
==== Front
Heliyon
Heliyon
Heliyon
2405-8440
Elsevier

S2405-8440(24)12714-4
10.1016/j.heliyon.2024.e36683
e36683
Research Article
Sex-based differences in the associations between abdominal obesity and diabetic retinopathy in diabetic patients with normal weight
Liu Yuan 1
Liu Kaiqun 1
Xie Liqiong
Zuo Chengguo zuochengguo@mail.sysu.edu.cn
⁎⁎
Wang Lanhua wanglanhua666666@126.com
⁎
Huang Wenyong
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou 510060, China
⁎ Corresponding author. Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-sen University No. 7, Jinsui Road, Guangzhou, 510060, China. wanglanhua666666@126.com
⁎⁎ Corresponding author. Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-sen University No. 7, Jinsui Road, Guangzhou, 510060, China. zuochengguo@mail.sysu.edu.cn
1 Co-first author.

22 8 2024
15 9 2024
22 8 2024
10 17 e3668323 5 2024
18 8 2024
20 8 2024
© 2024 Published by Elsevier Ltd.
2024

https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Purpose

To investigate sex-specific differences in associations of abdominal obesity indexes, systemic factors, and diabetic retinopathy (DR) in type 2 diabetes mellitus (T2DM) subjects with normal body mass index (BMI).

Methods

This cross-sectional study comprised 653 T2DM subjects (402 women and 251 men) with normal BMI (18.5 kg/m2<BMI<24.0 kg/m2). All participants completed a standard questionnaire and underwent comprehensive ocular and systemic examinations. Anthropometric parameters were measured and recorded, including weight, height, waist circumference (WC), hip circumference, waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR). Sex-specific associated factors for DR were assessed using logistic regression models.

Results

In the multivariate logistic regressions, the presence of any DR was associated with a longer duration of T2DM (OR = 1.07, p = 0.007) and higher HbA1c (OR = 1.40, p = 0.001) in women, while any DR was associated with younger age at T2DM diagnosis (OR = 0.94, p = 0.020) and higher HbA1c (OR = 1.29, p = 0.011) in men. For women, we identified a positive association between WC (OR = 1.07, p = 0.011), WHR (OR = 1.67, p = 0.002), and WHtR (OR = 1.57, p = 0.004) with any DR after adjusting for confounders, and the third tertiles of WC (OR = 2.29, p = 0.028), WHR (OR = 3.03, p = 0.003), and WHtR (OR = 2.84, p = 0.007) were at high risk of any DR. For men, there were no associations between abdominal obesity indexes and any DR in either continuous variables or categorical variables (all p > 0.05).

Main conclusions

There were sex differences in the relationships between WC, WHR, WHtR, and DR in this T2DM population with normal BMI. Our findings provide new insight into a sex-specific mechanism of DR and management of the condition.

Highlights

• The association between isolated abdominal obesity and the presence of any diabetic retinopathy differs according to sex.

• The World Health Organization criteria for abdominal obesity are not suitable for use in all body mass index categories.

• Our study offers novel insight into a sex-specific mechanism of diabetic retinopathy.

Keywords

Abdominal obesity
Body mass index
Diabetic retinopathy
Sex differences
==== Body
pmc1 Introduction

Diabetic retinopathy (DR) represents a major cause of global vision loss and is a prevalent complication of diabetes mellitus (DM) [1]. The worldwide incidence and impact of DR is expected to increase sharply in the coming decades, rising from approximately 103 million in 2020 to 130 million in 2030 and 161 million in 2045 [2]. In China, which has the largest number of cases of DR globally, it has emerged as a serious public health problem [3], imposing burdens on individuals, families, and society [4]. The personalized identification of risk factors for DR holds significant importance for guiding clinical prevention of the condition.

The association between obesity and DR has been a widely debated public health topic [[5], [6], [7]]. Some findings suggest a positive correlation between obesity and DR [8], while others indicate no link [9] or even a negative correlation [10], especially when using body mass index (BMI), which represents generalized obesity used to define obesity, resulting in the paradox of obesity [11]. These conflicting findings demonstrate the constraints of using BMI as the sole indicator of obesity to stratify the risk of DR. Waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) are commonly used to define abdominal obesity and are proven to have a stronger correlation with DR than BMI [6,10,12,13]. However, previous studies of the relationship between abdominal obesity and DR have not eliminated the interdependence of abdominal obesity and BMI. Individuals with a normal BMI but an elevated WHR reportedly have an increased risk of all-cause and cardiovascular mortality [14]. To date, no studies have investigated the correlation between abdominal obesity and DR in DM subjects with normal weight (that is, normal BMI).

In addition, previous studies have shown that sex differences exist in adipose tissue function and deposition [15] and that women with diabetes or insulin resistance, which are related to abdominal obesity, are more likely to experience an increase in the risk of cardiovascular complications [[16], [17], [18], [19]]. One study from Singapore showed WHR to be positively associated with DR, but only in women [10]. It remains uncertain whether anthropometric parameters due to sex differences result in varying levels of risk for DR in DM patients with normal BMI in Chinese populations.

The purpose of the current study was thus to explore sex-based differences in the associations of abdominal obesity indexes, systemic characteristics, and the presence of DR in diabetic subjects with normal BMI in the Guangzhou Diabetic Eye Study.

2 Methods

2.1 Study design and participants

The participants in the current study were part of the Guangzhou Diabetic Eye Study, a community-based, cohort study of T2DM conducted at the Zhongshan Ophthalmic Center (ZOC), Sun Yat-sen University, China [20]. The present study specifically focused on diabetic participants with normal BMI (18.5 kg/m2<BMI<24 kg/m2), as defined by Chinese guidelines [21,22]. Those with an ungradable fundus image caused by an abnormal refractive medium (severe cataract, corneal opacity, etc.) and poor fixation or for whom no WC and hip circumference (HC) data were available were excluded from the current study. The study protocol received approval from the Institutional Ethics Committee of the ZOC and adhered to the guidelines of the Helsinki Declaration (2017KYPJ094). All participants gave their informed written consent before participating in the study.

