SIRT1 as a Therapeutic Target in Diabetic Complications

Background SIRT1 is an epigenetic enzyme involved in histone and non-histone protein deacetylation. It acts primarily as a metabolic sensor, which responses to changing energy status by deacetylating crucial transcription factors and cofactors. In this way, SIRT1 regulates mitochondrial function and biogenesis, oxidative stress, inflammation, apoptosis and cellular senescence. Disturbance of all of these phenomena promotes the pathogenesis of diabetic complications. These disorders are inseparably connected with chronic hyperglycemia, which possesses a strong epigenetic determinant. Objective: The aim of this review is to summarize the contemporary knowledge concerning the role of SIRT1 in the development and progression of diabetes complications. We focus on the examples of synthetic and natural compounds-mediated SIRT1 upregulation along with SIRT1-associated epigenetics. Results: Reduction of SIRT1 is implicated in endothelial dysfunction and metabolic memory, underlying the development of micro- and macrovascular complications. Declined SIRT1 also participates in diabetic testicular and erectile dysfunction. SIRT1 is elevated by naturally occurring anti-oxidant and anti-inflammatory compounds such as resveratrol, trans-delta-viniferin, vitamin D and more. Similarly, SIRT1 level increases after treatment with standard antihyperglycemic (metformin, exenatide, liraglutide), antihypertensive (sartans), lipid-lowering (fibrates, statins) and anticoagulant (fidarestat) drugs. Focusing on epigenetics, a number of miRNAs trigger SIRT1 decrease, which further contributes to histone acetylation of SIRT1-regulated and relevant for diabetes genes. Conclusions: Evidence strongly suggest that SIRT1 upregulation may serve as a potent therapeutic approach against development and progression of diabetic complications.