Association Between Chinese Visceral Adiposity Index and Incident Type 2 Diabetes Mellitus in Japanese Adults

Introduction

Living standard improvements and lifestyle changes have made diabetes mellitus (DM), especially type 2 diabetes (T2DM), one of the most common diseases of public health concern worldwide.¹ According to a national, population-based, cross-sectional survey conducted in 2013, the estimated prevalence of DM in Chinese adults was up to 10.9%.² Similarly, the National Health and Nutrition Examination Survey (NHANES) data showed that T2DM prevalence in the USA increased from 8.8% in 1999/2000–to 11.7% in 2013/2014.³ Moreover, the latest data showed that approximately 1 in every 11 adults worldwide now suffers from DM.⁴ DM can result in serious complications, such as blindness, kidney failure, and cardiovascular diseases; it has a high disability and mortality rates.⁵ Therefore, it is crucial to find effective and simple tools to screen high-risk populations for DM and provide them with early intervention and management.

Obesity is a renowned risk factor for T2DM and also a routine-evaluation indicator to identify people at high risk of T2DM in current clinical practice.^6,7 Numerous studies have correlated various obesity indices and T2DM. Body mass index (BMI), the simplest and most widely accepted measure of obesity, was associated with an increased T2DM risk in a meta-analysis of Mendelian randomization studies.⁸ Recent studies have shown a strong correlation between visceral fat obesity indices indexes, including waist circumference (WC), neck circumference (NC), waist-to-hip ratio (WHR), lipid accumulation product (LAP), visceral adiposity index (VAI), and body shape index (ABSI), and the risk of T2DM.^9–14 Meanwhile, ectopic organs fat accumulation, such as ectopic fat storage in the pancreas and non-alcoholic fatty liver diseases, were implicated in T2DM onset.^15,16

Chinese visceral adiposity index (CVAI) is a newly established index to evaluate visceral fat obesity. It is calculated based on age, BMI, WC, triglycerides (TG), and high-density lipoprotein (HDL).¹⁷ It is considered a good marker of cardiometabolic risk and incident hypertension.^18,19 Studies have also shown that CVAI has a positive association with T2DM risk in Chinese adults,^20–22 and is strongly associated with the prevalence of diabetic complications such as cerebrovascular disease and diabetic kidney disease.²³ Secondary data analysis of publicly available data from a retrospective cohort study was performed; the relationship between CVAI and the incidence of T2DM in Japanese adults was investigated in this study to verify the effectiveness of CVAI in Asian populations further.

Materials and Methods

Data Source, Ethical Approval, and Informed Consent

The data analyzed in this study were downloaded from the “Dryad” website (www.datadryad.org).²⁴ Professor Takuro Okamura and colleagues uploaded the data to “Dryad”. They waived the copyright and ownership of the original data, making it available for secondary analysis with a different hypothesis without violating the authors’ rights. They investigated the impact of three obesity phenotypes (obesity, visceral fat obesity, and ectopic fat obesity) on T2DM incidence.²⁵ The study protocol was approved by Murakami Memorial Hospital ethics committee, and all participants provided written informed consent for data collection and usage.²⁵

Study Design and Population

The NAfld in the Gifu Area, Longitudinal Analysis (NAGALA) cohort is a population-based longitudinal study. From May 1994 to December 2016, 20,944 participants who underwent medical examination programs at Murakami Memorial Hospital (Gifu, Japan) were recruited.²⁵ Patients with important data missing, known liver disease, extreme heavy alcohol consumption, medication usage, and diagnosis of T2DM or fasting plasma glucose (FPG) ≥ 6.1 mmol/l at the baseline examination were excluded. Thus, 15,464 participants were included in the original analyses.²⁵ In our present study, the above study subjects were used without further elimination.

Baseline Data Collection and Definitions

The assessment of baseline data collection has been previously described in detail.²⁵ All participants were administered a questionnaire, had physical and blood biochemical examination. Demographic characteristics, including age, sex, and lifestyle, including smoking, drinking, and physical activity, were assessed. Participants were categorized into four groups according to the mean ethanol intake per week: no or minimal alcohol consumption (less than 40 g/week), light (40 to 140 g/week), moderate (140 to 280 g/week), or heavy alcohol consumption (more than 280 g/week).²⁶ Smoking status was classified as never, former, or current smoker based on smoking experience history at baseline.²⁵ Regular physical activity was defined as engaging in any sporting activity more than once weekly.²⁷

Physical examination included the measurement of height, weight, WC, blood pressure, and abdominal ultrasonography. BMI was calculated as weight (kg) divided by height squared (m²). Fatty liver was diagnosed by experienced technicians using abdominal ultrasonography.