2.2 Measurements of anthropometric parameters

An experienced nurse measured the weight (kg), height (m), WC (cm), and HC (cm) of each DM patient according to standard procedures. Weight was measured on a scale, with participants removing their shoes and any heavy items. Height was measured with a measuring stick while the participant was on the scale. Non-stretchable medical tape was utilized for the measurement of the WC and HC. The WC was measured at the narrowest point between the ribcage and the hip bones at the end of a normal exhalation. The HC was measured at the widest point of the buttocks.

BMI was calculated as weight (kg) divided by height (m2). According to the Chinese guidelines [22], BMI was categorized as normal, overweight, and obese for scores of 18.5–23.9, 24–27.9, and ≥28.0, respectively. The WHR was calculated as the ratio of WC to HC, while the WHtR was calculated by dividing the WC by the height. Abdominal obesity was defined based on the World Health Organization (WHO) criteria [23,24]: WC ≥ 80 cm for women and ≥94 cm for men; WHR ≥0.85 for women and ≥0.90 for men; or WHtR of ≥0.50. We defined the presence of isolated abdominal obesity as having a normal BMI while meeting one of the three criteria of abdominal obesity.

2.3 Ocular measurements

All participants underwent detailed ocular examinations, including the assessment of best-corrected visual acuity (KR-8800 auto kerato-refractometer; TOPCON Corporation, Tokyo, Japan), intraocular pressure (CT-1 non-contact tonometer; TOPCON Corporation, Tokyo, Japan), axial length (AL; Lenstar LS900; Haag-Streit Group, Koeniz, Switzerland), and standardized seven-field colorful retinal photographs (CR-2; Canon, Tokyo, Japan). The DR was graded by two trained graders using the grading and quality standards of the English National Screening Programme (UK guidelines) [25]. Any DR was defined as the presence of background DR (R1), pre-proliferative DR (R2), or proliferative DR (R3), maculopathy (M1). Vision-threatening DR (VTDR) was considered to be present if M1, R2, or R3 features were found. For individuals with bilateral gradable photographs, the eye with the more severe DR was included. Otherwise, the right eye was chosen for analysis. The presence or absence of DR resulted in the classification of individuals into either the Non DR (NDR) or any DR group, respectively.

2.4 Other measurements

Demographic information and medical histories, including age, gender, smoking and alcohol habits, duration of diabetes, history of systemic and ocular diseases, and medications, were gathered via standardized questionnaires. Systolic blood pressure (SBP; mmHg) and diastolic blood pressure (DBP; mmHg) were measured with a blood pressure monitor after the participant sat quietly for at least 5 min. Fasting (8 h) venous blood samples were collected to test for HbA1c, triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c) using standardized procedures from a certified laboratory in China.

2.5 Statistical analysis

Statistical analyses were performed with Stata software (version 17.0, StataCorp, College Station, TX, USA) and the GraphPad Prism 9 (GraphPad Software, CA, USA). The continuous variables were initially evaluated for normality via the Kolmogorov–Smirnov test, and the results were presented as mean ± standard deviation (SD) for normal distribution or the median with an interquartile range (IQR) for abnormal distribution. An independent t-test and a Mann–Whitney U test were applied if required. A chi-square test or Fisher's exact test were utilized for categorical variables. Univariate and multivariate logistic regression models were employed to investigate the sex-specific relationship between abdominal obesity indexes, systemic characteristics, and DR. The results were recorded as odds ratios (OR), along with 95 % confidence intervals (CI). Statistical significance is indicated by p < 0.05.

3 Results

A total of 653 diabetic subjects with normal BMI was enrolled in the current study, comprising 402 women (61.56 %) and 251 men (38.44 %). Compared with men, women had significantly lower levels of BMI, WC, HC, WHR, and AL, whereas they had higher levels of WHtR, SBP, HbA1c, TG, TC, LDL-c, and HDL-c (all p < 0.05, as shown in Table 1).Table 1 Comparison of baseline characteristics between women and men.

Table 1Characteristic	women, n = 402	men, n = 251	p-value	
Age, years	65.67 (61.00–71.00)	65.21 (61.00–70.00)	0.668b	
Age of DM diagnosis, years	55.19 (50.00–61.00)	54.43 (49.00–61.00)	0.420b	
Duration of diabetes, years	10.35 (5.00–15.00)	10.78 (4.00–16.00)	0.560b	
Use of insulin, n%	12.53	11.06	0.585c	
Smoking history, n%	0.50	33.87	<0.001c	
Alcohol drinking history, n%	2.74	18.95	<0.001c	
Weight, kg	52.07 (48.00–55.50)	62.04 (58.00–66.00)	<0.001b	
Height, m	1.54 ± 0.06	1.67 ± 0.06	<0.001a	
BMI, kg/m2	21.87 (20.74–23.00)	22.30 (21.46–23.33)	<0.001b	
WC, cm	79.54 ± 5.76	83.73 ± 5.39	<0.001a	
HC, cm	90.10 (87.00–93.00)	92.37 (90.00–95.00)	<0.001b	
WHR	0.88 (0.85–0.92)	0.91 (0.87–0.94)	<0.001b	
WHtR	0.52 (0.49–0.54)	0.50 (0.48–0.52)	<0.001b	
SBP, mmHg	133.54 (121.00–148.00)	130.25 (118.00–141.00)	0.015b	
DBP, mmHg	66.79 ± 9.85	68.13 ± 10.27	0.096a	
HbA1c, % (mmol/mol)	7.34 (6.40–7.90)	7.21 (6.20–7.80)	0.044b	
TG, mmol/L	2.24 (1.27–2.71)	1.99 (1.10–2.42)	0.003b	
TC, mmol/L	5.19 (4.37–5.96)	4.71 (3.95–5.35)	<0.001b	
LDL-c, mmol/L	3.15 (2.45–3.70)	2.91 (2.18–3.49)	<0.001b	
HDL-c, mmol/L	1.42 (1.11–1.65)	1.30 (1.03–1.48)	<0.001b	
Axial length,mm	23.32 (22.55–23.78)	23.87 (23.11–24.27)	<0.001b	
DM, diabetes mellitus; BMI, body mass index; WC, waist circumference; HC, hip circumference; WHR, waist to hip ratio; WHtR, waist to height ratio.

