| It is reported that the number of adults with diabetes reached 537 million worldwide in 2021,90 percent of which were type 2 diabetes(T2D).Therefore,it plays an important role that placing forward the threshold of prevention and control and actively exploring risk factors of T2 D,which is an urgent need to realize early diagnosis and treatment of T2 D and prevent complications to improve prognosis.The result of studies has confirmed that the elevated UA level is significantly positively correlated with T2 D.However,the current results are inconsistent.In addition,studies have shown that there is a significant gender difference in the association between UA levels and T2 D.Given that uric acid levels are influenced by genetic and ethnic factors,it is of great significance to explore the relationship between uric acid and T2 D in the Chinese population and the gender differences.Insulin resistance(IR)is a key pathological characteristic of T2 D.It’s important to control IR,which benefits blood glucose control and prevention or delay of diabetic complications.Studies have reported that elevated UA levels can predict the risk of IR in some races.However,few studies have investigated the relationship between UA and IR in T2 D patients.Mendelian Randomization(MR)analysis can avoid the influence of confounding factors,reverse causal association and other inherent limitations in observational studies,and evaluate the causal association between exposure factors and disease more clearly.An in-depth discussion of the causal association between UA and IR in newly diagnosed T2 D patients can deepen the understanding of the association between UA and T2 D from a new perspective.The increased uric acid level is widely recognized as a risk factor for macrovascular and microvascular complications of diabetes.A limited number of cohort studies have examined the association between uric acid levels and all-cause and CVD mortality in patients with diabetes,but the results remain contradictory.Exploring the association between UA levels and long-term health outcomes in patients with diabetes through a large sample of open databases with long follow-up will help us further understand the long-term effects of UA levels in patients with diabetes.Therefore,this study intends to focus on the newly diagnosed T2 D population.A casecontrol study was conducted firstly to investigate the correlation between UA levels with the risk of T2 D.Subsequently,the association and gender difference between UA levels and IR risk in newly diagnosed T2 D patients were investigated,the causal relationship between UA levels and IR in newly diagnosed T2 D patients was further explored by the MR method.To assess the association of UA levels with all-cause and CVD mortality among US adults with diabetes in two large nationally representative samples with long follow-up periods,which may help us,the main contents of our study are three parts as follow:Section 1: Association between Uric Acid Levels and Type 2 Diabetes-A Case-control StudyObjective: To investigate the correlation between UA levels with T2 D in human.Method: A case-control study was conducted to recruit people who underwent diabetes screening in the endocrinology outpatient Department of Tongji Hospital affiliated with Huazhong University of Science and Technology from 2012 to 2015 as study subjects.The subjects were divided into the T2 D group,and normal glucose tolerance(NGT)group,according to the 1999 World Health Organization’s diagnostic criteria,matched by age(±2).The correlation between UA levels and T2 D risk was analyzed by multivariate logistic regression analysis,and the nonlinear correlation between UA levels and T2 D was evaluated by generalized additive model.Stratified analysis was further conducted according to age,BMI,family history of diabetes,etc.,to evaluate the influence of the above factors on the association of UA levels with T2 D.Results: A total of 3696 volunteers were enrolled(2347 males),including 1464 newly diagnosed T2 D patients(mean age,52.09 years),and 2232 individuals as NGT controls(mean age,52.50 years).The findings showed that the average plasma UA concentrations in the T2 D and NGT groups were 5.66(SD: 1.79)mg/d L,and 5.48(SD: 1.68)mg/d L,respectively.The plasma UA level of T2 D cases was significantly higher than that of the NGT control group(P =0.001).The association between UA levels and T2 D risk was more significant in women(P interaction <0.001).In men,the association between UA levels and T2 D was more significant in those with age <45 years of age(P interaction =0.001)or those with no physical activity habit(P interaction =0.039).The risk of T2 D decreased firstly and then increased in a u-shaped curve with the increase of UA levels.In the female population, the risk of T2 D was lowest when the UA concentration ranged from 4.556 mg/d L to 5.245 mg/d L.Adjusting for potential confounders,compared with the Q3 group,the risk of T2 D increased by 82%(OR,1.82 [95%CI: 1.25,2.66]),28%(OR,1.28 [95%CI: 0.87,1.88]),and 133%(OR,1.82 [95%CI: 0.87,1.88])in Q1,Q2,and Q4 groups,respectively.In the male group,high UA levels were not significantly associated with T2 D.Conclusion: The results showed that there was a significant gender difference in the association between elevated UA levels with T2 D.In the female group,T2 D showed a Ushaped curve trend with the increase of UA levels.Section 2: Association between Plasma Uric Acid and Insulin Resistance in Type 2 Diabetes and its Mendelian Randomization AnalysisObjective: Investigate the association between uric acid levels and insulin resistance in newly diagnosed T2 D patients,and further explore the internal causal relationship through Mendelian Randomization.Method: Patients newly diagnosed with T2 D who underwent OGTT screening in the endocrine clinic of Tongji Hospital between January 2012 and June 2016 were recruited.Insulin resistance was estimated based on the Matsuda index and the HOMA2-IR.The independent relationship between UA levels and IR was assessed.The