The Sweet Spot

Akrit Sodhi – along with fellow researchers at Johns Hopkins Medicine – recently identified a link between diabetic people with low blood sugar levels and a molecular pathway that is triggered by oxygen-starved cells in the eye. The study suggests that people with diabetic retinopathy may be particularly vulnerable to periods of low glucose (1). Here, Sodhi shares more details.

Why did you explore the link between blood sugar and diabetic retinopathy?
 

Multiple clinical trials support a role for early and intensive glycemic control to reduce the onset and progression of diabetic microvascular complications. This body of work has motivated clinicians to encourage their patients with diabetes to achieve tight glycemic control (TGC) to prevent or delay the development of the vascular complications that characterize diabetes. However, TGC has also been associated with an early paradoxical worsening of diabetic retinopathy (DR) – the most frequent microvascular complication in patients with diabetes and the leading cause of severe vision loss in working-age Americans.

In the Diabetes Control and Complications Trial, 13.1 percent of the treatment group using intensive insulin therapy experienced a worsening of their DR compared with 7.6 percent of the treatment group that used a conventional insulin regimen. Although these effects are reversed by 18 months, the cause of DR progression in this setting was not clear. Similarly, high glycemic variability (transient episodes of very high, followed by very low glucose concentration) in patients with diabetes has also been implicated in the development or progression of micro- and macrovascular complications (and mortality) – independent of HbA1c concentration. For example, a patient with a HbA1c of 8.0 percent and high glycemic variability is at a higher risk of developing (or demonstrating progression of existing) DR than a patient with a HbA1c of 8.0 percent but who achieves low glycemic variability.

Although it has been speculated that retinal microvascular injury may result from even transient episodes of hyperglycemia, the molecular mechanism – whereby brief changes in serum glucose concentration influence the development or progression of DR – was also not clear. Our goal was to examine how the neurosensory retina responds to acute episodes of hypoglycemia, which may occur upon initiation with TGC or in patients with high glycemic variability.

And did you meet your goal?
 

In short, yes! Using a combination of complementary approaches, including human and mouse retinal cells, mouse retinal explants, human-induced pluripotent stem cell-derived 3-dimensional retinal organoids, and a mouse model for transient hypoglycemia, we observed that low glucose levels result in hypoxia-inducible factor (HIF)-1-dependent expression of the glucose transporter, Glut1, and key glycolytic enzymes in retinal Müller glial cells.

Enhanced nuclear accumulation of HIF-1α in these cells was independent of its canonical post-translational stabilization, but instead dependent on stimulation of HIF-1α translation and nuclear localization. In the presence of hypoxia, as occurs in the retinas of patients with DR, this physiologic response to low glucose resulted in a marked increase in the secretion of the HIF-1-dependent vasoactive mediators (for example, VEGF and ANGPTL4) that promote DR.

What do these findings tell us more broadly about diabetic retinopathy?
 

Importantly, this study does not undermine the importance of TGC. Rather, it suggests that transient episodes of low glucose – that can occur in patients who try to achieve TGC – can itself exacerbate DR.

More specifically, our results suggest that the physiologic response of Müller glial cells to low levels of serum glucose (hypoglycemia) is to upregulate HIF-1-dependent expression of Glut1 and glycolytic enzymes. The increased expression of this glucose transporter and HIF-1-regulated glycolytic enzymes was rapid (hours) allowing Müller glial cells to maintain glucose uptake for energy production through glycolysis. This presumably spares available oxygen for use by resident neurons for oxidative phosphorylation. However, this physiologic process, when combined with even modest hypoxia (as occurs in eyes of patients with diabetes), results in a marked increase in the accumulation of HIF-1α, and a paradoxical (pathological) increase in the HIF-regulated angiogenic mediators (e.g., VEGF and ANGPTL4) that promote DR. These results provide a molecular explanation for how early glucose control as well as high glycemic variability could contribute to DR.

How do you plan to move forward with this line of research?
 

There are several potential therapeutic interventions that could help prevent the pathologic consequences of HIF-1α accumulation in response to hypoglycemia; for example, preventing (or reducing) episodes of hypoglycemia, blocking the signaling pathways that connect low glucose with the accumulation of HIF-1α, inhibiting HIF-1α itself, or targeting the HIF-1- regulated gene products that promote DR.

The patient’s PCP and/or endocrinologist help manage (minimize) episodes of hypoglycemia, while anti-VEGF therapy is an available option to specifically target a key HIF-1-regulated angiogenic gene product (VEGF) that promotes DR.

Our lab is currently investigating the signaling pathways that link hypoglycemia to the accumulation of HIF-1α. These pathways could be vulnerable targets for patients newly diagnosed with diabetes or for patients with diabetes and high glycemic variability. We, and others, are also working on the development of therapies to directly target HIF-1α. These latter therapies could be effective for the treatment of all patients with DR.

We are further interested in examining whether the HIF-1-dependent response to low glucose influences other diabetic microvascular complications, including diabetic neuropathy and diabetic nephropathy.

How can healthcare professionals manage this balancing act in the meantime?
 

Balancing TGC with hypoglycemic episodes remains a challenge for patients with both insulin dependent and non-insulin-dependent diabetes mellitus. While severe hypoglycemia can cause disorientation, loss of consciousness, and death, recurrent subclinical (asymptomatic) hypoglycemic episodes have been implicated in the promotion of cardiovascular disease and cognitive decline. These prior observations emphasized the importance of renewed efforts to better understand the impact of hypoglycemia on the morbidity and mortality of the growing diabetic population. Our study suggests that these hypoglycemic episodes can also worsen DR.

Optimizing glucose management should be managed by the patient’s primary care doctor and/or endocrinologist. This can be achieved through diet, exercise, and medications. But managing the microvascular complications in patients with diabetes requires a team effort, which includes their ophthalmologist. While the focus of the ophthalmologist is on the diagnosis and treatment of diabetic eye disease, they also play an important role in reinforcing the importance of maintaining tight blood pressure, blood sugar, and cholesterol control in their patients with diabetes.