SBP, systolic blood pressure; DBP, diastolic blood pressure; HbA1c, haemoglobin A1c; TG, triglycerides; TC, total cholesterol; LDL-c, low-density lipoprotein cholesterol; HDL-c, high-density lipoprotein cholesterol.

(mean ± SD) or (median, IQR).

IQR = interquartile range, shown as (25 %, 75 %).

p < 0.05 was considered statistically significant and marked in bold.

a Independent-Samples t-test.

b Mann-Whitney U test.

c Chi-square test.

Compared to NDR participants, DR participants tended to be younger at the time of DM diagnosis, have a longer duration of DM and higher SBP and HbA1c levels, and be more likely to have insulin therapy in both men and women (all p < 0.05). For women, the levels of WC, WHR, WHtR, TG, and TC were higher in DR than NDR subjects (all p < 0.05), but these factors were not significant for DR in men (all p > 0.05). The DR group had a shorter AL than NDR participants in men only (p < 0.05, as shown in Table 2). The proportion of DR significantly increased with increased WC, WHR, and WHtR in women (all p < 0.05), but not in men (all p > 0.05) (Fig. 1A and B). In the multivariate regression analyses, the results showed sex differences in risk factors for any DR. For women, a longer duration of DM (OR = 1.07, 95 % CI 1.02–1.13, p = 0.007) and higher HbA1c (OR = 1.40, 95 % CI 1.15–1.70, p = 0.001) were associated with the presence of any DR. For men, we observed that younger age at DM diagnosis (OR = 0.94, 95 % CI 0.90–0.99, p = 0.020) and a higher HbA1c (OR = 1.29, 95 % CI 1.06–1.58, p = 0.011) were associated with the presence of any DR (Table 3).Table 2 Comparison of baseline characteristics between NDR and any DR stratified by sex.

Table 2	Women	Men	
Characteristic	NDR (n = 331)	any DR (n = 71)	p-value	NDR (n = 195)	any DR (n = 56)	p-value	
Age, years	65.64 (62.00–70.00)	63.72 (60.50–68.5)	0.396b	65.64 (62.00–70.00)	63.72 (60.50–68.50)	0.069b	
Age of DM diagnosis, years	55.78 ± 8.70	52.45 ± 8.46	0.004a	55.52 (50.00–62.00)	50.68 (45.00–57.00)	<0.001b	
Duration of diabetes, years	9.58 (4.00–13.00)	13.97 (7.50–21.00)	<0.001b	10.14 (4.00–15.50)	12.96 (7.00–18.00)	0.013b	
Use of insulin, n%	9.87	24.64	0.001c	7.14	24.53	<0.001c	
Smoking history, n%	0.60	0	1.000d	33.85	33.96	0.987c	
Alcohol drinking history, n%	2.73	2.82	1.000d	17.44	24.53	0.243c	
Weight, kg	52.16 ± 5.13	51.65 ± 4.83	0.443a	62.25 (58.00–66.50)	61.29 (59.00–65.25)	0.714b	
Height, m	1.54 ± 0.06	1.54 ± 0.05	0.404a	1.67 ± 0.06	1.66 ± 0.06	0.323a	
BMI, kg/m2	21.88 (20.77–23.04)	21.84 (20.68–22.94)	0.737b	22.32 (21.51–23.33)	22.22 (21.41–23.34)	0.604b	
WC, cm	79.19 ± 5.68	81.16 ± 5.87	0.009a	83.75 ± 5.47	83.63 ± 5.14	0.884a	
HC, cm	90.27 (87.00–93.00)	89.30 (86.00–92.00)	0.192b	92.54 ± 4.06	91.78 ± 3.70	0.207a	
WHR	0.88 (0.84–0.91)	0.91 (0.88–0.95)	<0.001b	0.91 ± 0.05	0.91 ± 0.05	0.417a	
WHtR	0.51 (0.49–0.54)	0.53 (0.50–0.55)	0.002b	0.50 ± 0.03	0.50 ± 0.03	0.643a	
SBP, mmHg	132.51 (119.00–147.00)	138.34 (126.00–149.00)	0.029b	128.78 (117.00–138.00)	135.36 (121.00–147.50)	0.004b	
DBP, mmHg	66.56 ± 9.44	67.83 ± 11.57	0.325a	67.93 ± 10.21	68.80 ± 10.54	0.577a	
HbA1c, % (mmol/mol)	7.13 (6.40–7.60)	8.27 (7.00–8.90)	<0.001b	7.01 (6.20–7.40)	7.96 (6.40–8.90)	<0.001b	
TG, mmol/L	2.16 (1.23–2.62)	2.61 (1.65–3.28)	0.023b	1.99 (1.06–2.43)	2.00 (1.14–2.42)	0.984b	
TC, mmol/L	5.14 ± 1.03	5.43 ± 1.17	0.035a	4.67 ± 1.00	4.85 ± 1.23	0.255a	
LDL-c, mmol/L	3.12 ± 0.93	3.33 ± 1.10	0.090a	2.86 (2.18–3.44)	3.06 (2.28–3.77)	0.294b	
HDL-c, mmol/L	1.43 (1.11–1.65)	1.37 (1.08–1.77)	0.287b	1.29 (1.03–1.47)	1.32 (1.04–1.55)	0.430b	
Axial length,mm	23.35 (22.55–23.82)	23.19 (22.47–23.49)	0.162b	23.96 (23.25–24.29)	23.55 (22.78–24.16)	0.017b	
NDR, non-diabetic retinopathy; any DR, any diabetic retinopathy; DM, diabetes mellitus; BMI, body mass index; WC, waist circumference; HC, hip circumference; WHR, waist to hip ratio; WHtR, waist to height ratio; SBP, systolic blood pressure; DBP, diastolic blood pressure; HbA1c, haemoglobin A1c; TG, triglycerides; TC, total cholesterol; LDL-c, low-density lipoprotein cholesterol; HDL-c, high-density lipoprotein cholesterol.

