-dependent or ESCRT-independent pathway and the sorting of biomolecules; (4a) Fusion of MVBs with lysosomes which results in degradation; (4b) Fusion of MVBs with the plasma membrane to (5) release ILVs as exosomes.

Figure 2. The roles of exosomal miRNAs in facilitating interorgan crosstalk between the primary sites of insulin action. miRNAs are differentially regulated in exosomes produced by different cell types. Exosomal miRNAs are shuttled between the primary sites of insulin action, thereby contributing to the development of T2DM by inducing obesity, insulin resistance, and β cell dysfunction.

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