Diabetes, a chronic condition characterized by elevated blood sugar levels, poses a significant global health challenge. By 2050, the prevalence of diabetes is expected to more than double, leading to increased cases of diabetes-related complications, including microvascular diseases. Among these, diabetic retinopathy (DR) is the most common and severe microvascular complication, affecting vision and quality of life for millions of individuals worldwide.

Current diabetes management strategies emphasize tight glycemic control (TGC), aiming to maintain blood glucose levels within a narrow range to reduce the risk of complications. TGC involves intensive monitoring and frequent insulin administration to achieve optimal glucose control. However, while TGC is crucial for preventing microvascular damage, it also carries a potential risk: transient episodes of hypoglycemia. Hypoglycemia occurs when blood sugar levels drop below normal, leading to symptoms ranging from mild discomfort to severe health consequences, including loss of consciousness and death.

Despite the benefits of TGC, clinical trials have observed an intriguing paradox: some patients with TGC experience an early worsening of DR, despite achieving target blood glucose levels. This initial worsening is followed by a reversal in the progression of DR after several months. The exact cause of this paradoxical worsening remains unclear, but it highlights the complex interplay between glucose control, hypoglycemia, and the development of DR.

In addition to hypoglycemia, glycemic variability, characterized by significant fluctuations in blood glucose levels, has also been associated with adverse outcomes in diabetic patients, including the development or progression of DR. Patients with high glycemic variability, even with glycated hemoglobin A1c (HbA1c) levels within target ranges, face a higher risk of developing DR compared to those with low glycemic variability. This suggests that brief changes in blood glucose levels, regardless of their magnitude, can impact the development of DR.

Given the potential adverse effects of hypoglycemia and glycemic variability on DR, it is essential to understand the underlying mechanisms and explore strategies to optimize diabetes management, balancing the benefits of TGC with minimizing the risk of hypoglycemia and glycemic variability. The study conducted by Guo et al. explored the complex relationship between hypoglycemia and diabetic eye disease, specifically diabetic retinopathy (DR). The research aimed to investigate the neurosensory retina's response to acute hypoglycemia and its potential contribution to the development and progression of DR.

To achieve this, the study employed a multifaceted approach, utilizing various experimental models and techniques. Mouse retinal explants were isolated and cultured in vitro to study the response to low glucose conditions, examining changes in glycolysis, NAD+/NADH levels, and glucose transporter1 (GLUT1) expression. Primary mouse retinal Müller cells and an immortalized human Müller cell line (MIO-M1) were cultured in vitro under hypoxic and hypoglycemic conditions to investigate hypoxia-inducible factor-1α (HIF-1α) accumulation and angiogenic mediator expression. Human induced pluripotent stem cell (hiPSC)-derived 3D retinal organoids were generated and cultured under normoxic and hypoglycemic conditions to study HIF-1α expression and Müller cell stress markers.

Western blotting and immunofluorescence were employed to assess the expression and localization of HIF-1α and GLUT1 in retinal cells and explants. qPCR was used to measure mRNA expression levels of GLUT1, HIF-1α, and angiogenic mediators. In vivo hypoglycemia was induced in mice by insulin injection, and retinal tissues were analyzed for HIF-1α accumulation and angiogenic mediator expression.

The research uncovered several crucial findings regarding the impact of hypoglycemia on retinal cells and DR. Hypoglycemia induced aerobic glycolysis in retinal explants, leading to a transient alteration in NAD⁺/NADH and lactate levels. This metabolic response was associated with increased expression of GLUT1, a glucose transporter, in Müller cells. Hypoglycemia enhanced the accumulation of HIF-1α protein in retinal cells, independent of its canonical post-translational stabilization. This increase was attributed to enhanced HIF-1α translation and nuclear localization.  Importantly, this phenomenon occurred even in the absence of hypoxia, suggesting a unique mechanism of HIF-1α regulation in response to hypoglycemia.

Hypoglycemia promoted the angiogenic phenotype of Müller cells, characterized by increased expression of HIF-regulated angiogenic mediators, including vascular endothelial growth factor (VEGF) and angiopoietin-like 4 (ANGPTL4). This effect was dependent on HIF-1α, as it was abolished in cells lacking functional HIF-1α. While the Akt/mTOR signaling pathway was activated in response to low glucose, inhibition of mTOR did not prevent the increase in HIF-1α accumulation or angiogenic mediator expression. This suggested that Akt/mTOR signaling was not necessary for the hypoglycemia-induced HIF-1α accumulation in retinal cells.

In vivo hypoglycemia in mice induced by insulin injection resulted in increased HIF-1α accumulation and ANGPTL4 expression in the retina, further supporting the findings from in vitro studies. These findings provide a novel mechanistic explanation for the paradoxical worsening of DR observed in patients with tight glycemic control. Transient hypoglycemic episodes, common in diabetic patients, can induce HIF-1α-dependent expression of angiogenic mediators, contributing to DR progression. This highlights the importance of considering glycemic variability and stability, rather than solely focusing on tight glucose control, in managing diabetes to prevent DR. Additionally, the research identifies HIF-1α as a potential therapeutic target for DR, particularly in patients with high glycemic variability. The findings also have implications for other diabetic microvascular complications, such as diabetic nephropathy and neuropathy, where hypoxia and HIF-1α play a role.

Reference:

1. Guo C, Deshpande M, Niu Y, Kachwala I, Flores-Bellver M, Megarity H, Nuse T, Babapoor-Farrokhran S, Ramada M, Sanchez J, Inamdar N, Johnson TV, Canto-Soler MV, Montaner S, Sodhi A. HIF-1α accumulation in response to transient hypoglycemia may worsen diabetic eye disease. Cell Rep. 2023 Jan 31;42(1):111976.