(mean ± SD) or (median, IQR).

IQR = interquartile range, shown as (25 %, 75 %).

p < 0.05 was considered statistically significant and marked in bold.

a Independent-Samples t-test.

b Mann-Whitney U test.

c Chi-square test.

d Fisher's exact test.

Fig. 1 The proportion of any DR stratified by tertile of abdominal obesity indexes. (A) Women; (B) Men. NDR, non-diabetic retinopathy; any DR, any diabetic retinopathy; WC, waist circumference; WHR, waist-to-hip ratio; WHtR, waist-to-height ratio; T, tertile.

Fig. 1

Table 3 Logistic regression analysis of related factors for any DR stratified by sex.

Table 3Variable	Women	Men	
Univariable analysis	Multivariable analysisa	Univariable analysis	Multivariable analysisa	
OR (95%CI)	p	OR (95%CI)	p	OR (95%CI)	p	OR (95%CI)	p	
Age of DM diagnosis (per 1 year increase)	0.96 (0.93–0.99)	0.005	1.00 (0.96–1.05)	0.856	0.94 (0.91–0.98)	0.001	0.94 (0.90–0.99)	0.020	
Duration of diabetes (per 1 year increase)	1.09 (1.05–1.13)	<0.001	1.07 (1.02–1.13)	0.007	1.05 (1.01–1.10)	0.013	1.01 (0.95–1.06)	0.862	
Use of insulin (unused = 0, used = 1; reference:unused)	2.98 (1.54–5.78)	0.001	1.92 (0.91–4.06)	0.089	4.23 (1.82–9.81)	0.001	2.30 (0.91–5.83)	0.078	
SBP (per 1 mmHg increase)	1.02 (1.00–1.03)	0.019	1.01 (0.99–1.03)	0.251	1.02 (1.00–1.04)	0.013	1.01 (1.00–1.03)	0.128	
DBP (per 1 mmHg increase)	1.01 (0.99–1.04)	0.325			1.01 (0.98–1.04)	0.576			
HbA1c (per 1 % increase)	1.63 (1.37–1.94)	<0.001	1.40 (1.15–1.70)	0.001	1.41 (1.17–1.69)	<0.001	1.29 (1.06–1.58)	0.011	
TG (per 1 mmol/L increase)	1.21 (1.03–1.42)	0.019	1.14 (0.94–1.38)	0.185	1.00 (0.83–1.21)	0.989	/	/	
TC (per 1 mmol/L increase)	1.30 (1.02–1.65)	0.036	1.21 (0.91–1.61)	0.191	1.18 (0.89–1.56)	0.254	/	/	
LDL-c (per 1 mmol/L increase)	1.26 (0.96–1.63)	0.091	/	/	1.23 (0.91–1.68)	0.181	/	/	
HDL-c (per 1 mmol/L increase)	0.72 (0.39–1.34)	0.303	/	/	1.25 (0.57–2.70)	0.579	/	/	
Axial length,mm	0.89 (0.70–1.12)	0.317	/	/	0.71 (0.52–0.97)	0.031	0.77 (0.55–1.06)	0.112	
any DR, any diabetic retinopathy; DM, diabetes mellitus; SBP, systolic blood pressure; DBP, diastolic blood pressure; HbA1c, haemoglobin A1c; TG, triglycerides; TC, total cholesterol; LDL-c, low-density lipoprotein cholesterol; HDL-c, high-density lipoprotein cholesterol.

p < 0.05 was considered statistically significant and marked in bold.

a Variables with P < 0.05 in the univariate analysis were included in the multivariate analysis.

There were sex differences in the associations between abdominal obesity indexes and any DR (Table 4 and Fig. 2). For women, when WC and WHtR were assessed as continuous variables, we identified a positive association of WC (OR = 1.07, 95 % CI 1.02–1.13, p = 0.011), WHR (OR = 1.67, 95 % CI 1.21–2.30, p = 0.002), and WHtR (OR = 1.57, 95 % CI 1.16–2.14, p = 0.004) with any DR in the logistic regression adjusted model. After categorization of these abdominal obesity indexes into tertiles, we persistently found that participants in the highest tertiles of WC (OR = 2.29, 95 % CI 1.09–4.81, p = 0.028), WHR (OR = 3.03, 95 % CI 1.44–6.36, p = 0.003), and WHtR (OR = 2.84, 95 % CI 1.33–6.06, p = 0.007) were more likely to have any DR than those in the lowest tertiles after adjusting for confounders(Table 4, Fig. 2A and B). However, we observed an absence of a relationship between the WHO-defined isolated abdominal obesity (all p > 0.05) and any DR in the adjusted model. No associations between abdominal obesity indexes and any DR were observed in men (all p > 0.05) (Table 4, Fig. 2C and D).Table 4 The relationship between indicators of abdominal obesity and any DR stratified by sex.

