Effects of prolonged type 2 diabetes on changes in peripapillary retinal nerve fiber layer thickness in diabetic eyes without clinical diabetic retinopathy

www.nature.com/scientificreports OPEN Effects of prolonged type 2 diabetes on changes in peripapillary retinal nerve fiber layer thickness in diabetic eyes without clinical diabetic retinopathy Min‑Woo Lee1, Hyung‑Bin Lim2, Min‑Su Kim2, Gi‑Seok Park2, Ki‑Yup Nam3, Young‑Hoon Lee1 & Jung‑Yeul Kim2* To identify the effects of prolonged type 2 diabetes (T2DM) on changes in peripapillary retinal nerve fiber layer (pRNFL) thickness in patients without clinical diabetic retinopathy. Subjects were divided into two groups: controls and patients with T2DM (DM group). After the initial visits, the pRNFL thicknesses were measured three more times at 1-year intervals. Subgroup analyses were performed in patients with T2DM duration ≥ 10 years. The mean pRNFL thickness at each visit was 95.8 ± 8.1, 95.4 ± 8.3, 94.9 ± 8.1, and 94.5 ± 8.3 μm in the control group (P = 0.138) (n = 55); and 93.4 ± 9.1, 92.1 ± 9.3, 90.9 ± 9.3, and 89.5 ± 9.2 μm in the DM group (P < 0.001) (n = 85). The estimated rate of reduction in mean pRNFL thickness was − 0.45 μm/year in the control group and − 1.34 μm/year in the DM group, respectively. In the DM group, the BCVA and HbA1c (both P = 0.001) were significant factors associated with pRNFL reduction. In patients with T2DM duration ≥ 10 years, the estimated pRNFL reduction rate was − 1.61 μm/year, and hypertension was a significant factor affecting the pRNFL reduction (P = 0.046). We confirmed rapid pRNFL reduction over time in T2DM, and the reduction rate was higher in patients with T2DM ≥ 10 years. Additionally, BCVA and HbA1c levels were significantly associated with the change in pRNFL thickness in T2DM patients. Type 2 diabetes (T2DM) constitutes a global health problem and induces macrovascular and microvascular complications causing more than 2 million deaths every y ear1. Moreover, its prevalence has increased from 108 million in 1980 to 422 million in 2014, and is expected to increase to 629 million by 2045 because of lifestyle changes2–4. This increase in T2DM is associated with an increase in diabetic retinopathy (DR)5. DR is one of the most common complications of T2DM and is the leading cause of preventable blindness among working-age subjects in most developed c ountries5,6. Even before clinical DR emerges, many studies have reported functional and anatomical damages on the retina by T2DM. Diabetic retinal neurodegeneration (DRN) is one of the representative damages on the retina by T2DM showing before clinical DR. Metabolic pathways triggered by hyperglycemia such as the polyol and hexosamine pathways, the de novo synthesis of diacylglycerol-protein kinase C, and the production of free radicals are closely associated with DRN, which causes the apoptosis of retinal ganglion c ells7,8. Such retinal ganglion cell loss would result in a reduction in the thickness of the retinal nerve fiber layer (RNFL). Vujosevic et al.9 reported early changes in the peripapillary microvasculature that correlated with peripapillary retinal nerve fiber layer (pRNFL) thinning in T2DM patients without DR. Lim et al.10 found that T2DM was associated with accelerated pRNFL loss regardless of whether or not DR progression, suggesting that DRN may proceed the microvascular abnormalities associated with DR progression. Additionally, they reported that the T2DM duration was 1 Department of Ophthalmology, Konyang University College of Medicine, Daejeon, Republic of Korea. 2Department of Ophthalmology, Chungnam National University College of Medicine, #640 Daesa‑dong, Jung‑gu, Daejeon 301‑721, Republic of Korea. 3Department of Ophthalmology, Chungnam National University Sejong Hospital, Sejong, Republic of Korea. *email: Scientific Reports | (2021) 11:6813 | https://doi.org/10.1038/s41598-021-86306-y 1 Vol.:(0123456789) www.nature.com/scientificreports/ associated with longitudinal changes in pRNFL thickness. However, few studies have explored the severity of DRN according to T2DM duration. The purpose of this study was to identify the effects of prolonged T2DM on longitudinal changes in pRNFL by comparing pRNFL thickness of normal individuals and DM patients. Methods Patients. This prospective, longitudinal, observational study adhered to the tenets of the Declaration of Hel- sinki and was approved by the Institutional Board and Ethics Committee of Chungnam National University Hospital, Daejeon, Republic of Korea. Patients with T2DM were enrolled in the ‘Changes in the inner retina in diabetes patients with or without diabetic retinopathy’, which is an ongoing prospective study. The control group included patients diagnosed with a unilateral epiretinal membrane, macular hole, or intraocular lens dislocation; all of the fellow eyes without any ophthalmic disease. Written informed consent was obtained from all subjects. Subjects were divided into two groups: controls and patients with T2DM (DM group). Additionally, we performer subgroup analyses for T2DM patients with DM duration ≥ 10 years in the DM group. All patients underwent complete ophthalmic examinations including measurements of best-corrected visual acuity (BCVA), intraocular pressure, the spherical equivalent, and axial length; a detailed fundus examination; and spectraldomain optical coherence tomography (OCT). After the initial visit, three further examinations were performed times at 1-year intervals. The exclusion criteria were a history of any systemic disease other than T2DM and hypertension, any ophthalmic diseases such as glaucoma, retinal diseases, or neuro-ophthalmic diseases, an axial length ≥ 26.0 mm, any prior intraocular surgery except cataract extraction, a BCVA < 20/40, and intraocular pressure > 21 mm Hg as previous s tudies10. We also excluded patients exhibiting clinical evidence of DR such as retinal hemorrhages or microaneurysm using fundus photo and dilated fundus examination. One eye was randomly selected in patients in whom both eyes met the inclusion criteria. OCT measurements. OCT measurements were performed by a skilled examiner using a Cirrus HD OCT (version 10.0; Carl Zeiss Meditec, Dublin, CA, USA). The pRNFL thicknesses were measured from optic disc cube scans. A 200 × 200 scan optic cube (measured in pixels) scanning protocol was used to image the optic disc and pRNFL over a 6 × 6-mm region of the optic nerve head. Images of signal strength < 7, any motion artifact, involuntary saccade, obvious decentration misalignment, or algorithm segmentation failure identified by the auto segmentation error on B-scan images were excluded as previous s tudies10. Statistical analyses. Demographic characteristics and ocular parameters were compared via the independent t-test and the chi-squared test. Repeated-measures ANOVA was used to analyze longitudinal changes in the pRNFL thicknesses in each group. Linear mixed models were performed to reveal the reduction rate of the pRNFL in each group and differences in such reduction over time among the groups. 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