Mediation effect of obesity on the association between triglyceride‐glucose index and hyperuricemia in Chinese hypertension adults

Abstract The triglyceride glucose (TyG) index was regarded as a simple surrogate marker of insulin resistance (IR). It is confirmed that IR was significantly associated with hyperuricemia, and obesity was the risk factor for IR and hyperuricemia. However, the relationship between the TyG index and hyperuricemia and the potential role of obesity in Han Chinese hypertension are not entirely elucidated. A community‐based cross‐sectional study was conducted in 4551 hypertension patients aged 40–75 years with clinical and biochemical data. The TyG index was calculated as ln [fasting triglyceride (mg/dl) × fasting plasma glucose (mg/dl)/2]. Hyperuricemia was determined as serum uric acid ≥357μmol/L (6 mg/dl) for females and ≥417μmol/L (7 mg/dl) for males. Our study suggested that the TyG index was higher in patients with hyperuricemia than in those without (8.99±0.61, 8.70±0.59, p < .001). The prevalence of hyperuricemia in patients with the lowest (≤8.32), second (8.33–8.66), third (8.67–9.07) and the highest quartile (≥9.08) of the TyG index was 6.0%, 10.4%, 15.4%, 21.4%, respectively. Logistic regression analysis suggested that the higher quartile of TyG index was associated with increased hyperuricemia risk whether in crude or adjusted models (p < .05). Mediation analysis showed that all of our obesity indexes partially mediated the association between the TyG index and hyperuricemia to some extent. In Conclusions, the TyG index is significantly associated with hyperuricemia in hypertension patients among Han Chinese, obesity plays a partial mediation role in this relationship.


INTRODUCTION
Hyperuricemia is caused by abnormal purine metabolism, including excessive uric acid production or insufficient renal excretion, which is one of the components of metabolic syndrome. Previous studies have shown that hyperuricemia is associated with the occurrence and development of many metabolic disorders and cardiovascular diseases. For example, hypertensive patients with hyperuricemia occurred more cardiovascular events than those without hyperuricemia. 1,2 Recently epidemiological study reported that there are 170 million patients with hyperuricemia in China, 3 which greatly increases the morbidity and mortality of cardiovascular events.
Therefore, it is very important to optimize the risk stratification method of hyperuricemia to identify people at high risk of cardiovascular events and other complications. Some studies have reported that IR and obesity are independent risk factors for hyperuricemia, which are significantly related to the occurrence and development of hyperuricemia. 4,5 It is recognized that the bidirectional correlation between IR and hyperuricemia. 6,7 The increase of uric acid level will lead to the impairment of endothelial function, which in turn reduces insulin sensitivity by reducing the bioavailability of nitric oxide, and eventually leads to IR. 8,9 In contrast, IR induces hyperuricemia by increasing the reabsorption of uric acid and sodium in renal tubules. 10 Some epidemiological studies have also confirmed the two-side effect of IR and hyperuricemia. A longitudinal study reported the unidirectional association between the two. They found that hyperuricemia leads to IR, then partially mediates the development of hypertension. 11 But another study found that the improvement of insulin sensitivity reduces the level of serum uric acid. 12 In short, IR and hyperuricemia promote each other to form a vicious circle, resulting in more serious organ damage. In addition, some studies confirmed that IR is related to obesity, 13 and obesity is a major risk factor for hyperuricemia, 14 so the correlation between IR and hyperuricemia may be partially or completely mediated by obesity.
At present, the TyG index is considered as an alternative index to identify IR, 15 and it is confirmed that the correlation with the occurrence and prognosis of many IR-related diseases. 16 It has been reported that there is a positive correlation between the TyG index and the risk of hyperuricemia, [17][18][19] and the IR was more significant in patients with hypertension complicated with hyperuricemia.
However, most of these studies were conducted in relatively healthy communities. The role of the TyG index in assessing the risk of hyperuricemia in hypertensive patients and the potential mechanism of obesity in it have not been fully clarified. Therefore, the purpose of our study is to explore the relationship between TyG index and the prevalence of hyperuricemia in the hypertensive population, and further to clarify whether obesity indexes (BMI, WC, HC) play an intermediary role in it, to optimize the risk stratification method of hyperuricemia and further identify people at very high risk of cardiovascular events and other complications in a hypertensive population.