Table 4		Women	Men	
Univariable analysis	Adjusteda	Univariable analysis	Adjustedb	
Variable		OR (95%CI)	p	OR (95%CI)	p	OR (95%CI)	p	OR (95%CI)	p	
WC categories	
WC ≥ 80 cm for females or ≥94 cm for males	NO	Ref.		Ref.		Ref.		Ref.		
	YES	1.77 (1.05–2.98)	0.033	1.75 (0.96–3.18)	0.066	0.43 (0.05–3.47)	0.425	1.07 (0.11–10.59)	0.951	
Tertile 1		Ref.		Ref.		Ref.		Ref.		
Tertile 2		1.45 (0.74–2.85)	0.278	1.59 (0.74–3.42)	0.239	1.75 (0.85–3.60)	0.128	1.72 (0.73–4.04)	0.213	
Tertile 3		2.19 (1.16–4.15)	0.016	2.29 (1.09–4.81)	0.028	1.08 (0.50–2.33)	0.851	1.44 (0.60–3.47)	0.410	
WC per 1 cm increase		1.06 (1.01–1.11)	0.009	1.07 (1.02–1.13)	0.011	1.00 (0.94–1.05)	0.884	1.02 (0.96–1.09)	0.490	
WHR categories	
WHR≥0.85 for females or ≥0.90 for males	NO	Ref.		Ref.		Ref.		Ref.		
	YES	1.55 (0.83–2.87)	0.165	1.28 (0.64–2.55)	0.482	1.85 (0.99–3.46)	0.055	1.96 (0.96–4.01)	0.064	
Tertile 1		Ref.		Ref.		Ref.		Ref.		
Tertile 2		1.14 (0.55–2.39)	0.723	1.07 (0.47–2.42)	0.872	1.77 (0.84–3.76)	0.135	1.40 (0.60–3.31)	0.439	
Tertile 3		3.29 (1.71–6.33)	<0.001	3.03 (1.44–6.36)	0.003	1.59 (0.74–3.40)	0.235	1.70 (0.72–4.01)	0.225	
WHR per 1-SD increase		1.68 (1.27–2.23)	<0.001	1.67 (1.21–2.30)	0.002	1.13 (0.84–1.53)	0.415	1.19 (0.83–1.72)	0.346	
WHtR categories	
WHtR ≥0.50	NO	Ref.		Ref.		Ref.		Ref.		
	YES	1.83 (1.02–3.30)	0.044	1.84 (0.93–3.64)	0.082	1.13 (0.62–2.05)	0.687	1.70 (0.83–3.48)	0.143	
Tertile 1		Ref.		Ref.		Ref.		Ref.		
Tertile 2		1.29 (0.64–2.62)	0.474	1.05 (0.47–2.34)	0.911	1.07 (0.52–2.22)	0.852	1.35 (0.56–3.25)	0.504	
Tertile 3		2.61 (1.36–4.99)	0.004	2.84 (1.33–6.06)	0.007	1.09 (0.52–2.26)	0.820	1.87 (0.78–4.52)	0.163	
WHtR per 1-SD increase		1.46 (1.13–1.89)	0.004	1.57 (1.16–2.14)	0.004	1.07 (0.80–1.45)	0.642	1.24 (0.86–1.78)	0.243	
any DR, any diabetic retinopathy; WC, waist circumference; WHR, waist to hip ratio; WHtR, waist to height ratio.

p < 0.05 was bolded to indicate statistical significance.

a Adjusted for age of T2DM diagnosis, duration of diabetes, use of insulin, SBP, HbA1c, total cholesterol, and triglycerides.

b Adjusted for age of T2DM diagnosis, duration of diabetes, use of insulin, SBP, HbA1c and axial length.

Fig. 2 The relationships between indicators of abdominal obesity and any diabetic retinopathy stratified by sex. (A) Univariate analysis in women; (B) Multivariate analysis in women; (C) Univariate analysis in men; (D) Multivariate analysis in men. WC, waist circumference; WHR, waist-to-hip ratio; WHtR, waist-to-height ratio.

Fig. 2

We further analyzed the associations of abdominal obesity indexes and VTDR by sex (Supplemental Figs. 1A–1D). We found that higher WHR was significantly associated with VTDR (OR = 1.97, 95 % CI 1.08–3.61, p = 0.027) in women after adjusting for confounders. Patients in the third tertiles of WHR were at higher risk of VTDR occurrence (OR = 3.75, 95 % CI 1.01–13.96, p = 0.048). No associations were observed between abdominal obesity indexes and VTDR in men (all p > 0.05).

4 Discussion

To the best of our knowledge, the current study is the first to evaluate sex-specific clinical characteristics and associated factors for DR in DM subjects with normal BMI. Higher HbA1c and longer duration of DM were associated with any DR in women, while higher HbA1c and younger age at diagnosis of DM were associated with the presence of any DR in men. Additionally, only among the women was there a significant association between abdominal obesity as measured by WC, WHR, WHtR, and any DR in both continuous and categorical variables. However, additional analysis found no relationship between the WHO-defined isolated abdominal obesity and any DR in women.

A higher HbA1c level was a strong risk factor for DR regardless of sex, which is consistent with previous studies [[26], [27], [28]]. Kawasaki et al. [8] suggested that the risks of onset and progression of DR increased linearly by 36 % and 66 %, respectively, for every 1 % (10.9 mmol/mol) increase in HbA1c. Some studies have indicated that long-term adequate glycemic control could significantly reduce the presence of DR or other microvascular complications of DM [3,29]. In addition, a longer duration of DM in women and a younger age at DM diagnosis in men were related to DR, possibly because the relatively longer duration of hyperglycemia (inadequate glycemic control) in these individuals renders them more likely to develop microvascular damage [30].

