Intermittent Fasting (IF) Prevents Development of Diabetic Retinopathy (DR) by regulating low-grade inflammation through changes in lipid metaobolism

Abstract

Purpose : Chronic low-grade inflammation plays a central role in the progression of diabetic complications, including diabetic retinopathy (DR). We hypothesized that an intermittent fasting (IF) diet would prevent the development of DR by improving glucose regulation and decreasing overall systemic inflammation.

Methods : Diabetic (db/db) and control (db/m) mice were maintained for 9 months on ad-lib or IF diet of fasting every other day. The development of DR was evaluated by enumeration of acellular capillaries. Inflammation was assessed as number of Ly6C^hi monocytes in the circulation and infiltrating the retina by flow cytometry and by TNF-α expression in the retina. Macrophage function was assessed by stimulation in vitro with LPS and IFN-γ. Global metabolomic analysis was performed by Metabolon Inc using UHPLC/MS/MS in plasma samples to characterize systemic metabolic changes.

Results : IF diet neither corrected blood glucose levels nor body weight. However, IF diet protected from DR. Diabetic ad-lib mice developed more acellular capillaries; however, IF prevented formation of acellular capillaries in the diabetic mice. Ad-lib diabetic mice had i) significantly more circulating Ly6C^hi monocytes and monocytes infiltrating into the retina; ii) significantly higher expression of TNF-a in the retina; and iii) macrophages that produced more TNF-a upon stimulation. IF diet reduced all these inflammatory indexes during the fasting period but unexpectedly not during the feeding period as inflammatory mediators remained upregulated. Global metabolite analysis of plasma samples indicated significant changes in the lipid metabolism of ad-lib diabetic mice after treatment with IF but only for during fasting phase. Specifically, free fatty acids and ketone bodies were increased while, eicosanoids, ceramides and products of cholesterol metabolism were decreased during fasting in the IF diabetic mice.

Conclusions : Overall, diabetic mice under the IF diet were not cured of diabetes; yet, they were protected from developing DR. Temporal regulation of the chronic inflammatory response through changes in lipid metabolism during the feeding/ fasting cycles of the IF diet, resulted in the IF-treated diabetic mice being exposed to lower levels of toxic lipid metabolites preventing the development of DR.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.