Abstract
ObjectiveThis study assessed temporal relationships of serum uric acid (SUA) with blood glucose and determine the mediating effects of body mass index (BMI) and dyslipidemia on the relation of SUA and risk of type 2 diabetes.MethodsParticipants aged ≥ 45 years were participated in 2011 and followed up until 2015. Cox proportional hazards regression with a robust variance estimator was performed to explore the association of SUA with the risk of diabetes, and crosslagged path analysis was introduced to examine the temporal relationships between SUA and blood glucose. A mediation analysis was finally used to identify the mediating effect of BMI and dyslipidemia on the relation of SUA and the future risk of diabetes.ResultsA total of 9,020 participants were included with an average age of 58.59 years at baseline in 2011, and 53.6% of them were women. Linear dose–response relationship was identified by restricted spline cubic analysis between baseline SUA and follow-up blood glucose (the non-linear trend for fasting plasma glucose (FPG): β2 = −0.71, p = 0.52; for HbA1c: β2 = 0.05, p = 0.07; for risk of diabetes: β2 = 0.12, p = 0.39). Additionally, compared with the lowest quartiles of SUA, the adjusted risk ratios of diabetes were 1.00 (95% CI: 0.82–1.23), 1.08 (95% CI: 0.89–1.31), and 1.37 (95% CI: 1.11–1.96) for quartile 2–4 (p-trend < 0.01), respectively. Further additional adjustments for BMI or dyslipidemia, these ratios were not statistically significant. In addition, a unidirectional relationship from baseline SUA to follow-up FPG (ρ1 = 0.24, p = 0.03) was further confirmed using crosslagged path analysis. After stratifying by genders, the above results were only significant in the women subgroup, and we thus conducted a mediation analysis in women and found that the BMI and dyslipidemia partially mediated the effect of SUA on diabetes with a 23.05 and 18.82% mediating effect, respectively.ConclusionsThese findings provide strong evidence that hyperuricemia preceded diabetes, and the effect of baseline SUA on follow-up type 2 diabetes was more pronounced among middle-aged and elderly Chinese women, especially in postmenopausal women, and this effect is partly mediated by BMI and dyslipidemia at baseline.
Highlights
Type 2 diabetes is a metabolic disease characterized by insulin resistance, which affected over 463 million people in 2019, and this number is expected to increase to 578 million in 2,030 and 700 million in 2045 [1]
The link between hyperuricemia and diabetes has been well documented in the previous studies [3,4,5,6], some of them demonstrated that for every 1 mg/dL increase in serum uric acid (SUA) concentration, the risks of type 2 diabetes were increased by 6–11% [6], and these studies showed differences between genders
Since new cases of diabetes were investigated at the 2013 or 2015 follow-up surveys, we were unable to estimate personyear accurately, in addition to the high incidence of diabetes in middle-aged and elderly people, prevented us from using odds ratios (OR) calculated by logistic regression to estimate relative risk (RR), since the use of OR instead of RR is artificially appropriate for rare events, Instead, we introduced the Cox proportional hazards regression with a robust variance estimator to estimate the RR, we set the follow-up time to 1, and we used the Breslow method to break ties [28]
Summary
Type 2 diabetes is a metabolic disease characterized by insulin resistance, which affected over 463 million people in 2019, and this number is expected to increase to 578 million in 2,030 and 700 million in 2045 [1]. The link between hyperuricemia and diabetes has been well documented in the previous studies [3,4,5,6], some of them demonstrated that for every 1 mg/dL increase in serum uric acid (SUA) concentration, the risks of type 2 diabetes were increased by 6–11% [6], and these studies showed differences between genders. About 44% of diabetes cases are overweight or obese [9], and adults with body mass index (BMI) > 35 kg/m2 are 20 times as likely to develop type 2 diabetes than those with a BMI between 18.5 and 24.9 kg/m2. Low levels of high-density lipoprotein cholesterol (HDL-C) are often associated with elevated triglyceride levels, the most prevalent form of dyslipidemia in patients with diabetes [14]. Studies illustrated that SUA can inhibit the synthesis of adiponectin in adipocytes by reducing the production of nitric oxide in arterial endothelial cells, disrupting the tricarboxylic acid cycle and the oxidation of fatty acid β, and promoting the oxidative activity of cells [15]
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