Diabetes mellitus is a major public health issue that projected to affect 693 million adults by 2045 (Cho et al., 2018). Diabetic retinopathy (DR) is a major microvascular complications of diabetes mellitus, occurring in about 30%–40% diabetic patients (Yau et al., 2012). DR has become one of the leading causes of low vision and blindness among working-age adult population (Ting et al., 2016). Recognition of people at higher risk for DR progression is important for preventing visual impairment.

In contrast to established systemic risk factors like duration of diabetes, hyperglycemia, hypertension, hyperlipidemia and obesity, there are few ocular risk factors associated with DR (Ting et al., 2016). Previous studies have demonstrated that myopia and increased axial length (AL) have a protective effect against DR progression (Chao et al., 2016; Lim et al., 2010; Man et al., 2012). The proposed mechanism for this protective effect is that the degenerative lesions caused by long-term fundus stretching may be more resistant to hypoxia and ischemia (Chao et al., 2016; Man et al., 2013). However, compared to AL alone, myopic fundus signs may be more indicative of choroidal thinning and thus may correlate more closely with decreased DR prevalence. On this basis, Tan, et al. enrolled 592 diabetic patients and compared their DR severity between eyes with or without conventional ophthalmoscopic beta zone of peripapillary atrophy (PPA) (Tan et al., 2018). The results showed that eyes with PPA-beta were less likely to have DR, independent of both AL and refractive status.

PPA is the most common myopic fundus change and is characterized by a shift and widening of the Bruch’s Membrane Opening (BMO) and retinal pigment epithelium (RPE) opening. PPA can be differentiated into an αlpha zone and a conventional beta zone based on its clinical appearance (Jonas et al., 1989). The αlpha zone presents with irregular hypopigmentation and hyperpigmentation of the RPE. The conventional beta zone shows exposed sclera and choroidal macrovascular with complete RPE atrophy, located between the optic border and αlpha zone. With the development of spectral-domain optical coherence tomography (SD-OCT), the conventional beta zone has been further categorized into a (new) beta zone and a gamma zone based on the BMO (Dai et al., 2013). Current studies found beta zone associated with older age and the glaucoma prevalence (Kim et al., 2014; Shang et al., 2019; Yamada et al., 2016), while gamma zone related to axial myopia (Jonas et al., 2016; Kim et al., 2013; Zhang et al., 2018). Most previous studies focused on the relationship between conventional beta zone and ocular diseases, with little known about new beta zone and the gamma zone. Therefore, the aim of our study was to investigate whether eyes with new beta or gamma zone involvement, or both, are less likely to have DR, and to explore the potential vascular factors associated with this phenomenon.

To assess peripapillary atrophy (PPA), we employed swept-source OCT (SS-OCT, BM-400K BMizar, TowardPi Medical Technology Co., Ltd., Beijing, China) and examined its characteristics on B-Scan. The beta zone was identified by the presence of BM without the RPE, whereas the gamma zone PPA was noted by the absence of BM, situated between the optic disc margin and the beta zone (Figure 1). We classified eyes into four categories: those without beta or gamma zone (Group A), those with only a beta zone (Group B), those with only a gamma zone (Group C), and those with both beta and gamma zone (Group D).

Figure 1. Representative images illustrating the subzones of PPA. The OCT images (A) and fundus photography (B) are centered on the same position. The beta zone between the purple and yellow arrow, and gamma zone between the yellow and red arrow on the serial B-scan images (C, D).

To delineate the conventional beta zone PPA, we utilized an innovative image segmentation algorithm, nnU-Net (Isensee et al., 2021), to precisely define the optic disc boundary and RPE atrophy on en face images. A dataset consisting of 200 manually annotated en face images was employed for the training and validation of our model. The dataset was partitioned into training and validation subsets in a 7:3 ratio. We selected the Stochastic Gradient Descent (SGD) with Nesterov momentum set to 0.99 as our optimizer, and initialized the learning rate at 0.001 for our experiments. The training process spanned 1,000 epochs, with each epoch containing 250 iterations. The segmentation results demonstrated robustness and effectiveness, achieving a Dice coefficient exceeding 0.95. Eyes lacking the conventional beta zone PPA were classified into Group A (without beta or gamma zone), were distributed among the remaining three groups based on the location of the Bruch’s membrane opening (BMO).

