2型糖尿病(T2DM)是一种威胁人类健康的终身性疾病。为了设计创新,迫切需要对其发病机制的深刻理解,预防性,和潜在的治疗药物干预措施。microRNAs(miRNA),很小,非编码,单链RNA分子,可以通过翻译抑制靶向并沉默大约60%的人类基因。MiR-155是一种古老的,进化上保守的miRNA,具有不同的表达谱和多功能性,和超过241个基因的目标库涉及许多生理和病理过程,包括造血谱系分化,豁免权,炎症,病毒感染,癌症,心血管疾病,尤其是糖尿病。MiR-155水平在老化过程中逐渐降低,肥胖,少肌症,和T2DM。因此,作为负调节因子的多个miR-155靶标的协同抑制的丧失,如C/EBPβ,HDAC4和SOCS1影响胰岛素信号,恶化的葡萄糖稳态,并引起胰岛素抵抗(IR)。此外,通过失去血管紧张素II1型受体下调调节肾素血管紧张素醛固酮系统(RAAS),和ETS-1的否定抑制,导致无相反的血管紧张素II效应,进一步推动IR。最后,BACH1和SOCS1抑制的丧失消除了细胞保护,抗氧化剂,抗凋亡,和抗炎细胞通路,并促进β细胞损失。与进一步降低已经降低的miR-155水平的RAAS抑制剂治疗相反,增加T2DM中miR-155产生的策略,例如,二甲双胍的使用,盐皮质激素受体阻滞剂(螺内酯,依普利酮,finerenone),和维拉帕米,单独或以各种组合,代表当前的治疗选择。在未来,miRNA类似物的直接组织递送是可能的。
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.