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Maria Grant, Yuanqing Yan, Tatiana Salazar, Ashay D Bhatwadekar, James M Dominguez, Dung Nguyen, Rui Gao, Elei Beli, Julia V Busik, Michael E Boulton; Long-term Intermittent Fasting (IF) Protects db/db Mice from Development of Diabetic Retinopathy (DR). Invest. Ophthalmol. Vis. Sci. 2014;55(13):5992. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Feeding is a strong circadian entrainer and continuous feeding disrupts normal circadian patterns. Disruption of the circadian clock contributes to disease pathogenesis including diabetes. Using a rat model of type 2 diabetes (T2D) we showed that loss of circadian release of vascular reparative cells is due to bone marrow (BM) neuropathy and precedes development of DR. In this study, we examined the impact of IF on DR in a model of T2D, db/db mice.
To ascertain whether IF could correct DR and circadian disruption, db/db mice underwent IF for 6 months (mice were fasted 24hr and fed for 24hr; food was removed 5~30min before lights were turned off; beginning of the active phase). Bones were harvested to assess denervation using neurofilament 200 nerve fiber immunohistochemistry. Acelluar capillaries were counted in retinas to assess DR. Bmal1 and Per2 gene expression was tested in suprachiasmatic nucleus (SCN; central clock), liver and BM lineage-sca1+ cells (peripheral clocks). cDNA microarray was performed from liver and cytokines levels were measured in BM supernatant.
T2D (11 months) exhibited DR (as demonstrated by a 2.37 fold increase in number of acellular capillaries), displayed neuropathy, disrupted circadian pattern of hematopoietic stem cells (HSCs) release from the BM, defective migration of HSC to SDF-1, and altered expression of clock genes in retina, HSCs and in the liver compared to controls. IF slightly reduced food intake (12% in db/m and 20% in db/db) and body weight, but there was no change in glycated hemoglobin. db/db mice on IF showed increased survival rate (95.13% survival compared to 83.08% db/db ad lib mice); prevention of DR (30.3 % decrease in acellular capillaries compared to db/db ad lib mice; p<0.05%), and absence of BM neuropathy (22.36±8.21 NF200+ fiber/field compared to 11.78±7.18 db/db ad lib; p<0.05). IF restored the altered circadian pattern of HSCs release from BM, HSCs migration capability in vitro and circadian clock gene expression to normal levels. IF increased liver eNOS expression and increased expression of key genes associated with reducing inflammation (Anxa1), enhancing insulin sensitivity (Lcn13) and lipid metabolism (Plac8).
The protective effects of IF support the notion that IF prevents circadian dysfunction and development of DR in db/db mice.
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