July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Altered Circadian Metabolites in Type 2 Diabetic Mice with Diabetic Retinopathy
Author Affiliations & Notes
  • Samantha Prabakaran
    University of Central Florida College of Medicine, Fort Myers, Florida, United States
  • Eleni Beli
    Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Yaqian Duan
    Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Sergio Li Calzi
    Department of Ophthalmology, Alabama University, Birmingham, Alabama, United States
  • Maria B Grant
    Department of Ophthalmology, Alabama University, Birmingham, Alabama, United States
  • Footnotes
    Commercial Relationships   Samantha Prabakaran, None; Eleni Beli, None; Yaqian Duan, None; Sergio Li Calzi, None; Maria Grant, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 2672. doi:
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      Samantha Prabakaran, Eleni Beli, Yaqian Duan, Sergio Li Calzi, Maria B Grant; Altered Circadian Metabolites in Type 2 Diabetic Mice with Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2672.

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

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Abstract

Purpose : Diabetes is associated with disturbed circadian rhythms. Previously, we have shown reduced circadian gene expression in the retina of both type 1 and type 2 diabetic rats and that circadian disruption preceded development of diabetic retinopathy (DR). This study was conducted to see if there is any association between the diurnal change in plasma metabolites and DR, with the goal to identify metabolites that could serve as biomarkers for DR.

Methods : 10 month old, control (db/m) and type 2 diabetic (db/db) mice were used. Presence of DR was assessed by enumerating acellular capillaries. Blood plasma samples were collected at two time points: during the day and during the night. Plasma was frozen and sent to Metabolon Inc for global metabolomics analysis using ultra-performance liquid chromatography and high resolution mass spectrometry. Two Way Anova was used to identify metabolites that were different due to time and disease, which were further analyzed with the Ingenuity Pathway Analysis (IPA) Software.

Results : Diabetic ad-lib mice had more acellular capillaries than control ad-lib (20 ± 4 vs 5±1mm-2, p<0.05). Among the 747 unique metabolites identified in plasma, 79 were significant altered by diabetes and time of draw (p<0.05). Of these, 76 had a metabolite identifier and 62 were mapped with the IPA. Top canonical pathways were histamine and cysteine biosynthesis (p=2.81E-04 and 1.13E-03) and methionine degradation (p=7.37E-03). Top upstream regulators were Betaine-Homocysteine Methyltransferase (p=2.09E-03) and Epidermal Growth Factor Receptor (p=1.37E-02). Top networks were lipid metabolism, small molecule biochemistry and developmental disorders (score 34). DR and circadian signaling pathways were overlayed with the top networks: During the day histamine, L-histidine, L-cysteine, adenosine, sorbitol, choline, and the transcription factors NFKb and AP1 were found to associate with DR but no metabolites connected with the circadian pathway. During the night, D-pathothenic acid, and oleoglycerol were found to associate with DR and cyclic AMP with the circadian rhythm signaling. Sirt 3 and Jun were the transcription factors for the top networks in the night.

Conclusions : Using metabolomics, we were able to identify certain metabolites that were regulated by time and were associated with DR. Further validation is needed to predict whether these metabolites could be used as biomarkers for DR.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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