SIRT6 Leaves the Nucleus in Diabetes, Fueling Dangerous Vascular Changes

Diabetic angiopathy — vascular damage driven by chronic high blood sugar and elevated lipids — is a leading cause of disability and death in type 2 diabetes. Vascular smooth muscle cells (VSMCs) are central players: under diabetic stress they shift from a quiescent, contractile state to a proliferative, synthetic phenotype fueled by enhanced glycolysis. Despite growing evidence linking glycolytic reprogramming to this pathology, the upstream molecular triggers have remained poorly understood.

This study identifies a surprising new mechanism: the protein SIRT6, a NAD⁺-dependent deacetylase best known for suppressing glycolysis from within the nucleus, physically relocates to the cytoplasm under hyperglycemic and hyperlipidemic conditions. Using diabetic mouse (db/db) and rat (HFD/STZ) models, human renal vascular tissue from diabetic patients, and cultured VSMCs exposed to high glucose plus palmitate, the researchers documented consistent cytoplasmic accumulation of SIRT6. The nuclear export is mediated by Importin 13 (IPO13), which interacts with SIRT6 and shuttles it out of the nucleus — a process driven by oxidative stress and impaired S-sulfhydration of SIRT6.

Once in the cytoplasm, SIRT6 binds the glycolytic enzyme enolase 3 (ENO3) — identified here as a novel downstream target via co-immunoprecipitation mass spectrometry and proteomics. SIRT6 deacetylates ENO3, boosting its enzymatic activity and elevating phosphoenolpyruvate (PEP) levels, thereby accelerating glycolytic flux. This metabolic reprogramming promotes VSMC hyperproliferation and migration, contributing to pathological vascular remodeling. Isotopic glucose tracing ([U-¹³C] glucose) in vivo confirmed enhanced glycolytic carbon flow in diabetic aortas, and transcriptomic and proteomic analyses corroborated the upregulation of glycolytic pathways.

A key therapeutic insight emerges from the role of hydrogen sulfide (H2S). Diabetic animals and cells show reduced endogenous H2S production (lower CSE, CBS, and 3-MST enzyme expression). Exogenous H2S supplementation — via the slow-releasing donor GYY4137 or NaHS — restores S-sulfhydration of SIRT6 specifically at cysteine 141. This post-translational modification prevents SIRT6 cytoplasmic translocation, disrupts the SIRT6–ENO3 interaction, suppresses ENO3 deacetylation and activity, reduces PEP accumulation, and ultimately attenuates VSMC proliferation and vascular remodeling in both cell and animal models. NAC (an antioxidant) similarly reduced SIRT6 cytoplasmic accumulation, reinforcing the role of oxidative stress in driving translocation.

The study reframes SIRT6 as a dual-compartment metabolic regulator whose subcellular location determines whether it suppresses or promotes glycolysis. It also positions the SIRT6–IPO13–ENO3 axis as a mechanistically coherent and therapeutically actionable pathway in diabetic vascular disease. Caveats include the use of pharmacological H2S donors rather than genetic models for the rescue experiments, and the need for further validation of ENO3 as the primary cytoplasmic SIRT6 substrate in human vascular tissue.