For precise detection of the BMO on B-scan series, we utilized the cutting-edge YoLo-V8 algorithm (Wang et al., 2024). This sophisticated object detection model is celebrated for its real-time processing of high-resolution images and its extensive application in medical image detection, ensuring accurate target identification. We adopted the Stochastic Gradient Descent (SGD) with a Nesterov momentum of 0.937 as the optimizer, with an initial learning rate of 0.001. The training consisted of a maximum of 300 epochs. The model was trained and validated using data from 20 subjects, incorporating 2,500 manually annotated B-scan images, with its reliability well-documented in prior studies (Li et al., 2024). If the BMO coincided with the optic disc border, indicating an absence of the gamma zone, the eyes were assigned to Group B (isolated beta zone). Conversely, if the BMO was located between the optic disc margin and RPE atrophy, the eyes were assigned to Group D (both beta and gamma zones). A minority of eyes displayed no new beta zone, with their BMO coinciding with the RPE atrophy border, thereby categorizing them into Group C (isolated gamma zone). Any discrepancies were adjudicated by a senior third reviewer (ZN).

Digital fundus photography (Canon CR-2; Tokyo, Japan) was employed for the diagnosis and staging of DR severity. The fundus camera captured two images, one centered on the macula and the other on the optic disc. In cases where the lesions were unclear, SS-OCT angiography was utilized. SS-OCTA employed a fovea-centered 12 mm × 12 mm scan pattern with an A-scan rate of 400 KHz and an axial scan depth of 6 mm, allowing for more precise identification of the lesions. After a qualitative assessment, two trained ophthalmologists (LY and XH) independently graded DR according to the International Clinical DR Disease Severity Scale (Wilkinson et al., 2003). In case of any uncertainties, a senior ophthalmologist (ZN) would reassess the images.

All participants were categorized based on PPA status into: 198 eyes without beta or gamma zone were classified into Group A, 391 eyes with isolated beta zone were classified into Group B, 73 eyes with isolated gamma zone were classified into Group C, 183 eyes with both beta and gamma zone were classified into Group D. Demographic and clinical characteristics among four groups were summarized in Table 1. No significant difference was observed among the groups in terms of sex, waist, BMI, hypertension, hyperlipidemia, DBP, SBP, MAP, UACR, TC, LDL, HDL, TG, and IOP. However, it was noted that patients in Group B and Group D with beta zone PPA were more likely to be older. Moreover, Group C and Group D had significantly longer AL when compared to Group A and Group B (P < 0.001). Additionally, compared to Group A, the other three groups exhibited lower FPG, HbA1c and DR grade (P = 0.037, P = 0.037, and P = 0.001, respectively).

Table 1. Comparison of demographic and clinical characteristics among four groups.

Associations between DR and systemic factors, AL, and PPA were assessed by logistic regression (Table 2). In the fully adjusted model, higher HbA1c and UACR were found to be associated with increased odds of DR (P < 0.001 and P = 0.039, respectively). While FPG exhibited a positive association with DR in the univariable model (P < 0.001), but this relationship was attenuated after controlling for confounding variables in the multivariable model (P = 0.47). Similarly, AL displayed a negative association with DR in the univariable model (P = 0.027), but this association became non-significant in the multivariable model (P = 0.89).

Table 2. Associations of risk factors with DR grade.

Regarding PPA, individuals with isolated beta zone (Group B) showed lower odds of developing DR compared to those without beta or gamma zone (Group A) (OR 0.651, 95% confidence interval [CI] 0.450–0.941, P = 0.022). Moreover, individuals with isolated gamma zone (Group C) and those with both beta and gamma zone (Group D) demonstrated additional protective effects against DR (OR 0.200, 95% CI 0.099–0.404, P < 0.001; and OR 0.348, 95% CI 0.214–0.568, P < 0.001; respectively). It should be noted that beta zone PPA is known to be associated with aging, and thus, we conducted a subgroup analysis based on age (≤60 years or >60 years), as shown in Table 3. Notably, the association between isolated beta zone PPA (Group B) and DR was no longer significant in this subgroup analysis.

Table 3. Subgroup analysis of four groups with DR by age (≤60 years or >60 years).

Considering the closer relationship that should exist between different groups (mainly the gamma zone) and axial length growth, we conducted a further subgroup analysis based on axial length classification. We conducted a subgroup analysis based on axial length (≤24 mm or >24 mm) (Table 4). For eyes with an AL of less than 24 mm, individuals with an isolated beta zone (Group B) showed a reduced likelihood of developing DR compared to those without beta or gamma zones (Group A) (OR 0.604, 95% CI 0.407–0.896, P = 0.012). Additionally, individuals with an isolated gamma zone (Group C) and those with both beta and gamma zones (Group D) exhibited further protective effects against DR (OR 0.252, 95% CI 0.108–0.587, P = 0.001; and OR 0.363, 95% CI 0.199–0.661, P = 0.001; respectively). For eyes with an AL greater than 24 mm, those with an isolated gamma zone (Group C) and those with both beta and gamma zones (Group D) demonstrated protective effects against DR compared to Group A (OR 0.113, 95% CI 0.027–0.477, P = 0.001; and OR 0.279, 95% CI 0.094–0.832, P = 0.022; respectively). Notably, the association between isolated beta zone PPA (Group B) and DR was not significant in this subgroup analysis, consistent with our previous findings. Furthermore, our subgroup analyses indicated that the protective association of gamma zone PPA (Groups C and D) against DR was more pronounced in eyes with longer AL (>24 mm). These results further confirm the protective effect of gamma zone PPA on DR is not solely due to AL.