Only one study from Singapore has investigated the sex difference in abdominal obesity and DR. The study's results showed that in women, a higher WHR was associated with DR. However, the participants of that study represented a mixed Asian population, and the interdependence of BMI with WHR was not excluded. In addition, no abdominal obesity index other than WHR was analyzed in the Singapore study.

In the current study, we first proved that the association between isolated abdominal obesity indexes and any DR exhibited sex differences. Moreover, we found that WC, WHR, and WHtR had significant positive associations with any DR in women only. Further, we showed that higher abdominal obesity indexes are associated with insulin resistance [[31], [32], [33]]. Insulin resistance without obvious hyperglycemia potentially acts as an early driver of DR [34]. This sex-specific susceptibility of abdominal obesity to any DR may be partly due to isolated abdominal obesity being more commonly observed in women than in men [12]. A previous study proposed that the presence of abdominal obesity is a more accurate marker of obesity-related metabolic risk in women than in men and leads to an increased probability of DR [35]. This difference may be related to the influence of sex hormones on adipose tissue function and deposition [15,36]. However, we should interpret the our results of sex differences with caution due to the relatively small numbers of male participants with DM and isolated abdominal obesity and the cross-sectional design. Thus, further longitudinal studies with larger samples are required to verify this relationship.

Interestingly, we found that although both continuous variables and higher tertiles of abdominal obesity indexes were significantly associated with any DR in women, the WHO-defined criteria for abdominal obesity were not related to any DR. The results revealed that a single abdominal obesity criterion for all BMI categories is inadequate to identify individuals at risk of DR. BMI category-specific thresholds for abdominal obesity may be used to enhance the detection of those at high risk of any DR in the future [37]. The WHO criteria are not suitable for detecting any DR risk in Chinese populations because these criteria were set based on mixed Asian populations, not Chinese ones, and there are differences in how body fat is distributed in individuals of Chinese and other ethnicities [23]. Other research has further confirmed our hypothesis that there is no predictive performance of the WHO criteria for cardiovascular disease or diabetes [38,39]. The ethnic differences in body size and distribution of body fat [40] highlight the need to establish population-specific abdominal obesity for Chinese populations. However, further longitudinal studies with larger sample sizes are required to confirm our findings.

The strengths of the current study lie in the detailed ocular and systemic examinations carried out using standard protocols. Additionally, we included only participants with normal BMI to eliminate the interdependence of generalized obesity and abdominal obesity. However, there are several limitations. First, we cannot evaluate the causal relationships between abdominal obesity and DR in this cross-sectional study. Second, the study sample was relatively small, and we included only 38.44 % men with normal BMI, which may induce bias. Third, our study focused on a population from a single community in southern China. Differences in diet and lifestyle among different areas may affect the generalizability of the results. In conclusion, our study found that sex differences exist between the WC, WHR, WHtR, and DR of DM subjects with normal BMI, and these abdominal obesity indexes were only associated with DR in women, not in men. Further longitudinal studies with larger sample sizes are required to confirm the sex difference and causal relationship between WC, WHR, WHtR, and DR in DM subjects with normal BMI. Additionally, besides WC, WHR, and WHtR, which represent traditional abdominal obesity, other newly established indexes for central or abdominal obesity exist, such as the visceral adiposity index, lipid accumulation product, body shape index, body adiposity index, and Chinese visceral adiposity index [41,42]. Future research should focus on exploring the relationship between these enriched obesity indicators and DR by sex in DM subjects with normal BMI.

Declarations: The authors have no financial or other conflicts of interest concerning this study.

Ethical approval statement: The study protocol received approval from the Institutional Ethics Committee of ZOC and adhered to the guidelines of the Helsinki Declaration (2017KYPJ094). All participants gave their informed written consent before participating in the study.

Funding

This study was funded by the 10.13039/501100001809 National Natural Science Foundation of China (82171084, 82301236), the 10.13039/501100021171 Guangdong Basic and Applied Basic Research Foundation (2021A1515110775), the Guangzhou Science & Technology Plan of 10.13039/100016691 Guangdong Pearl River Talents Program (202102010162), and the Fundamental Research Funds of the 10.13039/501100018634 State Key Laboratory of Ophthalmology (303060202400362).

Data availability statement

Data are not available for ethical reasons. Further enquiries can be directed to the corresponding author.

CRediT authorship contribution statement

Yuan Liu: Writing – original draft, Methodology, Conceptualization. Kaiqun Liu: Writing – original draft, Methodology, Conceptualization. Liqiong Xie: Formal analysis, Data curation. Chengguo Zuo: Writing – review & editing, Funding acquisition. Lanhua Wang: Writing – review & editing, Writing – original draft, Methodology, Funding acquisition, Conceptualization. Wenyong Huang: Writing – review & editing, Funding acquisition.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A Supplementary data

The following is the Supplementary data to this article.figs1 figs1

Acknowledgements

The authors would like to thank the medical technicians from the Zhongshan Ophthalmic Center clinic of the 10.13039/501100002402 Sun Yat-sen University for their support during the study.

Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.heliyon.2024.e36683.
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References

1 Cheung N. Mitchell P. Wong T.Y. Diabetic retinopathy Lancet 376 2010 124 136 10.1016/s0140-6736(09)62124-3 20580421
2 Teo Z.L. Tham Y.C. Yu M. Chee M.L. Rim T.H. Cheung N. Global prevalence of diabetic retinopathy and projection of burden through 2045: systematic review and meta-analysis Ophthalmology 128 2021 1580 1591 10.1016/j.ophtha.2021.04.027 33940045
3 Song P. Yu J. Chan K.Y. Theodoratou E. Rudan I. Prevalence, risk factors and burden of diabetic retinopathy in China: a systematic review and meta-analysis J Glob Health 8 2018 010803 10.7189/jogh.08.010803
4 Mazhar K. Varma R. Choudhury F. McKean-Cowdin R. Shtir C.J. Azen S.P. Severity of diabetic retinopathy and health-related quality of life: the Los Angeles Latino Eye Study Ophthalmology 118 2011 649 655 10.1016/j.ophtha.2010.08.003 21035872
5 Zhu W. Wu Y. Meng Y.F. Xing Q. Tao J.J. Lu J. Association of obesity and risk of diabetic retinopathy in diabetes patients: a meta-analysis of prospective cohort studies Medicine (Baltim.) 97 2018 e11807 10.1097/md.0000000000011807
6 Yi Q.X. Zhu L.N. Ma J. Yu X.J. Liu L. Shen J. Use of anthropometric measures of obesity to predict diabetic retinopathy in patients with type 2 diabetes in China Diabetes Metab Syndr Obes 14 2021 4089 4095 10.2147/dmso.S321030 34594120
7 Zheng C. Wei X. Cao X. The causal effect of obesity on diabetic retinopathy: a two-sample Mendelian randomization study Front. Endocrinol. 14 2023 1108731 10.3389/fendo.2023.1108731
8 Kawasaki R. Tanaka S. Tanaka S. Yamamoto T. Sone H. Ohashi Y. Incidence and progression of diabetic retinopathy in Japanese adults with type 2 diabetes: 8 year follow-up study of the Japan Diabetes Complications Study (JDCS) Diabetologia 54 2011 2288 2294 10.1007/s00125-011-2199-0 21630126
9 Han X. Wu H. Li Y. Yuan M. Gong X. Guo X. Differential effect of generalized and abdominal obesity on the development and progression of diabetic retinopathy in Chinese adults with type 2 diabetes Front. Med. 9 2022 774216 10.3389/fmed.2022.774216
10 Man R.E. Sabanayagam C. Chiang P.P. Li L.J. Noonan J.E. Wang J.J. Differential association of generalized and abdominal obesity with diabetic retinopathy in Asian patients with type 2 diabetes JAMA Ophthalmol 134 2016 251 257 10.1001/jamaophthalmol.2015.5103 26720805
11 Bowman K. Atkins J.L. Delgado J. Kos K. Kuchel G.A. Ble A. Central adiposity and the overweight risk paradox in aging: follow-up of 130,473 UK Biobank participants Am. J. Clin. Nutr. 106 2017 130 135 10.3945/ajcn.116.147157 28566307
12 Raman R. Rani P.K. Gnanamoorthy P. Sudhir R.R. Kumaramanikavel G. Sharma T. Association of obesity with diabetic retinopathy: sankara nethralaya diabetic retinopathy epidemiology and molecular genetics study (SN-dreams report no. 8) Acta Diabetol. 47 2010 209 215 10.1007/s00592-009-0113-8
13 Zhong P. Tan S. Zhu Z. Zhu Z. Liang Y. Huang W. Normal-weight central obesity and risk of cardiovascular and microvascular events in adults with prediabetes or diabetes: Chinese and British cohorts Diabetes Metab Res Rev 2023 e3707 10.1002/dmrr.3707
14 Sahakyan K.R. Somers V.K. Rodriguez-Escudero J.P. Hodge D.O. Carter R.E. Sochor O. Normal-weight central obesity: implications for total and cardiovascular mortality Ann. Intern. Med. 163 2015 827 835 10.7326/m14-2525 26551006
15 Palmer B.F. Clegg D.J. The sexual dimorphism of obesity Mol. Cell. Endocrinol. 402 2015 113 119 10.1016/j.mce.2014.11.029 25578600
16 Pan W.H. Cedres L.B. Liu K. Dyer A. Schoenberger J.A. Shekelle R.B. Relationship of clinical diabetes and asymptomatic hyperglycemia to risk of coronary heart disease mortality in men and women Am. J. Epidemiol. 123 1986 504 516 10.1093/oxfordjournals.aje.a114266 3946397
17 Lundberg V. Stegmayr B. Asplund K. Eliasson M. Huhtasaari F. Diabetes as a risk factor for myocardial infarction: population and gender perspectives J. Intern. Med. 241 1997 485 492 10.1111/j.1365-2796.1997.tb00006.x 10497624
18 Prior J.O. Quiñones M.J. Hernandez-Pampaloni M. Facta A.D. Schindler T.H. Sayre J.W. Coronary circulatory dysfunction in insulin resistance, impaired glucose tolerance, and type 2 diabetes mellitus Circulation 111 2005 2291 2298 10.1161/01.Cir.0000164232.62768.51 15851590
19 Benites-Zapata V.A. Toro-Huamanchumo C.J. Urrunaga-Pastor D. Guarnizo-Poma M. Lazaro-Alcantara H. Paico-Palacios S. High waist-to-hip ratio levels are associated with insulin resistance markers in normal-weight women Diabetes Metab Syndr 13 2019 636 642 10.1016/j.dsx.2018.11.043 30641781
20 Zhang S. Chen Y. Wang L. Li Y. Tang X. Liang X. Design and baseline data of the diabetes registration study: Guangzhou diabetic eye study Curr. Eye Res. 48 2023 591 599 10.1080/02713683.2023.2182745 36803011
21 Chen C. Lu F.C. The guidelines for prevention and control of overweight and obesity in Chinese adults Biomed. Environ. Sci. 17 Suppl 2004 1 36