Biochemical parameters
Fasting blood samples were obtained from an antecubital vein of participants after overnight fasting. Serum was separated from the blood samples by centrifuged on-site. Then the serum samples were delivered to the Beijing center laboratory on the dry ice for analysis. To further examine the impact of BMI, WC, and HC on the association between TyG index and hyperuricemia, we constructed mediation models for analysis in the whole population, hyperuricemia, and non-hyperuricemia. In the model, TyG index is predictor, BMI, HC, and WC are mediators respectively, uric acid is the outcome, and the con-

Clinical characteristics of patients by hyperuricemia
In the whole group of 4551 hypertension patients, there were 605 patients with hyperuricemia, the prevalence of hyperuricemia was 13.29%. The clinical characteristics of the study population by hyperuricemia are described in Table 1. The average age of all participants was 58.63±8.33 years, of which patients with hyperuricemia were 60.11±8.76 years, and it was 58.41±8.24 years in people without hyperuricemia. Males comprised 33.6% of the total participants, 51.2% of the hyperuricemia group, and 30.9% of the non-hyperuricemia group. Compared to patients without hyperuricemia, those with hyperuricemia were more likely to be older, with a higher proportion of males, had higher weight, height, BMI, WC, HC, serum TG, TC, HDL-C, LDL-C, uric acid, BUN, and creatinine, and more CAD status and stroke history (all p<.05). In addition, Echocardiographic indicators (IVSd, PWTd, LVM, and LVMI) were significantly higher in the hyperuricemia F I G U R E 1 Mediation effect to BMI (A) or WC (B) or HC (C) on the relationship between TyG index and uric acid in the hyperuricemia group. The parameter estimate of total effect is 0.1528(0.0730-0.2325), p<.001. Adjusted for age, sex, systolic blood pressure, diastolic blood pressure, serum creatinine, blood urea nitrogen, glomerular filtration rate, the history of stroke, coronary artery disease and diabetes mellitus, serum cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol group than in the non-hyperuricemia group. Particularly worth mentioning is the TyG index is significantly higher in patients with hyperuricemia than without it (8.99±0.61, 8.70±0.59, p<.001).

Clinical characteristics of patients by TyG index
Based on the above results, the TyG index was grouped by quartile, and we presented the baseline characteristics of the patients in Table 2 according to the TyG index categorical. In all participants, the preva-lence of hyperuricemia with the lowest, second, third, and highest quar-

Association of TyG index with hyperuricemia
To explore the relationship between the TyG index and hyperuricemia, we built logistics regression models, and the results were presented in Table 3. Our study revealed a positive correlation between the TyG index and hyperuricemia. As shown in Table 3

The mediating role of obesity indexes
To further examine the impact of obesity indexes on the association between the TyG index and hyperuricemia, we constructed a mediation model for analysis in the whole population, hyperuricemia, and non-hyperuricemia. The results of mediation analysis were displayed in Table 5  The results in the non-hyperuricemia group were similar to those in the general population, but the proportion of mediators was increased (9.0%, 19.0%, and 12.0%, respectively). However, in the hyperuricemia group, BMI and WC also partially mediated this correlation, which the total effect was 0.1528(0.0730-0.2325) and the mediating proportion of 10.2% and 16.2%, respectively. But the indirect effect of HC was not significant, that is, HC did not mediate the relationship between TyG index and hyperuricemia in the hyperuricemia group.

