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• W3033423088 startingPage "107647" @default.
• W3033423088 abstract "Sodium-glucose cotransporter 2 (SGLT2) inhibitors ameliorate the progression of diabetic chronic kidney disease, but the mechanisms underlying this nephroprotective effect have not been fully elucidated. These drugs induce a fasting-like transcriptional paradigm, which includes activation of sirtuin-1 (SIRT1) and its downstream effectors, peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and fibroblast growth factor 21 (FGF21). This triad of enzymes and transcription factors serve as master regulators of nutrient and cellular homeostasis, and each acts to enhance gluconeogenesis, fatty acid oxidation and ketogenesis, the hallmarks of treatment with SGLT2 inhibitors. At the same time, SIRT1/PGC-1α/FGF21 signaling also promotes autophagy, a lysosome-dependent degradative pathway that cleanses the cytosol of dysfunctional organelles. This action alleviates cellular stress, ameliorates inflammation, and is strikingly nephroprotective. Interestingly, type 2 diabetes is characterized by both a deficiency of SIRT1/PGC-1α signaling and an impairment of autophagic flux, thus explaining the high levels of oxidative stress in the diabetic kidney. SIRT1 gene polymorphisms have been linked with an increased risk of diabetic nephropathy in several epidemiological studies. Importantly, there is an inverse relationship between the activity of SGLT2 and signaling through the SIRT1/PGC-1α/FGF21 pathway, and SGLT2 inhibition leads to activation of these ketogenic nutrient deprivation sensors. Therefore, activation of SIRT1/PGC-1α/FGF21 may explain the effect of SGLT2 inhibitors not only to promote ketogenesis, but also to preserve renal function in type 2 diabetes." @default.
• W3033423088 created "2020-06-12" @default.
• W3033423088 creator A5042766753 @default.
• W3033423088 date "2020-09-01" @default.
• W3033423088 modified "2023-09-30" @default.
• W3033423088 title "Role of ketogenic starvation sensors in mediating the renal protective effects of SGLT2 inhibitors in type 2 diabetes" @default.
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• W3033423088 doi "https://doi.org/10.1016/j.jdiacomp.2020.107647" @default.
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• W3033423088 hasPublicationYear "2020" @default.
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