Triglyceride Glucose-Waist Circumference to Height Ratio Exceeds Commonly Used Anthropometric Markers in Predicting 10-Year Diabetes Risk: the REACTION Research


 Purpose
 Although Triglyceride glucose-waist-to-height ratio (TyG-WHtR) is an indicator for insulin resistance, the relationship between TyG-WHtR and newly diagnosed diabetes is unclear. The intention of this research is to examine the causative association between TyG-WHtR and new-onset diabetes.
Methods
 We conducted a retrospective 10-year cohort study of 10150 Chinese adults. After screening out the unqualified people, the TyG-WHtR level of 8279 participants was calculated in this study, and a multivariate logistic regression model was used to investigate the possibility that it has a connection with diabetes.
Results
 Within 10 years, 271 men (3.27%) and 532 women (6.43%) were newly diagnosed with diabetes. Multivariate Cox regression analysis reveals a linear relationship between TyG-WHtR index and newly diagnosed diabetes mellitus (HR=8.889, 95% CI: 4.703 to 16.801, P < 0.001), and TyG-WHtR shows great AUC (0.750, 95% CI: 0.733-0.767). Addionally, TyG-WHtR associated diabetes was shown to be substantially more prevalent in people aged 71 to 80, with a BMI below 24 kg/m2 and no hypertensive condition (P < 0.05), according to subgroup analysis.
Conclusion
 According to the study, TyG-WHtR might be an accuracy indicator of future diabetes risk and outperform other commonly used anthropometric indices.


Introduction
In recent years, diabetes, as one of the most common and prevalent chronic diseases, greatly affects the quality of life and life expectancy of patients and can even lead to disability [1,2]. The latest report from the International Diabetes Federation reveals that there will be 536.6 million adults aged 20-79 with diabetes in 2021, rising to 783.2 million by 2045 [3]. Type 2 diabetes (T2DM) affects more than 90% of diabetics [3][4][5]. T2DM and its complications are a major cause of disability, functional impairment or premature death, and therefore have enormous social and economic costs[6-8]. As a result, it is critical to improve diabetes prevalence prediction [9,10].
It is worth noting that a key pathogenic hallmark of T2DM in its early stages is insulin resistance [11]. IR is a signi cant underlying abnormality that contributes to diabetes [12,13]. Numerous indices derived from triglyceride glucose (TyG) and anthropometric measurements have been proposed in recent years, including TyG-body mass index (TyG-BMI), TyG-waist circumference (TyG-WC), and TyG-waist to height ratio (TyG-WHtR) [14,15]. TyG-WHtR is de ned as ln[fasting triglycerides (mg/dL) * fasting blood glucose (mg/dL)/2]*WC(cm)/Height(cm) has been posited as a straightforward, low-cost, and convincing surrogate marker for IR and T2DM [15,16]. Numerous cross-sectional studies have established a link of TyG-WHtR index with IR, T2DM, non-alcoholic fatty liver disease, metabolic syndrome, and hyperuricemia [15][16][17][18][19]. However, no cohort study has established the capability of TyG-WHtR index to anticipate the development of T2DM. For this reason, we compared TyG-WHtR index with other routine anthropometric indices, as well as follow-up data from the earlier REACTION study, in order to see if there was a link between the occurrence of diabetes and this index.

Study subjects
This study originated from a multi-center national REACTION study initiated by Ruijin Hospital A liated to Shanghai Jiaotong University School of Medicine [20][21][22]. Furthermore, the research sample originated in Luzhou, Sichuan Province.
Initial recruitment took place from May to December 2011, with a total of 10,150 participants (all over the age of 40) being recruited.
Exclusion criteria included participants with diabetes mellitus, lack of data on psychological or clinical characteristics, inability to calculate baseline TyG-WHtR values, or missing follow-up data. Eventually, 8279 people were involved in the research.
Baseline assessments (2011) As part of the REACTION study's baseline examination, all of the study's information and data was collected using standard questionnaires and calibrated devices by trained personnel (e.g., cardiologists, general practitioners, dietitians, and nurses). Each participant provided demographic information (e.g., age, sex, and education level) and medical history information (e.g., smoking habits, drinking habits, used medications, and family medical history). Smokers were divided into three categories based on their history of smoking: none, occasionally, and daily smoke [21]. In addition, participants were classi ed as none, occasionally, or weekly drink depending on the type, frequency and average quantity of their alcohol consumed [21,22]. Anthropometric indices like BMI (kg/m 2 ), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) were calculated based on the results of standard measurements of body weight (in kilograms; kg), height (in centimeters; cm), waist circumference (WC) (in centimeters; cm), and hip circumference (in centimeters; cm). After resting for at least 30 minutes in a quiet environment during a physical examination, the arterial blood pressure of the right arm was measured three times continuously, and the average value was taken as the mean arterial blood pressure of the patient. Hypertension was de ned as being receiving any antihypertensive medication currently or mean systolic blood pressure (SBP) ≥140 mmHg, mean diastolic blood pressure (DBP) ≥90 mmHg.