DISCUSSION
In this study, we observed that a strong cross-sectional correlation between the higher TyG index and the increased prevalence of hyperuricemia in Chinese patients with hypertension, which was statistically significant even after adjusting for clinical data and risk factors for hyperuricemia. We further evaluated the mediation effect of different obesity factors on the link of TyG index and serum uric acid level, we found that higher TyG index was associated with higher obesity index (BMI, WC, HC) and serum uric acid level, while the obesity factors partially mediated the relationship between TyG index and uric acid to a varied extent.
Hyperuricemia is a common metabolic abnormality and an independent risk factor for cardiovascular disease. 22 A meta-analysis of 44 studies showed that the total prevalence of hyperuricemia in the Chinese community population was 13.3%, 21 our study was included hypertensive people, but the prevalence was similar to that in community people, which is abnormal. We speculated that may be due to the deviation of the sex ratio of our participants. Previous studies have reported that the prevalence of hyperuricemia in hypertensive people is higher than that in normal people, 23 and the prevalence of hyperuricemia in males is significantly higher than that in females (19.4% vs. 7.9%), 21 and our participants are far fewer in males than in females (19.4% vs. 7.9%).
Hypertensive patients with hyperuricemia have a very high risk of developing cardiovascular disease. 24 A large number of cross-sectional and prospective studies have shown that high levels of uric acid increased the risk of target organ damage and cardiovascular events in patients with hypertension. 25,26 In our study, the prevalence of stroke and CAD in the hyperuricemia group was significantly higher than that in the normal uric acid group, and the significant differences in echocardiographic indicators between the two groups also indicated the damage of high uric acid levels to the heart. The potential mechanism involves many aspects. Due to increased blood pressure caused by renal blood flow decreased, the body compensatory to perceive less blood volume will increase heavy absorption decrease urine output, to maintain endovascular blood volume. Therefore, high blood pressure in patients with renal blood flow reduction will cause uric acid absorption increases, caused by high uric acid hematic disease occurred. 27 In addition, the damage of high uric acid to vascular endothelial function leads to vascular dilatation dysfunction, increased vascular resistance, stimulation of vascular smooth muscle cell proliferation, resulting in vascular sclerosis, which in turn leads to increased blood pressure, forming a small vicious cycle. 28 Hypertension is the most important risk factor for cardiovascular disease due to its damage to the function and structure of blood vessels, 29  IR plays a key role in the occurrence and development of hyperuricemia. In terms of mechanism, IR inhibits uric acid excretion by increasing renal tubular sodium reabsorption, while uric acid, in turn, causes IR by reducing the bioavailability of nitric oxide, mitochondrial oxidative stress, inflammation, and other mechanisms. 32,33 In short, there is a bidirectional relationship between IR and hyperuricemia. At present, it has been reported that there are many methods to evalu-ate IR according to simple biochemical indexes, such as the TyG index, TG/HDL-C, METS-IR, and so on. The ability of the TyG index to identify metabolic disorders in the Chinese population and its applicability in different populations are significantly better than other indexes. 34,35 As a new, simple and effective substitute for IR, the correlation between the TyG index and hyperuricemia may be due to its ability to accurately predict IR. In addition, TyG index was calculated as ln (fasting triglyceride [mg/dL] × fasting blood glucose [mg/dL] / 2). Triglyceride and fasting blood glucose also affected uric acid metabolism. 6,36 A part of free fatty acids generated by triglyceride decomposition will be re-esterified or enter other tissues, and this process will accelerate the utilization rate of ATP. Every 1 mol of triglyceride will promote the utilization of 7-8 mol of ATP. The increase of blood triglyceride will lead to the generation and utilization of more free fatty acids, thus accelerating the decomposition of ATP and leading to the increase of uric acid production. 37 In addition, studies have also analyzed the mechanism of interaction between triglyceride and uric acid metabolism from the perspective of pentose phosphate metabolism. Phosphoric ribose and NADPH are the raw materials for purine synthesis. The hydrogen of NADOH is also the source of hydrogen needed for fat synthesis.
The enhancement of pentose phosphate metabolism can promote the increase of fat synthesis, which leads to the increase of blood triglyceride, and also promotes the synthesis of purine, which further promotes the production of uric acid, which leads to the increase of blood uric acid. 38 There is an inverted U-shaped relationship between fasting blood glucose and uric acid level, 39,40 the level of fasting serum uric acid in prediabetic patients was higher than the normal blood glucose people, but the level of fasting serum uric acid in diabetic patients was lower, 18,41 which may be due to hyperinsulinemia associated with IR increasing uric acid levels by increasing uric acid production and/or reducing uric acid excretion. 6 However, when fasting glucose rises to a certain threshold, elevated glucose levels in urine lead to competitive inhibition of uric acid reabsorption and increased uric acid excretion. 36 The above mechanism has been verified by epidemiological studies. A cross-sectional study of the Chinese general population reported that the risk of hyperuricemia increases proportionally with the increase of the TyG index. They think the TyG index can significantly improve the risk identification ability of the risk prediction model for hyperuricemia, suggesting its important value in optimizing the risk stratification of hyperuricemia. 