SIRT1 is critical to vascular health and regulates glucose and lipid metabolism through its deacetylase activity. Type 2 diabetes-associated decreases in SIRT1 levels result in increased levels of acetylated LXR leading to reduced expression of reverse cholesterol transport genes and increased expression of NFκB-controlled pro-inflammatory genes. Diabetic circulating angiogenic cells (CAC) which are critical in vascular repair also demonstrate reduced SIRT1 and increasing its levels corrects CAC dysfunction (1). db/db mice were given SRT-1720 hydrochloride (100 mg/kg body weigh/day for 2 or 6 mo.) in their chow or fed normal chow beginning at diabetes onset. Retinal tissue, blood and bone marrow (BM) were collected. Electroretinograms (ERG) were performed at 2 and 6 mo. The BM supernatant was analyzed for cytokines. BM hematopoietic stem cells and CACs were assessed by flow cytometry. Retinal lipids were assessed by Mass Spectroscopy. At 2 mo, the retina of SRT1720-treated db/db mice demonstrated an increase in the ratio of total cholesterol/demosterol/lanosterol (197±85) compared to db/db (65±12. p<0.05). The percent of CAC was increased in db/db mice treated with SRT1720 (2.1±0.6 vs. 0.2±0.1 db/db. p<0.01). Most interestingly, SRT1720-treated db/db mice showed a decrease in the percentage of proinflammatory granulocyte-macrophage progenitors (1.7±0.3 vs. 2.8±0.6 db/db, p<0.008) and BM IL-1 beta (5±0.5 SIRT vs. 10±2.4 control db/db, p<0.01) levels. db/db mice with 6 months of diabetes showed a significant reduction in the ERG scotopic response and SRT-1720 treatment corrected this dysfunction (165±60 in SRT1720 db/db vs. 76±20µV, p<0.03), compared to controls (194±60µV). These findings support that activation of SIRT1 has multiple LXR-mediated beneficial effects. Namely, it improved the visual response in T2D model by regulating retinal cholesterol metabolism, increased vascular protective CACs and decreased pro-inflammatory progenitor cells and cytokines in the BM.


C.P. Vieira: None. A. Longhini: None. S. Li Calzi: None. M.D. DuPont: None. J.V. Busik: None. M.B. Grant: None.


National Institutes of Health (EY025383)

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