Fasting and fasting-mimicking treatment activate SIRT1/LXRα and alleviate diabetes-induced systemic and microvascular dysfunction – published online 26/03/2021

Sandra S. Hammer, Cristiano P. Vieira, Delaney McFarland, Maximilian Sandler, Yan Levitsky, Tim F. Dorweiler, Todd A. Lydic, Bright Asare-Bediako, Yvonne Adu-Agyeiwaah, Micheli S. Sielski, Mariana Dupont, Ana Leda Longhini, Sergio Li Calzi, Dibyendu Chakraborty, Gail M. Seigel, Denis A. Proshlyakov, Maria B. Grant, Julia V. Busik

Intermittent fasting has been shown to exert beneficial effects by improving metabolic health. It has also been shown to prevent the development of diabetic retinopathy in mouse models of diabetes. The mechanism(s) responsible for these advantageous effects, however, remains undefined. Sirtuin 1 (SIRT1) is a nutrient-sensing deacetylase that is activated in low-nutrient environments (such as intermittent fasting) and downregulated in diabetes. In this issue, Hammer et al (https://doi.org/10.1007/s00125-021-05431-5) demonstrate that activation of SIRT1/liver X receptor alpha (LXRα) signalling prevents diabetes-induced retinal damage in both cell culture and animal models of diabetes. Specifically, the authors show prevention of inflammation and cell death in neurovascular retinal cells in diabetes, as well as improvement of bone marrow health in diabetic mice via SIRT1 activation. Pharmacological SIRT1 activation also prevented diabetes-induced visual function impairment in mouse models of type 2 diabetes. The authors conclude that these findings suggest that activation of SIRT1 signalling can provide a mechanistic link between the advantageous effects associated with fasting regimens and improvements in metabolic health in diabetes.

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