HIF-1α accumulation in response to transient hypoglycemia may worsen diabetic eye disease.

Jan 16, 2023

Experts: Chuanyu Guo,Monika Deshpande,Yueqi Niu,Isha Kachwala,Miguel Flores-Bellver,Haley Megarity,Taylor Nuse,Savalan Babapoor-Farrokhran,Michael Ramada,Jaron Sanchez,Neelay Inamdar,Thomas V Johnson,Maria Valeria Canto-Soler,Silvia Montaner,Akrit Sodhi

Tight glycemic control (TGC), the cornerstone of diabetic management, reduces the incidence and progression of diabetic microvascular disease. However, TGC can also lead to transient episodes of hypoglycemia, which have been associated with adverse outcomes in patients with diabetes. Here, we demonstrate that low glucose levels result in hypoxia-inducible factor (HIF)-1-dependent expression of the glucose transporter, Glut1, in retinal cells. Enhanced nuclear accumulation of HIF-1α was independent of its canonical post-translational stabilization but instead dependent on stimulation of its translation and nuclear localization. In the presence of hypoxia, this physiologic response to low glucose resulted in a marked increase in the secretion of the HIF-dependent vasoactive mediators that promote diabetic retinopathy. Our results provide a molecular explanation for how early glucose control, as well as glycemic variability (i.e., oscillating serum glucose levels), contributes to diabetic eye disease. These observations have important implications for optimizing glucose management in patients with diabetes.
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

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ABOUT THE EXPERTS

Chuanyu Guo,Monika Deshpande,Yueqi Niu,Isha Kachwala,Miguel Flores-Bellver,Haley Megarity,Taylor Nuse,Savalan Babapoor-Farrokhran,Michael Ramada,Jaron Sanchez,Neelay Inamdar,Thomas V Johnson,Maria Valeria Canto-Soler,Silvia Montaner,Akrit Sodhi

Chuanyu Guo

Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Monika Deshpande

Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Yueqi Niu

Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Isha Kachwala

Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Miguel Flores-Bellver

CellSight Ocular Stem Cell and Regeneration Research Program, Department of Ophthalmology, Sue Anschutz-Rodgers Eye Center, University of Colorado School of Medicine, Aurora, CO 80045, USA.

Haley Megarity

Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Taylor Nuse

Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Savalan Babapoor-Farrokhran

Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Michael Ramada

Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Jaron Sanchez

Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Neelay Inamdar

Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Thomas V Johnson

Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Maria Valeria Canto-Soler

CellSight Ocular Stem Cell and Regeneration Research Program, Department of Ophthalmology, Sue Anschutz-Rodgers Eye Center, University of Colorado School of Medicine, Aurora, CO 80045, USA.

Silvia Montaner

Department of Oncology and Diagnostic Sciences, School of Dentistry, Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201, USA.

Akrit Sodhi

Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address: asodhi1@jhmi.edu.