Published online Sep 15, 2023. doi: 10.4239/wjd.v14.i9.1334
Peer-review started: April 14, 2023
First decision: June 13, 2023
Revised: June 18, 2023
Accepted: July 13, 2023
Article in press: July 13, 2023
Published online: September 15, 2023
Type 2 diabetes mellitus (T2DM) is a lifelong condition and a threat to human health. Thorough understanding of its pathogenesis is acutely needed in order to devise innovative, preventative, and potentially curative pharmacological interventions. MicroRNAs (miRNA), are small, non-coding, one-stranded RNA molecules, that can target and silence around 60% of all human genes through translational repression. MiR-155 is an ancient, evolutionarily well-conserved miRNA, with distinct expression profiles and multifunctionality, and a target repertoire of over 241 genes involved in numerous physiological and pathological processes including hematopoietic lineage differentiation, immunity, inflammation, viral infections, cancer, cardiovascular conditions, and particularly diabetes mellitus. MiR-155 Levels are progressively reduced in aging, obesity, sarcopenia, and T2DM. Thus, the loss of coordinated repression of multiple miR-155 targets acting as negative regulators, such as C/EBPβ, HDAC4, and SOCS1 impacts insulin signaling, deteriorating glucose homeostasis, and causing insulin resistance (IR). Moreover, deranged regulation of the renin angiotensin aldo-sterone system (RAAS) through loss of Angiotensin II Type 1 receptor downregulation, and negated repression of ETS-1, results in unopposed detrimental Angiotensin II effects, further promoting IR. Finally, loss of BACH1 and SOCS1 repression abolishes cytoprotective, anti-oxidant, anti-apoptotic, and anti-inflammatory cellular pathways, and promotes β-cell loss. In contrast to RAAS inhibitor treatments that further decrease already reduced miR-155 Levels, strategies to increase an ailing miR-155 production in T2DM, e.g., the use of metformin, mineralocorticoid receptor blockers (spironolactone, eplerenone, finerenone), and verapamil, alone or in various combinations, represent current treatment options. In the future, direct tissue delivery of miRNA analogs is likely.
Core Tip: MicroRNAs (miRNA) are small, non-coding, one-stranded RNA molecules that can target and silence over 60% of human genes thereby effectively regulating huge genetic networks. MiRNAs are abundantly found in every human cell and their production is tightly controlled. They play critical roles in regulating almost every cellular pathway, numerous human diseases, and have been linked to the development of diabetes mellitus (DM) and the regulation of blood pressure. In this minireview, we comment on crucial miR-155 effects in type 2 DM (T2DM). Deeper mechanistical understanding of this miRNA’s permeating action may lead to innovative therapeutic approaches in T2DM.