Fasting blood samples were collected from all participants. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), total cholesterol (TC), TG, and HDL-c levels were determined by routine enzymatic laboratory methods.

CVAI values were calculated according to the parameters in the downloaded data using the following formula: CVAI = −267.93 + 0.68 * age + 0.03 * BMI + 4.00 * WC + 22.00 * log₁₀TG - 16.32 * HDL (in males); CVAI = −187.32 + 1.71 * age + 4.23 * BMI + 1.12 * WC + 39.76 * log₁₀TG - 11.66 * HDL (in females).¹⁷

Follow-Up and Outcome

All participants underwent regular medical examinations at Murakami Memorial Hospital, and 60% of participants were examined once or twice per year as previously described.²⁵ Incident T2DM was defined as the occurrence of at least one of the following conditions during the follow-up period: HbA1c ≥ 6.5%, FBG ≥ 7 mmol/L, or self-reported diagnosis of T2DM.

Statistical Analysis

Data analysis was performed using R software (version 3.6.3) and EmpowerStats (version 2.2). Continuous data were presented as means ± standard deviation (SD) and were compared using the Student’s t-test. Categorical data were presented as percentages of the total in each category and were compared using the Pearson chi-square test. Participants were stratified by CVAI quartiles. Cox regression analysis and Kaplan-Meier analysis were used to analyze CVAI risk in patients with T2DM. The risk was presented as hazard ratio (HR) at 95% confidence interval (95% CI). The nonlinear relationship between CVAI and T2DM events was investigated using a smooth curve fitting. Receiver operating characteristic (ROC) curve analysis was used to determine the predictive value of CVAI, BMI, and WC for incident T2DM. All tests were two-sided, and P-value <0.05 was considered statistically significant.

Results

Baseline Characteristics of the Study Population

Our secondary analysis had 15,464 participants; 8430 (54.51%) males and 7034 (45.49%) females, with an overall mean age of 43.71±8.90 years. The clinical characteristics of the male and female participants are presented in Table 1. There were statistically significant differences in anthropometric indicators, lifestyles, blood pressure, and biochemical indices between males and females. Furthermore, the average CVAI in men was significantly higher than that in women (62.8 ± 38.0 vs 26.9 ± 34.3, P-value < 0.001), males had the two higher quartiles of CVAI while most of the females were in the two lower quartiles. Thus, in the subsequent analyses, male and female participants were divided into respective baseline CVAI quartiles.

Table 1 Baseline Characteristics of Study Population

Overall, participants in the 4th CVAI quartile group had higher levels of age, BMI, WC, SBP, DBP, ALT, AST, GGT, FBG, HbA1c, TC, and TG, and were more likely to have fatty liver, and had a lower level of HDL (Table 2, all P-values <0.001). With the increasing CVAI quartiles, smoking and heavy alcohol intake were more frequent in men, while no statistically significant difference was observed in women’s smoking habits between the CVAI quartile groups. Additionally, as the CVAI quartiles increased, the proportion of male participants with regular physical activity decreased; however, the opposite trend was found in females.

Table 2 Baseline Characteristics of Study Population According to Quartiles of CVAI and Gender

Incidence and Risk of T2DM Stratified by CVAI

During a median follow-up time of 5.39 years, 373 new-onset T2DM events were observed (incidence rate 4.48 per 1000 person-years). As shown in Figure 1A and B, increased T2DM incidence risk was observed with increasing CVAI quartiles in both males and females (log-rank χ² = 187.1076 and 129.6067, respectively, both P-values: <0.001).

Figure 1 Kaplan-Meier plots of incidence rate of T2DM for CVAI quartiles groups during follow-up. (A) In male participants; (B) In female participants.

Univariate and multivariate Cox regression models were used to evaluate the association between CVAI and new-onset T2DM in males and females (Tables 3 and 4). The higher CVAI levels were significantly associated with incident T2DM in both males and females. An increase of 1 in CVAI was associated with a 1.0133-fold and 1.0246-fold higher risk of incident T2DM in males and females, respectively, after adjusting for age, smoking, alcohol consumption, exercise, and fatty liver (both P- values: <0.001). Being at the top CVAI quartile group remained significantly associated with T2DM after multiple-test correction (HR = 3.1568 and 5.8415 in males and females, respectively, both P-values: <0.05).

