June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Intermittent fasting prevents cholesterol accumulation, cholesterol crystal formation and the development of diabetic retinopathy.
Author Affiliations & Notes
  • Sandra S Hammer
    Physiology, Michigan State University, East Lansing, Michigan, United States
  • Maria B Grant
    Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Julia V Busik
    Physiology, Michigan State University, East Lansing, Michigan, United States
  • Footnotes
    Commercial Relationships   Sandra Hammer None; Maria Grant None; Julia Busik None
  • Footnotes
    Support  R01EY025383, F32EY028426
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 782 – F0341. doi:
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    • Get Citation

      Sandra S Hammer, Maria B Grant, Julia V Busik; Intermittent fasting prevents cholesterol accumulation, cholesterol crystal formation and the development of diabetic retinopathy.. Invest. Ophthalmol. Vis. Sci. 2022;63(7):782 – F0341.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Time restricted feeding has multiple benefits without the detrimental side effects of calorie restriction. However, the mechanism of action in which time the restricted eating paradigm exerts positive outcomes remains inadequately studied. Previously, we showed that a high caloric state in diabetes leads to downregulation of SIRT1/LXRα activity resulting in retinal cholesterol accumulation. Herein, we investigated the retinal specific effects of long term IF using in vitro and in vivo models.

Methods : To model IF, we used human retinal endothelial cells (HREC) and serum depleted the cultures for 24hrs followed by exposure to cholesterol crystals for 24hrs. A type 2 diabetes (T2D) model, the db/db mouse was used and db/m mice was used as controls. Food restriction for 24hrs was followed by a 24hrs feeding period during this time mice had access to water ad libitum. After 6 months of diabetes, animals were sacrificed, and retinas analyzed for cholesterol crystal formation, inflammatory cytokine expression, and levels of SIRT1/LXRα and cholesterol. CC were quantified using ImageJ software analysis. Quantitative Real Time PCR was used to assay inflammatory marker production. Trypan blue exclusion assay was used to measure cell death.

Results : In vitro CC administration resulted in elevated levels of inflammatory markers (IL6, IL8, VCAM1, ICAM1, IL-1ß, n=3; p<0.001), complement pathway activation (C5aR, n=3; p<0.001) and apoptosis (n=3; p<0.01) in HREC which were improved by serum starvation. Long term diabetes resulted in decreased SIRT1 expression (n=5; p<0.05), elevated retinal cholesterol levels, CC formation (n=5; p<0.05) and inflammation marker expression (n=5; p<0.05). While CC were not found in retinas of non-diabetic aged, matched controls, they were observed in db/db mice. Long term IF increased retinal SIRT1/LXRα signaling, cholesterol efflux, prevented retinal cholesterol accumulation, CC formation and inflammation.

Conclusions : IF-mimicking conditions improved HREC response to CC exposure and lowering retinal cholesterol levels via IF prevented formation of CC and DR progression. Thus, this study suggests that IF is an effective and safe therapeutic strategy in combating the deleterious retinal effects associated with long term diabetes by reducing retinal levels of cholesterol, CC formation and deceasing retinal inflammation.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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