MicroRNAs as stress regulators in pancreatic beta cells and diabetes

Abstract

BackgroundMicroRNAs have emerged as important regulatory non-coding RNAs that tune cellular responses to physiological perturbations and disease conditions. An increasing body of literature underlines the important roles of miRNA function in pancreatic β-cells in response to metabolic, genetic and inflammatory stress. Lessons from genetic loss- and gain-of-function studies have implicated several highly expressed and evolutionary conserved miRNAs in stress signal modulation, resolution and buffering, thereby forming stabilizing miRNA networks that preserve β-cell differentiation, function, proliferation and cell survival.Scope of ReviewThis review will summarize our current knowledge of how biologically relevant miRNAs regulate stress responses in pancreatic β-cells, discuss the challenges and opportunities associated with using secreted miRNAs as biomarkers and forecast how mechanistic knowledge of miRNA function can be exploited in developing miRNA-based therapeutics.Major ConclusionsmiRNAs play important roles in the function, differentiation, proliferation, and survival of pancreatic β-cells. Many miRNA families that are regulated by metabolic, genetic, and inflammatory stressors have been found to coordinate the adaptive responses of β-cells in vivo in conditions such as obesity and diabetes.

Epigenetic silencing of microRNA‐874‐3p implicates in erectile dysfunction in diabetic rats by activating the Nupr1/Chop‐mediated pathway

“…We found that miR-874-3p overexpression, similar to Nupr1 silencing, improved erection duration in DMED rats. 42 Moreover, miRNAs are also involved in cardiovascular complications arising from diabetes, 43 especially microcirculation dysfunctions. 40 Although miR-874-3p has not previously been implicated in diabetes, many other miRNAs are involved in diabetes.…”

MicroRNAs in islet hormone secretion

“…Interestingly, genetic deletion of miR‐200 family also confers positive effect on β‐cells but this is seen only during metabolic stress conditions such as when the pancreatic islets are under oxidative and ER stress . Taken together, these highly expressed miRNAs can both have positive and negative influence on the pancreatic β‐cell and their interplay may be highly important especially during metabolic stress …”

“…It is obvious that the expression of mir‐375 is not significantly different in islets from non‐diabetic (ND) versus T2D donors (Figure A), whereas miR‐130a showed differential expression (Figure B). A list of abundant miRNAs, and another of differentially expressed miRNAs in human T2D or in mouse animal models were summarized in a recent review by LaPierre and Stoffel . Comparing the lists, it becomes obvious that there is large discordance, and that diabetes seldom associates with differential expression of the more abundant miRNAs, like miR‐375.…”

“…Upon increased insulin resistance, the demand on the β‐cells increases and the cells adjust to the new condition. We and others have suggested that microRNAs (miRNAs) participate in β‐cell compensation during pregnancy, obesity and T2D development . miRNAs are short non‐coding RNAs that mediate RNA silencing and posttranscriptional regulation of gene expression.…”

“…The multitude of molecular components involved in β‐cell failure highlights the complexity of the β‐cell and is another reason why miRNAs are suitably involved in β‐cell adjustments. miRNAs have been shown to regulate several different cellular processes in the β‐cell . These include the regulation of β‐cell development and maintenance, the downregulation of β‐cell “disallowed genes,” and the capacity to control β‐cell function, including insulin production and secretion (Figure A).…”