MicroRNA Networks in Pancreatic Islet Cells: Normal Function and Type 2 Diabetes

Abstract

Impaired insulin secretion from the pancreatic β-cells is central in the pathogenesis of type 2 diabetes (T2D), and microRNAs (miRNAs) are fundamental regulatory factors in this process. Differential expression of miRNAs contributes to β-cell adaptation to compensate for increased insulin resistance, but deregulation of miRNA expression can also directly cause β-cell impairment during the development of T2D. miRNAs are small noncoding RNAs that posttranscriptionally reduce gene expression through translational inhibition or mRNA destabilization. The nature of miRNA targeting implies the presence of complex and large miRNA–mRNA regulatory networks in every cell, including the insulin-secreting β-cell. Here we exemplify one such network using our own data on differential miRNA expression in the islets of T2D Goto-Kakizaki rat model. Several biological processes are influenced by multiple miRNAs in the β-cell, but so far most studies have focused on dissecting the mechanism of action of individual miRNAs. In this Perspective we present key islet miRNA families involved in T2D pathogenesis including miR-200, miR-7, miR-184, miR-212/miR-132, and miR-130a/b/miR-152. Finally, we highlight four challenges and opportunities within islet miRNA research, ending with a discussion on how miRNAs can be utilized as therapeutic targets contributing to personalized T2D treatment strategies.

miR-140-5p Aggravates Insulin Resistance via Directly Targeting GYS1 and PPP1CC in Insulin-Resistant HepG2 Cells

“…The above results suggested that miR-140-5p might be valuable as a diagnostic biomarker and a potential therapeutic target for insulin resistance in diabetes mellitus.MiRNAs exert their biological function by regulating their target genes in T2DM. 42 In order to explore the mechanism of miR-140-5p, bioinformatics tools were used to predict target genes of miR-140-5p, and the results revealed that the 3ʹ-untranslated region (3ʹUTR) of target gene including glycogen synthetase1 (GYS1) and protein phosphatase 1, catalytic subunit gamma (PPP1CC) contained the conserved binding site of miR-140-5p ( Figure 3A ). A variety of bioinformatics tools were used to predict the target genes of miR-140-5p, and the results showed that PicTar, TargetScan and Diana databases all predicted the presence of binding sites of miR-140-5p in the 3 ‘untranslated region of GYS1 and PPP1CC.…”

miR-7 Regulates GLP-1-Mediated Insulin Release by Targeting β-Arrestin 1

“…The key importance of miR-7 in β cell physiology is also corroborated by the fact that this miR has been shown to be one of the most abundant miRs in both human and murine islets [ 19 ], with a ratio >150 as compared with its expression between islet and surrounding acinar tissue [ 48 ].…”

“…They play crucial regulatory roles in a variety of biological processes, including regulation of differentiation, development, and function of β cells [ 14 , 15 , 16 ]. Specifically, recent studies have identified a number of miRs involved in the regulation of insulin release [ 17 , 18 , 19 ]. In terms of therapeutic potential, miRs represent a novel and very appealing strategy to manipulate metabolic processes as their activity can be efficiently modulated with RNA-based technologies [ 20 , 21 , 22 ].…”

mRNA Processing: An Emerging Frontier in the Regulation of Pancreatic β Cell Function

“…RBPs regulate several classes of RNAs, including both coding (mRNA) and non-coding (ncRNA) RNAs. A recent comprehensive review has discussed the critical role of RBPs Dicer and Argonaut in the regulation of miRNAs for β cell function and in T2D (Eliasson and Esguerra, 2020). Here we will provide a brief survey of the expression and function of several prominent RBP families that regulate mRNAs in pancreatic β cells.…”