22 Zhang X. Yue Y. Liu S. Cong X. Wang W. Li J. Relationship between BMI and risk of impaired glucose tolerance and impaired fasting glucose in Chinese adults: a prospective study BMC Publ. Health 23 2023 14 10.1186/s12889-022-14912-0
23 World Health Organization EN Nutrition - Publications - Obesity - Waist Circumference and Waist-Hip Ratio: Report of a WHO Expert Consultation 2011 December 2008
24 Ashwell M. Gibson S. A proposal for a primary screening tool: 'Keep your waist circumference to less than half your height' BMC Med. 12 2014 207 10.1186/s12916-014-0207-1 25377944
25 Lian J.X. Gangwani R.A. McGhee S.M. Chan C.K. Lam C.L. Wong D.S. Systematic screening for diabetic retinopathy (DR) in Hong Kong: prevalence of DR and visual impairment among diabetic population Br. J. Ophthalmol. 100 2016 151 155 10.1136/bjophthalmol-2015-307382 26271268
26 Yau J.W. Rogers S.L. Kawasaki R. Lamoureux E.L. Kowalski J.W. Bek T. Global prevalence and major risk factors of diabetic retinopathy Diabetes Care 35 2012 556 564 10.2337/dc11-1909 22301125
27 Liu Y. Yang J. Tao L. Lv H. Jiang X. Zhang M. Risk factors of diabetic retinopathy and sight-threatening diabetic retinopathy: a cross-sectional study of 13 473 patients with type 2 diabetes mellitus in mainland China BMJ Open 7 2017 e016280 10.1136/bmjopen-2017-016280
28 Aljehani E.A. Alhawiti A.E. Mohamad R.M. Prevalence and determinants of diabetic retinopathy among type 2 diabetic patients in Saudi Arabia: a systematic review Cureus 15 2023 e42771 10.7759/cureus.42771
29 Mohamed Q. Gillies M.C. Wong T.Y. Management of diabetic retinopathy: a systematic review JAMA 298 2007 902 916 10.1001/jama.298.8.902 17712074
30 Parameswarappa D.C. Rajalakshmi R. Mohamed A. Kavya S. Munirathnam H. Manayath G. Severity of diabetic retinopathy and its relationship with age at onset of diabetes mellitus in India: a multicentric study Indian J. Ophthalmol. 69 2021 3255 3261 10.4103/ijo.IJO_1459_21 34708783
31 McKeigue P.M. Shah B. Marmot M.G. Relation of central obesity and insulin resistance with high diabetes prevalence and cardiovascular risk in South Asians Lancet 337 1991 382 386 10.1016/0140-6736(91)91164-p 1671422
32 Swainson M.G. Batterham A.M. Tsakirides C. Rutherford Z.H. Hind K. Prediction of whole-body fat percentage and visceral adipose tissue mass from five anthropometric variables PLoS One 12 2017 e0177175 10.1371/journal.pone.0177175
33 Gadekar T. Dudeja P. Basu I. Vashisht S. Mukherji S. Correlation of visceral body fat with waist-hip ratio, waist circumference and body mass index in healthy adults: a cross-sectional study Med. J. Armed Forces India 76 2020 41 46 10.1016/j.mjafi.2017.12.001 32020967
34 Bao Y.K. Yan Y. Wilson B. Gordon M.O. Semenkovich C.F. Rajagopal R. Association of retinopathy and insulin resistance: nhanes 2005-2008 Curr. Eye Res. 45 2020 173 176 10.1080/02713683.2019.1659977 31460803
35 Deepa M. Farooq S. Deepa R. Manjula D. Mohan V. Prevalence and significance of generalized and central body obesity in an urban Asian Indian population in Chennai, India (CURES: 47) Eur. J. Clin. Nutr. 63 2009 259 267 10.1038/sj.ejcn.1602920 17928807
36 Wang Y. Pang X. Gu C. Li C. Li B. Zhou C. Different associations of anthropometric indices with diabetic retinopathy and diabetic kidney disease in Chinese patients with type 2 diabetes mellitus Acta Diabetol. 60 2023 1187 1198 10.1007/s00592-023-02111-1 37179497
37 Ross R. Neeland I.J. Yamashita S. Shai I. Seidell J. Magni P. Waist circumference as a vital sign in clinical practice: a consensus statement from the IAS and ICCR working group on visceral obesity Nat. Rev. Endocrinol. 16 2020 177 189 10.1038/s41574-019-0310-7 32020062
38 Wildman R.P. Gu D. Reynolds K. Duan X. He J. Appropriate body mass index and waist circumference cutoffs for categorization of overweight and central adiposity among Chinese adults Am. J. Clin. Nutr. 80 2004 1129 1136 10.1093/ajcn/80.5.1129 15531658
39 Chen A. Zhou W. Hou J. Nevill A. Ding Y. Wan Y. Impact of older age adiposity on incident diabetes: a community-based cohort study in China Diabetes Metab. J 46 2022 733 746 10.4093/dmj.2021.0215 35487506
40 Rush E.C. Freitas I. Plank L.D. Body size, body composition and fat distribution: comparative analysis of European, Maori, Pacific Island and Asian Indian adults Br. J. Nutr. 102 2009 632 641 10.1017/s0007114508207221 19203416
41 Wan H. Wang Y. Xiang Q. Fang S. Chen Y. Chen C. Associations between abdominal obesity indices and diabetic complications: Chinese visceral adiposity index and neck circumference Cardiovasc. Diabetol. 19 2020 118 10.1186/s12933-020-01095-4 32736628
42 Chen J. Li Y.T. Niu Z. He Z. Xie Y.J. Hernandez J. Association of visceral obesity indices with incident diabetic retinopathy in patients with diabetes: prospective cohort study JMIR Public Health Surveill 10 2024 e48120 10.2196/48120