Table 4. Subgroup analysis of four groups with DR by AL (≤24 mm or >24 mm).

Significant differences between-group differences were observed in superficial retina, deep retina, and choroid metrics (Table 5). The average superficial retinal vessel density for each group was as follows: Group A - 40.5% (2.2), Group B - 40.4% (2.3), Group C - 39.4% (3.3), and Group D - 39.5% (2.6). Notably, individuals with no beta or gamma zone (Group A) and those with isolated beta zone (Group B) exhibited higher superficial retinal vessel density compared to individuals with both beta and gamma zone (Group D) (all P = 0.002) (Figure 2A).

Table 5. Comparison of microstructural characteristics among four groups.

Figure 2. Box plots showing the comparison of superficial retinal vessel density (A), choroidal vascularity index (B) and choroidal thickness (C) in each group. Group A = without beta or gamma zone; Group B = isolated beta zone; Group C = isolated gamma zone; Group D = with both beta and gamma zone. Significance was set at P < 0.00833 for multiple testing in Bonferroni correction.

Regarding the choroidal metrics, the average choroidal vascularity index (CVI) across the four groups was as follows: Group A - 33.2% (5.0), Group B - 30.6% (4.9), Group C - 27.9% (5.9), and Group D - 26.5% (5.9). Individuals with no beta or gamma zone (Group A) showed the highest CVI, while those with both beta and gamma zone PPA (Group D) demonstrated the lowest CVI among the groups (P < 0.001) (Figure 2B). Similar statistically significant differences were observed in choroidal thickness (CT) (Figure 2C). The average CT for each group was as follows: Group A - 192.0 μm (69.0), Group B - 153.8 μm (54.1), Group C - 127.3 μm (48.0), and Group D - 113.3 μm (48.0). Individuals with no beta or gamma zone (Group A) displayed the thickest CVI among four groups (P < 0.001). However, there was no significant difference in any microstructural measurement between individuals with isolated gamma zone (Group C) and those with both beta and gamma zone PPA (Group D).

The beta zone PPA is defined as the absence of RPE with continued presence of BM. Kim, et al. reported that the PPA with intact BM (defined as beta zone PPA in this study) was associated with older age, theorizing it represents an age-related atrophic change (Kim et al., 2013). Shang, et al. also found a positive correlation between the beta zone area and age (standardized coefficient beta = 0.3, P = 0.001) (Shang et al., 2019). Consistent with these findings, our data also demonstrated a higher prevalence of beta zone PPA among older individuals. This may stem from age-related RPE apoptosis and choriocapillaris atrophy (Kim et al., 2013; Lin et al., 2022). We also found no significant difference in axial length (AL) between eyes with or without beta zone PPA, aligning with previous studies suggesting that beta zone PPA is unrelated to axial myopia. Interestingly, our study further revealed that beta zone PPA was not associated with DR odds, while previous studies have found conventional PPA-beta correlated with lower DR odds. The conventional PPA-beta is characterized by exposed sclera and choroidal macrovascular with complete RPE atrophy (Jonas et al., 1989). Previous studies have suggested that development of PPA-beta is associated with axial elongation, leading to optic deviation and directional stretching of the retina and peripheral areas, especially in the temporal section (Jonas et al., 1989; Nakazawa et al., 2008). Tan, et al. reported that individuals with PPA-beta had a lower odds ratio of DR compared to those without (Tan et al., 2018). Additionally, Lin, et al. found differential effects of hyperglycemia on the optic nerve head between type 1 and type 2 diabetes (T1DM, T2DM) without DR (Lin et al., 2022). Specifically, children with T1DM exhibited a significantly smaller area of PPA-beta, while adults with T2DM demonstrated higher optic disc ovality (ODO) compared to corresponding healthy controls. However, as previously mentioned, conventional PPA-beta comprises both new beta zone and gamma zone, which are associated with different ophthalmic diseases. Determining whether the beta zone, gamma zone, or both confer protection against DR was a key goal of our study.