17 Recently, Li and coworkers found that the correlation between TyG index and the risk of hypertension with hyperuricemia is more significant than that with hyperuricemia or hypertension alone, suggesting that IR is more significant in patients with hyperuricemia with hypertension. 19 Mazidi and coworkers also reported a significant correlation between serum uric acid levels and IR in general communities of the United States, and they further found that a variety of obesity indicators mediated this correlation in varying degrees. 18 In addition, some studies have suggested that obesity is a prerequisite for metabolic syndrome, and IR, hyperuricemia, and hypertension are all manifestations of metabolic syndrome. 42 Unfortunately, no studies have reported the effect of obesity on TyG index and hyperuricemia in hypertensive people, and previous studies on the role of obesity in the link between TyG index and hyperuricemia are inconsistent. In 2017, Mazidi and coworkers reported that a variety of obesity indicators mediated the relationship between TyG and serum uric acid to varying degrees, of which the regulatory ratio of BMI to WC was 46.8% and 57.1%, respectively. 18 However, a recent study reports that the link between the TyG index and hyperuricemia is not related to the mediation of BMI in the general community population in China. 17 Our study found that BMI, WC, and HC did partially mediate the relationship between TyG and serum uric acid, but the intermediary proportion was significantly lower than that of the NHANES study. We speculate that the reason for this difference may be due to ethnic differences and medical history differences in the included population. Previous studies have been reported that race affects insulin sensitivity and obesityrelated diseases, 43 while the incidence of overweight and IR in patients with hypertension is significantly higher than that in healthy people, 44 suggesting that IR and obesity indicators are also affected by hypertension. Perhaps for the above reasons, our study shows that the intermediary role of obesity in Chinese hypertensive people, which is different from that of the general population in China and weaker than that of the American population. It is worth mentioning that our study found that HC did not mediate the relationship between TyG index and uric acid in people with hyperuricemia, suggesting that the mediating effect of HC is only applicable to low-risk people.
The incidence of cardiovascular events and metabolic diseases in patients with hyperuricemia is significantly higher than that in healthy Our study observed that a higher TyG index is significantly associated with a higher prevalence of hyperuricemia in hypertensive people. Therefore, the TyG index may be used as a monitoring indicator of hyperuricemia, which is helpful to formulate prevention and intervention strategies.
This study has several limitations to consider. First of all, our study only included the hypertensive population of the Han nationality in rural China, which could not represent the urban population. Second, the proportion of men and women included in this study is uneven, and men are far less than women, which may be because a large number of male rural residents leave home to work in cities. However, previous studies have reported that the incidence of hyperuricemia in men is significantly higher than that in women, 21 so follow-up studies with a more balanced sex ratio may be needed to prove our point of view. Third, there is a lack of information about uric acid and antihypertensive drugs in our study. Due to the early study design, we did not obtain data on the usage of uric acid drugs, which may have an unknown effect on hyperuricemia, but considering that many previous studies did not report the use of hypouricemia drugs in the investigation of hyperuricemia, 10,17,18 we believe our results are still acceptable.
Fourth, there is a high correlation (collinearity) between WC, HC, and BMI, so the mediating effect of WC and HC may be affected by BMI, and vice versa. However, it is not feasible to include two mediations in the same model to test the above problems. Therefore, this study may underestimate the relationship between obesity and uric acid. In addition, although a high correlation between WC, HC and BMI, there are still differences between these three indicators. BMI is the most commonly used indicator of obesity in clinical practice and epidemiological studies, which takes into account factors such as height and weight, simple and convenient. WC and HC reflect the regional distribution of fat, and WC is a widely used indicator of central obesity. 45 Therefore I think our study is still meaningful. Finally, this is a cross-sectional study, so that we can only observe the correlation between the TyG index, hyperuricemia, and obesity indicators, but not know their time sequence. More rigorous prospective studies are needed to support our conclusions.

CONCLUSIONS
Our results show that a higher TyG index is significantly associated with the prevalence of hyperuricemia in hypertensive people. We further proved this link may be partially mediated by obesity and discussed the differences in the mediating effects of obesity in different populations. Therefore, as a non-invasive and low-cost indicator of noninsulin-dependent IR, the TyG index may become a potential monitoring index in the treatment of hyperuricemia and better identify highrisk patients in people with traditional risk factors, because it can further identify the extremely high-risk population of hyperuricemia in patients with hypertension, and then contribute to the formulation of prevention and intervention strategies. Our study quantifies the role of obesity in the association between TyG index and uric acid, and the control of obesity may contribute to the primary prevention of IR and hyperuricemia. In summary, we recommend routine determination of the TyG index in hypertensive people, which is a simple, low-cost but very beneficial test. In addition to screening patients with IR, it is also helpful to identify hypertensive people with hyperuricemia, who with a high risk of cardiovascular complications. S.W. contributed significantly to data collection, the conception of the study, and revising the comment of reviewers. P.Z. contributed to the conception of the study and helped perform the analysis with constructive discussions.