Table 3 Correlation Between CVAI and Incident T2DM in Males

Table 4 Correlation Between CVAI and Incident T2DM in Females

Nonlinear Relationship Exploration Between CVAI and T2DM

A smooth curve fitting analysis was conducted to investigate a nonlinear relationship between CVAI and T2DM risk, as presented in Figure 2. The smooth curve showed the association between CVAI and T2DM events as nonlinear in males and females after adjusting for age, smoking, alcohol consumption, exercise, and fatty liver (P values < 0.05). However, there were no saturation effects or threshold effects in both sexes (P values > 0.05).

Figure 2 The association between CVAI and T2DM events. A nonlinear relationship was observed after adjusting for age, smoking, alcohol consumption, exercise, and fatty liver. (A) In male participants; (B) In female participants.

Predicting Value of CVAI in Incident T2DM

According to the results of ROC analysis, as shown in Table 5 and Figure 3, the area under the curve (AUC) for CVAI in males and females was 0.7334 (95% CI: 0.7030–0.7638) and 0.8014 (95% CI: 0.7531–0.8497), respectively. CVAI exhibited the largest AUC compared with BMI and WC in both sexes (P-values <0.05).

Table 5 Predictive Performance of CVAI, BMI, and WC for Incident T2DM

Figure 3 Receiver operating characteristic curves of CVAI, BMI, and WC to predict incident T2DM among study population. (A) In male participants; (B) In female participants.

Discussion

The study revealed that an increase in CVAI was strongly associated with new T2DM onset in Japanese adults. Participants in the highest CVAI quartile had a significantly elevated risk of developing T2DM than those in the lowest quartile in both males and females. Moreover, CVAI might be a better predictor of T2DM than BMI and WC in the Japanese population.

T2DM has become a major public health problem worldwide. Early diagnosis and treatment may be beneficial, such as reducing complications risk and limiting the healthcare burden.²⁸ Therefore, a simple, inexpensive, and practical indicator for evaluating incident T2DM risk is critically needed. Obesity is the most significant key risk factor for T2DM.²⁹ In addition, recent studies have developed and validated new adiposity phenotypes to identify individuals with elevated risk for metabolic diseases, such as DM and cardiovascular diseases. Similar to previous studies,^20,21 this study showed that CVAI was significantly associated with T2DM risk and predicted T2DM more than BMI and WC. This might be because CVAI is a comprehensive index that includes age, BMI, WC, and blood lipids; hence, it is better than a single index.

Many previous studies showed that aging, obesity, and dyslipidemia increase T2DM risk.^30–32 Recently, a study investigated the effectiveness of cardiometabolic indices to estimate atherosclerotic cardiovascular disease risk in Taiwanese adults. The study found that CVAI was more effective than various cardiometabolic indices, including BMI, WC, VAI, LAP, ABSI, triglyceride-glucose (TyG) index, TyG-BMI, and TyG-WC.³³ Thus, CVAI is a better predictor of the state of visceral fat than conventional obesity indicators. Therefore, this study suggests that CVAI is a valuable predictive biomarker for new-onset T2DM.

The study results corroborated previous studies and strengthen the relationship between visceral adiposity index and incident T2DM in a population of Japanese adults. However, the calculated CVAI in Japanese females was much lower than in Chinese populations.^19,23 We guessed this would be relative to physical status and circulating lipid levels differences between Chinese and Japanese adults,³⁴ which might have led to the unsuitable CVAI components coefficient in Japanese adults. Furthermore, CVAI did not show a linear association with incident T2DM in male and female Japanese adults. Therefore, CVAI cannot be considered an ideal T2DM predictor in Japanese adults. More comprehensive studies are still required to identify the appropriate parameters of visceral obesity in the Japanese population.

This study’s several limitations should be recognized. First, these secondary analyses are limited by the disclosed data; thus, unpublished or unmeasured confounding variables in the original study could not be fully adjusted. Second, the oral glucose tolerance test was not used in follow-up visits, and this might have underestimated the T2DM incidence rate. Third, the study was unable to evaluate the impact of CVAI changes on incident T2DM, since the calculation of CVAI was not continuous. Further studies are required to support our conclusions.

Conclusion

In summary, CVAI was significantly associated with new-onset T2DM in Japanese adults. However, further studies are still required to identify the appropriate parameters of visceral obesity for predicting T2DM in the Japanese population.