The gamma zone PPA is defined by absence of BM between the beta zone PPA and optic disc. The mechanism behind the formation and enlargement of the gamma zone can be partly explained by the disproportionate growth between retinal structures and the sclera during axial elongation (Chui et al., 2011; Lee et al., 2018). Hayashi, et al. classified PPA in to three categories based on the BM configuration: straight-BM, curved-BM, and defect-BM (Hayashi et al., 2012). Their results indicated a close association between defect-BM and myopia. Similarly, Kim, et al. found that eyes with discontinuous BM (defined as with both beta and gamma zone PPA (Group D) in this study) or lacking BM (defined as isolated gamma zone (Group C) in this study) were associated with longer AL (Kim et al., 2013). Furthermore, they demonstrated a positive correlation between AL and the width of the gamma zone. Our data aligns with these prior studies linking gamma zone PPA to axial myopia. We add evidence that the gamma zone correlated with lower DR odds. This is a novel finding that has not been previously investigated by other researchers, highlighting the originality of our research.

Several mechanisms have been proposed to clarify the protective effect of axial myopia against DR. Lim, et al. found that myopic refractive error and longer AL were associated with longer and narrower retinal arterioles and venules, less tortuous arterioles, lower retinal blood flow, and consequently, decrease retinal capillary pressure and leakage in DR (Lim et al., 2011). Man, et al. proposed that longer AL results in decreased retinal function and oxygen consumption in the outer retina (Man et al., 2013). The decreased metabolic requirement and photoreceptor density in a stretched retina may help to alleviate the effects of hypoxia in DR, thereby reducing the production of inflammatory or proangiogenic cytokines such as vascular endothelial growth factor (VEGF) (Jonas et al., 2009; Ting et al., 2016). Additionally, an elongated eye with increased ocular volume may lead to dilution of VEGF and increased incidence of posterior vitreous detachment (PVD), which served as the vitreous scaffold for neovascular proliferation (Akiba et al., 1990; Yamamoto et al., 2005). The results of our study on microstructural characteristics also demonstrated that eyes with gamma zone PPA were associated with lower vessel density and thinner thickness of choroid. This suggest that the gamma zone is a sign of fundus stretching and thinning, partially explaining its protective mechanism against DR. Interestingly, we observed that individuals without gamma zone PPA showed higher FPG and HbA1c levels, which may lead to choroidal thickening in the early stage of DR (Wang et al., 2020). We hypothesize that hyperglycemia may increase peripapillary blood flow early on, inhibiting ischemic atrophic changes to Bruch’s membrane (BM) and slowing gamma zone progression. Further research should investigate peripapillary microvascular parameters and associated metabolic biomarkers around the beta and gamma zones in diabetic patients. Delineating the impact of glycemic control on peripapillary tissue remodeling may clarify DR changes and inform future interventions to modulate myopia’s protective effects against retinopathy advancement.

This study has several limitations that should be acknowledged. First, the cross-sectional design prevents assessment of DR progression over time in eyes with beta and gamma zone PPA. Second, those with isolated gamma zone changes in DR represented a relatively small subgroup, raising potential for statistical bias. Third, we lacked quantitatively determine the microstructure and microcirculation of PPA subzones, limiting our exploration of the full protective effect of the gamma zone against DR. Thus, the mechanisms underlying gamma zone-mediated protection against DR are incompletely defined. Further research should delineate impacts of gamma zone microvascular remodeling on DR-related pathology. Additional limitations include lack of data on insulin dependence, and other systemic factors that may influence DR risk profiles. Longitudinal follow-up is necessary to clarify causal relationships between PPA subtype progression patterns and incident DR. Larger patient cohorts could also increase power for subanalyses. Nonetheless, our study provides initial evidence to motivate further investigation on the gamma zone’s structural influence in deterring vision-threatening diabetic complications.

In conclusion, we found that gamma zone PPA associated significantly with reduced odds of DR, independent of known systemic risk factors and axial length. The gamma zone seems to represent progressive myopia-driven stretching and thinning of posterior ocular tissues. These structural changes may underpin myopia’s protective effects, conferring resilience of the peripapillary retina and choroid to microvascular complication in diabetes. Further investigation is warranted to confirm the gamma zone’s influence on DR risk and elucidate the intricate relationship between progressive myopia remodeling and development of retinal vasculopathy. Advancing our understanding of structural factors governing susceptibility versus resistance to retinopathy may unveil new therapeutic targets for intervention. Mapping pathological processes from the earliest asymptomatic stages is key to unveiling new strategies to deter vision loss for millions with diabetic eye disease.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors.

We thank Home for Researchers (www.home-for-researchers.com) for basic language editing of a draft of this manuscript.

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fcell.2024.1501625/full#supplementary-material

Supplementary Figure 1 | Representative images showcasing eyes without the conventional beta zone PPA. The optic border is outlined by a red line and red arrow (A, C, D).

Supplementary Figure 2 | Representative images depicting eyes with an isolated new beta zone PPA. The new beta zone is located between the red and purple arrows on the serial B-scan images (C, D).

Supplementary Figure 3 | Representative images illustrating eyes with an isolated gamma zone PPA. The gamma zone is demarcated between the red and yellow arrows on the serial B-scan images (C, D).

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