UA-related single nucleotide polymorphisms(SNPs)were screened out by reviewing literature and existing genetic database.Based on the MR analysis method,the weighted genetic risk score(w GRS)was applied as the genetic tool variable,the potential causal relationship between UA levels and the risk of IR in T2 D patients was investigating.In addition,two-sample Mendelian randomization(TWO-sample MR)analysis was performed in a full European population based on the GWAS open database to verify the robustness of the results.Results: Based on the first part of the population,some samples were included,and due to the lack of sample size loss caused by case-control matching,1938 newly diagnosed T2 D patients(1081 males)were eventually included in this part of the analysis,with an average UA concentration of 5.26 mg/d L(SD: 1.46)in males and 4.31 mg/d L(SD: 1.25)in females.After multiple linear regression and adjustment for confounders,UA levels were negatively correlated with The Matsuda index of insulin sensitivity and positively correlated with HOMA2-IR.For each 1 mg/d L UA increase,the natural logarithmic conversion of Matsuda index value and HOMA2-IR increment value were–0.070(95%CI: –0.089,–0.052)and 0.057(95%CI: 0.039,0.075),respectively.The correlation was more significant in women(P interaction <0.01).In female T2 D patients,after adjusting for age,gender,and other related factors,the Matsuda index value of natural logarithm transformation in the Q4 group decreased by 0.290(95%CI: 0.396,0.185;P linear <0.001),and HOMA2-IR value increased by 0.231(95%CI: 0.128,0.334;P linear <0.001),compared with Q1 group,while in male T2 D patients,the correlation was not strong after adjusting for relevant factors.Three SNPs were selected as instrumental variables for w GRS in this study.Uric acid level increased by 0.225 mg/d L(95% CI: 0.138,0.312)for each SD increase of the w GRS.However,after adjusting for potential confounding factors,the results of Mendelian randomization analysis showed that the differences of the observed and expected values of Matsuda index and HOMA2-IR value were not significant,with the differences of Matsuda index and HOMA2-IR in the total population(P =0.373,P =0.372),in males(P =0.360,P =0.360),and females(P =0.395,P =0.393),respectively.No significant effect was observed when stratified by sex,age,and BMI,and stratified by individual SNP.Twenty-five SNPs loci(P<5×10-8)related to blood UA were selected from GUGC common dataset of blood UA and GWAS dataset of HOMA2-IR as instrumental variables.Heterogeneity and pluripotency were not found by Cochran’s Q test and MR Egger intercept item test(P >0.05).The results of IVW,MR Egger and WM methods did not support the causal correlation between blood UA level and HOMA2-IR,and the analysis of leaving one method did not find the sustained significant causal effect of blood UA level on HOMA2-IR.Conclusion: The increased UA level was correlated with the increased risk of insulin resistance in T2 D patients,and the associations were more pronounced among women than men.The result of MR analysis did not support a direct causal association between UA levels and IR level in newly diagnosed T2 D patients.Section 3: Association between Uric Acid Levels and Mortality Outcomes in Patients with DiabetesObjective: To investigate whether uric acid levels are associated with long-term mortality outcomes(all-cause and cardiovascular mortality)in patients with type 2 diabetes.Method: In this prospective cohort study,we included the patients with type2 diabetes from the Third National Health and Nutritional Examination Survey(NHANES III)(1988 to1994)and Continuous NHANES(1999-2014).The follow-up ended in December 2015.Weighted Cox proportional hazards regression models were used to evaluate the hazard risks(HRs)and 95% confidence intervals(95%CIs)for all-cause and CVD mortality in patients with diabetes.A systematic literature search was further performed on Embase and Pub Med databases of published cohort studies.Results: Among the 2,864 diabetes(mean age 57.81 years;44.76% male)from NAHENS III and 6,301 diabetes(mean age 59.20 years,51.5% male)from NAHENS 1999-2014,the weighted mean of uric acid level was 5.60 mg/d L and 5.78 mg/d L,respectively.During 48,188 person-years of follow-up in NHANES III and 42,877 person-years of follow-up in NHANES 1999-2014,1,906 deaths(600 deaths from CVD)occurred and 1,515 deaths(380 deaths from CVD)occurred,respectively.In multivariable analysis of NHANES III,when compared to patients with diabetes in Q2 group,group Q4 had the HRs(95% CIs)of 1.30(1.08 to 1.57)for all-cause mortality and 1.51(1.06 to 2.15)for CVD mortality.Relatively,using group Q2 as the reference in NHANES 1999-2014,the HRs(95% CIs)in group Q4 were 1.35(1.09 to 1.68)for all-cause mortality and 1.55(1.10 to 2.20)for CVD mortality.A total of 14 studies were included in Meta-analysis with a total sample size of 54,243 including 7,155 deaths,among them 2,258 deaths from cardiovascular disease,with a median follow-up period of 3.1 to 19.0 years.The results showed that the pooled HRs(95% CIs)were 1.08(1.05 to 1.11)for all-cause mortality and 1.05(1.03 to 1.06)for CVD mortality,with per 1 mg/d L increment of SUA level in patients with diabetes.Conclusion: This study indicated the J-shaped associations of UA levels with all-cause and CVD mortality among patients with type 2 diabetes.Higher UA levels were associated with the increased risks of all-cause and CVD mortality.Summary 1.There was a gender difference in the association between UA levels and the risk of T2 D disease.The U-shaped association of T2 D risk with increased UA levels was more significant in women.2.In newly diagnosed T2 D patients,the increase of UA levels was significantly correlated with the increase of IR level,and the correlation was gender different,and was more significant in women.3.Elevated UA levels were associated with increased risk of all-cause and cardiovascular death in T2 D populations. |
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