June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Transient Hypoglycemic Episodes Increase Hypoxia Inducible Factor-1α Nuclear Accumulation and Enhances the Angiogenic Response in Diabetic Eye Disease
Author Affiliations & Notes
  • Monika Deshpande
    ophthalmology, Johns Hopkins University, Baltimore, Maryland, United States
  • Haley Megarity
    ophthalmology, Johns Hopkins University, Baltimore, Maryland, United States
  • Isha Kachwala
    ophthalmology, Johns Hopkins University, Baltimore, Maryland, United States
  • Savalan Babapoor-Farrokhran
    ophthalmology, Johns Hopkins University, Baltimore, Maryland, United States
  • Gregg Semenza
    Pediatrics, Institute for cell Engineering, Baltimore, Maryland, United States
  • Silvia Montaner
    Pathology, School of medicine, Baltimore, Maryland, United States
  • Akrit Sodhi
    ophthalmology, Johns Hopkins University, Baltimore, Maryland, United States
  • Footnotes
    Commercial Relationships   Monika Deshpande, None; Haley Megarity, None; Isha Kachwala, None; Savalan Babapoor-Farrokhran, None; Gregg Semenza, None; Silvia Montaner, None; Akrit Sodhi, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 5620. doi:
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      Monika Deshpande, Haley Megarity, Isha Kachwala, Savalan Babapoor-Farrokhran, Gregg Semenza, Silvia Montaner, Akrit Sodhi; Transient Hypoglycemic Episodes Increase Hypoxia Inducible Factor-1α Nuclear Accumulation and Enhances the Angiogenic Response in Diabetic Eye Disease. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5620.

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

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Abstract

Purpose : Tight control of serum glucose levels – the cornerstone of diabetic management – reduces the incidence and progression of diabetic microvascular disease. Nonetheless, oscillating glucose levels (i.e., glycemic variability) can influence the risk for diabetic retinopathy independent of HbA1c levels. While it is hypothesized that transient episodes of hyperglycemia in patients with high glycemic variability contributes to the progression of retinopathy, the molecular mechanism whereby oscillating serum glucose levels influences diabetic eye disease is not known.

Methods : Immortalized (MIO-M1) and primary retinal Müller cells were exposed to low (1-4 mM), normal (5 mM) or high (25-50 mM) glucose and the angiogenic potential of media conditioned from these cells was evaluated in vitro (tubule formation) and in vivo (directed in vivo angiogenesis). The contribution of the transcription factor, hypoxia inducible factor (HIF)-1α was assessed by western blot and immunofluorescence. HIF-1 target gene expression was examined by qPCR and ELISA. These results were corroborated in vivo using the insulin-induced hypoglycemia mouse model.

Results : Transient exposure to low – but not high – glucose resulted in increased secretion of angiogenic mediators from retinal Müller glial cells and this enhanced angiogenic phenotype is strictly dependent on the transcription factor, HIF-1. Exposure of Müller cells to decreasing concentrations of D-glucose increased HIF-1α nuclear accumulation and promoted expression of the HIF-1-regulated angiogenic mediators, VEGF and angiopoietin-like 4 (ANGPTL4). This increase was synergistic with hypoxia, and resulted in a marked increase in VEGF and ANGPTL4 secretion. These results were confirmed in vivo. Interestingly, nuclear accumulation of HIF-1α in response to hypoglycemia was independent of its canonical post-translational stabilization. Instead, we demonstrate a unique and previously unrecognized mechanism whereby low D-glucose independently promotes HIF-1α protein translation and nuclear localization.

Conclusions : Our results provide a molecular explanation for how glycemic variability can promote the progression of diabetic eye disease independent of HbA1c or hyperglycemia and have important clinical implications for optimizing glucose management in diabetic patients.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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