Progranulin in tears potential biomarker for diabetes-related corneal innervation changes
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Key takeaways:
- Patients with diabetic retinopathy had significantly reduced concentration of tear progranulin, researchers found.
- Tear progranulin level correlated with nerve fiber density and length and branch density.
Patients with type 2 diabetes recently diagnosed with diabetic retinopathy had a significantly reduced concentration of progranulin in their tears compared with control patients, according to prospective study results.
Considering the correlation researchers found between progranulin (PGRN) levels and corneal subbasal nerve changes, PGRN may serve as a biomarker for noninvasively diagnosing and predicting the progression of diabetic neurotrophic keratopathy (DNK), the researchers wrote in the study published in Translational Vision Science & Technology.
Previous studies have revealed the tear as a significant source of biomarkers for ocular diseases, including diabetic retinopathy (DR), but they have not evaluated the glycoprotein PGRN as a diagnostic tool in this context, according to the researchers.
This inspired Tianyi Zhou, with the department of ophthalmology at Shanghai Ninth People’s Hospital and Shanghai Jiao Tong University School of Medicine, and colleagues to investigate the expression level of PGRN in the tears of patients with DR compared with normal controls. They also explored the correlation between PGRN and the severity of dry eye and corneal innervation changes caused by type 2 diabetes.
In a prospective, single-visit, cross-sectional study, Zhou and colleagues recruited 48 patients (96 eyes; mean age, 59.15 ± 9.51 years; men, n = 29) with type 2 diabetes recently diagnosed with DR and 22 age-matched healthy controls (44 eyes; 57.32 ± 9.66 years; men, n = 10) between November 2022 and April 2023.
The researchers performed dry eye examinations, collected tear fluid and evaluated the subbasal nerve plexus through in vivo confocal microscopy for all participants.
According to results, the DR group experienced more severe dry eye symptoms compared with controls, including lower tear secretion (6.98 ± 6.62 mm vs. 12.41 ± 6.37 mm; P = .002) and higher Ocular Surface Disease Index questionnaire scores (14.56 ± 5.69 vs. 6.5 ± 3.13; P < .001).
The researchers also found that patients with DR had a significant reduction in median nerve fiber density (3 per frame vs. 5.5 per frame), median nerve fiber length (1,216.85 m vs. 2,971.53 m) and median nerve branch density (1.5 per frame vs. 8.67 per frame; P < .001 for all) compared with the control group.
Additionally, patients with diabetes had significantly lower tear PGRN levels (174,346 ± 116,994 pg/mL) compared with controls (388,802 ± 169,485 pg/mL; P < .001), whereas inflammatory markers such as tumor necrosis factor alpha and matrix metalloproteinase-9 were increased among the patient group.
Finally, Zhou and colleagues found that PGRN level significantly correlated with nerve fiber density (R = 0.48), nerve fiber length (R = 0.65) and nerve branch density (R = 0.69; P < .001 for all).
The researchers noted several limitations to this study, including its small population and the need for testing additional clinical parameters such as corneal esthesiometry.
“These data provide evidence of the potential of using tear fluid-based PGRN as a biomarker for the diagnosis and staging of DNK; however, further research is necessary to validate these findings,” Zhou and colleagues wrote.
Perspective
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There are over 400 million people currently living with diabetes, and in the United States, one in 10 people are diagnosed with it, most often type 2.
Ophthalmic complications related to diabetes can present in every major anatomical structure of the eye, including the cornea and ocular surface. A better understanding of the pathophysiology at the cellular level offers insight for novel therapeutic approaches.
In this cross-sectional study, the researchers identified a correlation between decreased tear fluid PGRN and corneal subbasal nerve plexus alternations at greater rates among participants with type 2 diabetes and diabetic retinopathy.
We understand that corneal nerve damage in dry eye patients is known to alter tear production, blink rate and neuroimmune regulatory processes. Identification of a biomarker, like PGRN, that may correlate with corneal nerve injury offers an avenue for further investigation for clinically significant ocular surface disease and DNK. Of benefit in this study is the noninvasive approach of tear film collection that offers a realistic clinical use for many practitioners.
Limitations of the study include study type, participant number and recruitment from a single clinic site. Longitudinal data are also necessary to better determine dynamic changes and correlation vs. causation among PGRN, corneal nerve morphology and DNK.
Given the increasing incidence of diabetes across patient populations, clinicians should be well-informed on the broad ophthalmic implications and adverse ocular events. Additionally, the growing investigation and understanding of corneal nerve integrity in ocular surface disease may offer novel approaches to tackling the disease state and improving patient symptoms and quality of life.
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