By Esma Yerlikaya

Diabetes is a pandemic affecting over 500 million people globally¹. By its simplest definition, diabetes is a condition that disrupts the utilization of sugar in the bloodstream. Due to its inability to enter the cells, sugar accumulates in the blood. Type 1 and type 2 diabetes are two distinct forms of diabetes. In type 1, the body cannot produce enough insulin, a hormone essential for regulating blood sugar levels, and in type 2 the body either doesn’t produce enough insulin or becomes resistant to the effects of insulin. Insulin resistance refers to the body’s reduced ability to use insulin effectively. Serious complications of diabetes can affect the eyes, kidneys, and nerves; the main goal of diabetes treatment, therefore, is to lower blood sugar levels and prevent these negative outcomes. Despite various treatment combinations and the close monitoring of blood sugar, almost all people with type 1 diabetes and many with type 2 diabetes eventually develop a condition called diabetic retinopathy (DR)². DR is a disease of the eye and is the leading cause of vision loss in working-age adults. However, researchers don’t fully understand the detailed biological processes that lead to damage in the eye and result in vision loss.

Before we delve further, let’s review what is already known. DR is a condition affecting the retina, a tissue layer located at the back of the eye. The retina is comprised of specialized neurons that sense light, glial cells that support and maintain a healthy environment for these neurons, and blood vessels that circulate nutrients and oxygen. To diagnose DR, doctors examine whether neovascularization, the process where new blood vessels form, is occurring. Increased sugar levels have a detrimental impact on blood vessels, impeding the effective transport of oxygen from the bloodstream to retinal cells. In response to this oxygen deprivation, retinal cells initiate a series of reactions that stimulate the development of new blood vessels (neovascularization) in order to augment the oxygen supply to the retina. However, these newly formed vessels are structurally weak and tend to leak, exacerbating the damage to the retina.

Until the mid-1900s, it was unknown how neovascularization occurred. Then, a groundbreaking discovery was made: scientists identified a growth factor previously known as “Factor X” – a placeholder name indicating known presence, but not identity, of a critical piece in the neovascularization puzzle – as vascular endothelial growth factor (VEGF). The researchers observed that the presence of this factor triggers the formation of new blood vessels³. Today, the field’s main treatment approach for DR patients involves injecting anti-VEGF drugs directly into the afflicted eye to prevent abnormal vessel formation. Unfortunately, only 31-46% of patients exhibit prolonged benefits from the anti-VEGF treatments⁴. This suggests that solely targeting VEGF may not be enough to cure DR because there are likely other factors involved in the pathophysiology of the disease.

This is where my lab’s research enters the picture. Since other researchers found that Müller cells, the primary glial cell of the retina, are the major source of increased VEGF in diabetic mice, we used this finding as the basis for our studies⁵. In my research (Figure 1), I aimed to understand how Müller cells are affected in both type 1 diabetes and pre-/type 2 diabetes by studying genetically manipulated mice. These mice had a specific tag on the ribosomes of Müller cells. By analyzing the sequencing data, I found that there was an increase in the levels of certain receptor complex subunits called TREM2 and DAP12 in both diabetes groups. This receptor complex, which functions together as a group of proteins to carry out a specific task, is involved in transmitting signals, such as low oxygen levels or high blood glucose, from outside to inside of the cells via activating an enzyme called spleen tyrosine kinase (SYK)⁶. SYK, initially discovered in the spleen of mice⁷, is now known to be found in various organs, including the eye. My recent manuscript, Spleen Tyrosine Kinase Contributes to Müller Glial Expression of Proangiogenic Cytokines in Diabetes, published in IOVS, describes in detail how we identified SYK as a novel regulator of VEGF.

My research showed, for the first time, that SYK becomes activated in response to diabetes. To further investigate this, I conducted experiments using cell cultures from human-immortalized Müller cells. I discovered that when SYK was inhibited, it prevented the accumulation of a key VEGF regulator called hypoxia-inducible factor-1a (HIF-1a)⁶. Therefore, SYK activation and its effects on HIF-1a and VEGF could be important factors contributing to the development of complications in the retina associated with diabetes. Understanding these signaling pathways and their regulation could potentially lead to the development of new treatments or interventions to prevent or manage diabetic eye complications. In particular, targeting SYK could hold promise as a potential therapeutic strategy for DR patients.

TL:DR

• Diabetes often leads to vision loss through diabetic retinopathy (DR).
• DR treatments target VEGF but are only effective in 31-46% of patients.
• Our recent publication found a regulator of VEGF is activated in diabetic retinal cells, spleen tyrosine kinase (SYK).
• SYK can be a potential therapeutic target for DR patients.

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References

1. International Diabetes Federation. IDF Diabetes Atlas, 10th edn. Brussels, Belgium: International Diabetes Federation, 2021.

2. Fong DS, Aiello L, Gardner TW, King GL, Blankenship G, Cavallerano JD, Ferris FL, Klein R, for the American Diabetes Association. Retinopathy in Diabetes. Diabetes Care. 2004 Jan 1;27(suppl_1):s84–s87.

3. Miller JW. VEGF: From Discovery to Therapy: The Champalimaud Award Lecture. Trans Vis Sci Tech. 2016 Mar 11;5(2):9.

4. Abraham JR, Wykoff CC, Arepalli S, Lunasco L, Yu HJ, Hu M, Reese J, Srivastava SunilK, Brown DM, Ehlers JP. Aqueous Cytokine Expression and Higher Order OCT Biomarkers: Assessment of the Anatomic-Biologic Bridge in the IMAGINE DME Study. American Journal of Ophthalmology. 2021 Feb;222:328–339. PMID: 32896498

5. Wang J, Xu X, Elliott MH, Zhu M, Le YZ. Müller Cell-Derived VEGF Is Essential for Diabetes-Induced Retinal Inflammation and Vascular Leakage. Diabetes. 2010 Sep 1;59(9):2297–2305. PMCID: PMC2927953

6. Yerlikaya EI, Toro AL, Sunilkumar S, VanCleave AM, Leung M, Kawasawa YI, Kimball SR, Dennis MD. Spleen Tyrosine Kinase Contributes to Müller Glial Expression of Proangiogenic Cytokines in Diabetes. Invest Ophthalmol Vis Sci. 2022 Oct 28;63(11):25. PMCID: PMC9624266

7. Zhao Y, Liu R, Li M, Liu P. The spleen tyrosine kinase (SYK): A crucial therapeutic target for diverse liver diseases. Heliyon. 2022 Dec;8(12):e12130.