TY - JOUR
T1 - HIF-1α accumulation in response to transient hypoglycemia may worsen diabetic eye disease
AU - Guo, Chuanyu
AU - Deshpande, Monika
AU - Niu, Yueqi
AU - Kachwala, Isha
AU - Flores-Bellver, Miguel
AU - Megarity, Haley
AU - Nuse, Taylor
AU - Babapoor-Farrokhran, Savalan
AU - Ramada, Michael
AU - Sanchez, Jaron
AU - Inamdar, Neelay
AU - Johnson, Thomas V.
AU - Canto-Soler, Maria Valeria
AU - Montaner, Silvia
AU - Sodhi, Akrit
N1 - Funding Information:
This work was supported by the National Eye Institute, National Institutes of Health grants R01EY029750 to A.S., R01EY025705 to S.M. and A.S., and EY001765 (the Wilmer Core Grant for Vision Research, Microscopy and Imaging Core Module); the Research to Prevent Blindness , Special Scholar Award to A.S., and unrestricted grants to the Wilmer Eye Institute , Johns Hopkins School of Medicine , and the Department of Ophthalmology at University of Colorado ; the CellSight Development Fund to V.C.S.; the Doni Solich Family Chair in Ocular Stem Cell Research to V.C.S.; and the Branna and Irving Sisenwein Professorship in Ophthalmology to A.S. The funding organizations had no role in the design or conduct of this research.
Funding Information:
This work was supported by the National Eye Institute, National Institutes of Health grants R01EY029750 to A.S. R01EY025705 to S.M. and A.S. and EY001765 (the Wilmer Core Grant for Vision Research, Microscopy and Imaging Core Module); the Research to Prevent Blindness, Special Scholar Award to A.S. and unrestricted grants to the Wilmer Eye Institute, Johns Hopkins School of Medicine, and the Department of Ophthalmology at University of Colorado; the CellSight Development Fund to V.C.S.; the Doni Solich Family Chair in Ocular Stem Cell Research to V.C.S.; and the Branna and Irving Sisenwein Professorship in Ophthalmology to A.S. The funding organizations had no role in the design or conduct of this research. A.S. is the primary contributor to research design. C.G. M.D. Y.N. I.K. M.F.B. T.N. H.M. S.B.F. M.R. T.J. N.I. and J.S. are responsible for research execution and contributors to data acquisition. A.S. C.G. and M.D. are the primary contributors to data analysis and interpretation. Manuscript preparation by A.S. with revisions provided by C.G. M.D. V.C.S. and S.M. A.S. is co-founder of and holds equity in HIF Therapeutics, Inc. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies.
Publisher Copyright:
© 2022 The Author(s)
PY - 2023/1/31
Y1 - 2023/1/31
N2 - 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.
AB - 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.
KW - Akt
KW - CP: Cell biology
KW - CP: Metabolism
KW - angiogenesis
KW - angiopoietin-like 4
KW - diabetic retinopathy
KW - glucose transporter
KW - glycemic variability
KW - hypoglycemia
KW - hypoxia-inducible factor
KW - mTOR
KW - vascular endothelial growth factor
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U2 - 10.1016/j.celrep.2022.111976
DO - 10.1016/j.celrep.2022.111976
M3 - Article
C2 - 36640318
AN - SCOPUS:85146092529
SN - 2211-1247
VL - 42
JO - Cell Reports
JF - Cell Reports
IS - 1
M1 - 111976
ER -