ESPE Yearbook of Paediatric Endocrinology

Sci Transl Med. 2025;17(796):eadq5355. PMID: 40305573

Brief summary: This experimental study in mouse models showed that even transient episodes of hypoglycemia lead to the accumulation of the transcription factors hypoxia-inducible factor-1α (HIF-1α) and HIF-2α in the retina. This accumulation promotes the expression of vasoactive mediators, resulting in increased retinal permeability and breakdown of the inner blood-retinal barrier (iBRB). Intravitreal administration of a small-molecule HIF-1/2α inhibitor prevented both iBRB disruption and hypoglycemia-induced retinal vascular hyperpermeability.

Diabetic retinopathy (DR), characterized by the breakdown of the inner blood–retinal barrier (iBRB), is a major vascular complication of diabetes and a leading cause of vision loss (1). While hyperglycemia is a key risk factor in the development of DR, evidence also suggests an increased risk during periods of rapid glucose improvement (2). This is a timely concern in the era of automated insulin delivery systems, which often lead to swift glucose correction. Previous research from the authors of the present paper showed that transient hypoglycemic episodes caused the accumulation of HIF1α in retinal glial cells, leading to increased expression of HIF-dependent vasoactive mediators that exacerbated vascular leakage (3).

To further explore these findings, they used mouse models where they show that hypoglycemia resulted in the accumulation of HIF-1α and HIF-2α and the expression of several HIF-dependent vasoactive agents. These factors were not sufficient to induce iBRB breakdown in the retinas of healthy mice but did so in the retina of mice with streptozotocin-induced diabetes.

Genetic deletion of Hif1a or Hif2a alone was insufficient to prevent the increased expression of vasoactive factors during hypoglycemia. In contrast, in diabetic mice, intravitreal administration of 32-134D, a dual HIF1α and HIF2α inhibitor, prevented the increase in expression of HIF-regulated vasoactive genes after transient episodes of hypoglycemia, blocking both breakdown of the iBRB and the promotion of retinal vascular hyperpermeability.

These findings are relevant because they explain why people with diabetes experiencing rapid improvements in their glycemia may have worsening of their DR and provide the foundation for clinical studies assessing HIF inhibition with 32-134D for its prevention.

References: 1. Shyam M, Sidharth S, Veronica A, et al. Diabetic retinopathy: a comprehensive review of pathophysiology and emerging treatments. Mol Biol Rep 2025;52(1):380.2. Bain SC, Klufas MA, Ho A, Matthews DR. Worsening of diabetic retinopathy with rapid improvement in systemic glucose control: A review. Diabetes ObesMetab 2019;21(3):454-466. (In eng). DOI: 10.1111/dom.13538.3. Guo C, Deshpande M, Niu Y, et al. HIF-1α accumulation in response to transient hypoglycemia may worsen diabetic eye disease. Cell Rep 2023;42(1):111976.