Assessment of sample size of study
In this 10 year retrospective cohort study, we collected detailed interview information directly from 10,150 participants from 2011-2021. Eventually, 649 individuals with diabetes at baseline and 1222 with missing follow-up data were omitted from the study for the purpose of this study's' objectives and analyses, resulting in a sample size of 8279 participants.

Statistical analysis
Baseline clinical characteristics were compared for target participants using standard descriptive statistics across the baseline TyG-WHtR quartiles. The Kruskal-Wallis test was used to determine whether the variables were normally distributed, where differences in normally distributed continuous variables were assessed by one-way analysis of variance (ANOVA) and differences in non-normally distributed variables were assessed by the Wilcoxon rank sum test. The Mean-Whitney test was used to determine whether there was a statistically signi cant difference in means between each pair of groups. The association between the risk of developing diabetes and TyG-WHtR quartiles was analyzed Page 4/14 using Kaplan-Meier curves and log-rank test. Using the receiver operating characteristic curves (ROC curves), we explored the predicted accuracy of the TyG-WHtR index. All statistical analyses were conducted by SPSS (version 26.0).

10-year T2DM incidence
From 2011 to 2021, a total of 8279 people were enrolled in the study, including 2715 males and 5564 females. During this period, there were 803 newly diagnosed diabetes patients, and the incidence of diabetes was 9.7%.

Quartiles of TyG-WHtR index in the study participants
Baseline clinical and biochemical characteristics of participants by TyG-WHtR index quartiles are presented in Table 1.
Through data analysis, we revealed a positive association between TyG-WHtR index quartiles and risk factors of diabetes, such as age, BMI, WC, SBP, DBP, fasting blood glucose, total cholesterol, triglycerides, low-density lipoprotein cholesterol, current smoking, alcohol consumption, and high prevalence of hypertension and coronary heart disease (all p < 0.001); negatively correlated with high-density lipoprotein cholesterol (p < 0.001). However, no powerful correlations were found between TyG-WHtR index quartiles and tea or coffee consumption. TyG-WhtR and diabetes incidence over 10 years The analysis revealed a total of 803 patients with newly diagnosed diabetes during the 10-year follow-up period, with an incidence of n = 44 (2.1%), n = 89 (4.3%), n = 184 (8.9%), n = 486 (23.5%) in the baseline TyG-WHtR quartiles (Table 1). It can be found that with the increase of TyG-WHtR index, the prevalence of diabetes also increased (5.5%, 11.1%, 22.9% and 60.5%, respectively). To adjust for other residual confounders, we performed a conditional logistic regression analysis with a binary outcome of diabetes in relation to TyG-WHtR index ( As illustrated in Figure.1 survival statistics analysis were performed using Kaplan-Meier survival curve with log rank test, and the results indicated that the aggregate prevalence of diabetes was signi cantly different among the four TyG-WHtR index groups (P< 0.001) . Increases in the TyG-WHtR index were signi cantly associated with an increased risk of developing diabetes.

Subgroups analysis
As previously stated, TyG-WHtR is an indicator that can more accurately re ect the body's metabolic state. In order to explore the effect of additional risk factors on the correlation between TyG-WHtR index and future diabetes risk, subgroup comparisons were conducted using the previously mentioned strati cation factors.  The ability of TyG-WHtR index to predict new-onset diabetes Receiver operating characteristic (ROC) curves were used to assess the accuracy of TyG-WHtR index in predicting newly diagnosed diabetes (Fig. 2). Compared to BMI, WC, WHtR, TyG-BMI and TyG-WC, the AUC of TyG-WhtR was considerably higher (P < 0.0001). However, FPG and TyG performed better than TyG-WhtR in this research when it came to predicting new-onset diabetes. With a 72.98 % sensitivity and 65.10 % speci city, the best cut-off value for TyG-WhtR was 4.746.

