Major Eldgridge

Background:  Diabetic retinopathy (DR), a leading cause of vision loss, affects one in four individuals with diabetes mellitus (DM) in the U.S.¹ Chronic hyperglycemia triggers inflammation, oxidative stress, and increased endothelial cell permeability in the retina. Retinal microvascular ischemia occurs, leading to pathological angiogenesis mediated by vascular endothelial growth factor (VEGF).^2,3 While anti-VEGF intravitreal injections are currently the primary treatment, there is growing interest in exercise-induced biological mechanisms that could provide non-invasive adjuncts or alternatives. Adiponectin (APN), an adipokine and myokine upregulated by physical activity, exhibits anti-inflammatory, insulin-sensitizing, and anti-angiogenic properties.^4,5 However, its therapeutic potential in DR remains underexplored. This review highlights how exercise-induced APN modulates angiogenesis, inflammation, and retinal cell proliferation in DR, offering a promising avenue for future therapies.

Objective: In this narrative review, I investigated the mechanisms by which exercise-induced adiponectin regulates pathological angiogenesis in diabetic retinopathy.

Search Methods: A literature search was conducted using PubMed for articles published from 2017 to 2024. Keywords included “exercise,” “adiponectin,” “diabetic retinopathy,” “angiogenesis,” and “VEGF”.

Results:  Epidemiological data demonstrate a significant inverse relationship between physical activity and DR prevalence (p=0.009).⁶ Exercise upregulates APN expression and signalling in skeletal muscle, with rodent studies showing up to a six-fold increase in APN mRNA and related signaling proteins following sustained physical activity.⁷ APN inhibits VEGF-induced human retinal endothelial cell proliferation and tube formation by suppressing ERK1/2 phosphorylation via MAPK signaling, showing similar efficacy to a current gold-standard treatment bevacizumab (Avastin).⁸ Under hyperglycemic conditions, APN restores the PI3K/AKT/mTOR pathway to physiological levels, reducing autophagy-related proteins (LC3B, Atg5) and increasing p62 expression, thereby inhibiting rhesus choroid-retinal endothelial cell migration and tube formation.⁹ APN also mediates the anti-angiogenic and anti-inflammatory effects of dietary ω-3 long-chain polyunsaturated fatty acids. APN knockout mice experience a marked increase in the extracellular matrix clearing activity of matrix metalloproteinases, MMP2/MMP9, giving  an avenue for new blood vessels to form in the retina. APN also significantly increases IL-10 signaling similar to ω-3, reducing inflammation.¹⁰ Furthermore, the synthetic APN receptor agonist AdipoRon significantly decreases retinal cell proliferation, colony formation, and migration without altering pro-inflammatory cytokine levels, offering potential therapeutic relevance to DR.¹¹

Conclusion:  DR is a vision-threatening complication of DM that affects over 10 million Americans. Increased physical activity is strongly associated with a decrease in DR prevalence. APN experiences a multi-fold increase following physical activity regimens. APN exerts protective effects in DR by inhibiting pathologic angiogenesis, restoring autophagic balance, and mediating anti-inflammatory pathways. Its ability to replicate or augment anti-VEGF therapy responses positions APN as a promising adjunct in the management of DR. These findings support further investigation into lifestyle-based and pharmacologic strategies that harness APN signaling.

Works Cited

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9. Li R, Du J, Yao Y, Yao G, Wang Adiponectin inhibits high glucose-induced angiogenesis via inhibiting autophagy in RF/6A cells. J Cell Physiol. Nov 2019;234(11):20566-20576. doi:10.1002/jcp.28659
10. Fu Z, Liegl R, Wang Z, et Adiponectin Mediates Dietary Omega-3 Long-Chain Polyunsaturated Fatty Acid Protection Against Choroidal Neovascularization in Mice. Invest Ophthalmol Vis Sci. Aug 1 2017;58(10):3862-3870. doi:10.1167/iovs.17-21796
11. Mallardo M, Costagliola C, Nigro E, Daniele A. AdipoRon negatively regulates proliferation and migration of ARPE-19 human retinal pigment epithelial cells. Peptides. Dec 2021;146:170676. doi:10.1016/j.p