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Maria Grant; Circadian dysfunction in the pathogenesis of diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1587.
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Presentation Description :
Diabetic metabolic abnormalities and the ensuing diabetic complications, including diabetic retinopathy (DR), remain a leading cause of global morbidity and mortality. One well-recognized yet poorly understood feature is diabetes-induced disruption of diurnal patterns. Loss of synchrony between light- and feeding-controlled metabolic pathways results in dire metabolic consequences. Proper alignment of the daily metabolic rhythms and light entrainment is crucial for preventing metabolic abnormalities. Disruption of food anticipatory activity and feeding entrainment disturbs diurnal rhythms of hepatic glucose and lipid metabolism leading to increased body weight, hyperphagia and hyperinsulinemia as is observed in type 2 diabetes (T2D). Intermittent fasting (IF) optimizes energy metabolism and promotes health. In this presentation, data describing how long term-IF prevented development of DR in a T2D model will be presented. The study found that after 8 months of IF, diabetes-induced increases in triglycerides, cholesteryl esters and diglycerides and increased survival in db/db mice occurred. The db/db mice on the IF protocol were protected from development of DR as assessed by enumeration of acellular capillaries which were similar to age matched non-diabetic controls. As host frequency and time of food intake can affect gut microbiome composition, we examined microbiome composition and diurnal levels in db/db mice on IF or ad libitum regimens. IF led to restoration of diurnal variation of key bacteria and also to reductions of Clostridiales and Akkermansia muciniphila in db/db mice. These changes in flora were accompanied by increased gut mucin, goblet cell number and villus length. Increased levels of Firmicutes in db/db mice on IF supported improved bile acid metabolism. To confirm that the restoration of bile acid function could contribute to the beneficial effects induced by IF on DR, the dual FXR/TGR-5 agonist INT-767 was administered to a second diabetes model, DBA2J mice injected with streptozotocin and placed on Western diet. In this model, INT-767 prevented development of DR. These findings support the concept that long-term IF mediates it beneficial effects on DR by restoring the circadian regulation of gut-liver axis homeostasis.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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