Discussion
The incidence of diabetes is expanding at an astonishing speed at present [10]. It was estimated that 10.5% of adults aged 20-79 had diabetes (uncertainty interval: 8.3%-12.0%), with 10.8% of men and 10.2% of women having the condition [3]. The increase in the global burden of diabetes is accompanied by an increase in medical expenditures to treat this disease, which will signi cantly increase the economic burden of society. Therefore, it is critical to enhance preventive care as well as screening of high-risk groups [23]. Insulin resistance and the failure of beta cells are hallmarks of T2DM [24]. The glucose-clamp technique, which was pioneered by DeFronzo, is widely regarded as the gold standard for quantifying insulin resistance [25]. Unfortunately, this method is time-consuming and expensive, so IR is typically measured by less invasive methods, such as TyG index and obesity-related metrics including BMI, WC, and WHtR[26,27].

Lim, Jinsook et al. combined the TyG and WHtR indices for the rst time and demonstrated that TyG-WHtR outperformed
TyG index alone in assessing insulin resistance [15].
Previous studies have shown a connection between diabetes mellitus and TyG-WHtR index. A cross-study of 24 0.647, P = 0.002) and other indexes in ROC analysis. Additionally, it was con rmed that the TyG-WHtR index, which combines TyG and obesity parameters, is more effective at detecting hepatic steatosis than TyG alone [29].
A longitudinal, multi-center representative cohort data was used to examine the connection between TyG-WHtR index and diabetes in this study. New-onset diabetes were found to be linked to a high TyG-WHtR index, even after correcting for potential related confounders, such as coronary heart disease and hypertension risk factors. In addition, these conclusions were shown in analyses of age, BMI, and hypertension subgroups, highlighting the consistency of this connection even further. As previously reported , in Asian countries such as China and India, where the prevalence of T2DM is characterized by a lower BMI at onset, our study con rms that people with a BMI < 24 kg/m 2 are at a much higher risk of having T2DM than those who are obese or overweight [30,31]. Observational studies should be construed with caution, but this large national survey with 10,150 participants discovered that a higher TyG-WHtR score might be a considerable indicator of forthcoming diabetes cases[32].
A few advantages came out of this research. Using TyG-WHtR as a marker for predicting diabetes is the main advantage of this study, which assesses the risk of developing diabetes. Additionally, the study was followed for a period of up to 10 years, making it more relevant. An additional step to ensure the accuracy and avoid the contingency of the data was taken by using TyG-WHtR index was analyzed as a continuous variable and as a categorical variable (quartiles), which was then followed by performing a trend test and a sensitivity analysis. However, the present study has a limitation in that it only included a sample of adults in southwest China who were 40 years old or older, failing to cover all regions in China. Secondly, the parameters used to calculate TyG-WHtR were collected throughout the study, and TyG-WHtR changes were not monitored during follow-up. As a result, additional investigation is necessary to determine the clinical value of TyG-WHtR in patients with T2DM.

Conclusions
Eventually, using a longitudinal multi-center representative cohort data, we demonstrated a substantial rise in diabetes risk as TyG-WHtR index grew. Because of observation-based study design has internal limitations, this study does not imply a causal relationship. Our ndings indicate that TyG-WHtR index, a proxy marker for insulin resistance, is an independent and reliable indicator of risk for the development of diabetes.

Declarations
Funding A portion of this work was supported by the grants 2016YFC0901200 and 2016YFC0901205 from the Chinese Ministry of Science and Technology.

Con ict of Interest
All the authors declare that there is no con ict of interest.

Author Contributions
All the authors contributed to the discussion and manuscript preparation. Jie Lin and Hang Li contributed equally to this work, who organized data collaboration, interpreted statistical analyses, and wrote the Article; Yahui Qin and Xin Xiang checked multiple-site data, Qin Wan designed the study. All authors read and approved the nal manuscript.

Ethics approval
The research adhered to the ethical standards of the Helsinki Declaration (1975) and the research protocol was reviewed and approved by the ethics committee of the A liated Hospital of Southwest Medical University.

Consent to participate
Everyone who took part in this research gave their explicit, verbal, and/or written consent before participating. Throughout the data collection and analysis processes, the privacy of participants was protected.

Consent to publish
The authors a rm that human research participants provided informed consent for publication of all data.  Figure 1 Kaplan-Meier estimates of the risk of developing diabetes strati ed by quartiles of TyG-WHtR index (P < 0.001) Figure 2 ROC analysis is used to anticipate diabetes