Association between tea intake and alcohol consumption and diabetes complications: A two sample Mendelian randomization study

Association between tea intake and alcohol consumption and diabetes complications: A two sample Mendelian randomization study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Association between tea intake and alcohol consumption and diabetes complications: A two sample Mendelian randomization study Ming-Jie Jia This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3767369/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Studies have indicated that there is a relationship between tea drinking, alcohol consumption, and a reduced risk of diabetes and its complications. However, there is currently no consensus on the potential relationships between tea drinking, alcohol consumption, and diabetes as well as its complications. In this study, we employed a two-sample Mendelian randomization (MR) analysis for the first time to systematically explore the causal relationships between tea intake, alcohol consumption, and diabetes as well as its complications. Methods: Genetic instruments for tea drinking were identified from a genome-wide association study (GWAS) involving 447,485 individuals. Genetic instruments for alcohol intake were identified from a GWAS involving 462,346 individuals. Summary data for diabetes and its complications were obtained from various GWAS meta-analyses. Causal effects between tea drinking, alcohol consumption, and diabetes as well as its complications were examined. Inverse variance-weighted Mendelian randomization (MR) analysis was conducted as the primary method for causal inference. Further sensitivity analyses were performed to ensure the robustness of the results. Results: The IVW assessment showed a causal relationship between alcohol intake and three diabetic complications. Type 2 diabetes with other specified/multiple/unspecified complications , Type 2 diabetes with ophthalmic complications and Type 2 diabetes with renal complications indicated an association with alcohol intake. However, there was horizontal pleiotropy in the study of alcohol intake and three diabetic complications, making the conclusions unreliable. The IVW assessment showed a causal relationship between tea intake and two diabetic complications. Type 1 diabetes with neurological complications, Type 1 diabetes with peripheral circulatory complications showed an association with tea intake. Conclusion: Our research shows that tea and alcohol consumption have a protective effect against diabetic complications.This research contributes to a deeper understanding of dietary influences on diabetes, offering potential directions for future research and public health advocacy. Health sciences/Endocrinology Health sciences/Medical research tea alcohol diabetes complication diabetes mellitus type 1 diabetes type 2 diabetes Figures Figure 1 Figure 2 Figure 3 Figure 4 1 Introduction Diabetes is a serious metabolic disorder with an increasing incidence rate. It is estimated that by 2030, there will be over 578 million people worldwide affected by diabetes( 1 ). As the diabetes progresses, patients may gradually develop various vascular complications, including macrovascular diseases such as cerebrovascular disease, cardiovascular disease, and peripheral vascular disease, as well as microvascular diseases such as diabetic nephropathy, retinopathy, and neuropathy( 2 ). Among adults (aged 20–79) with diabetes worldwide, diabetic vascular complications are the leading cause of death( 2 ).Among the numerous complications associated with diabetes, diabetic neuropathy caused by damage to the peripheral and autonomic nervous systems is the most common ( 3 ). According to the International Diabetes Federation, it is estimated that by 2050, half of the individuals with type 2 diabetes will develop some form of neuropathy without effective intervention ( 4 , 5 ). The main types of nerve damage in diabetic neuropathy include distal symmetric polyneuropathy, small-fiber-predominant neuropathy, radiculoplexopathy, and mononeuropathy ( 6 ). These syndromes lead to a high incidence of morbidity, increased mortality, and pain in patients ( 7 ).Peripheral artery disease (PAD) is a chronic arterial occlusive disease of the lower limbs, and it is particularly closely associated with diabetes. Approximately 20–30% of individuals with PAD also have diabetes( 8 ). The incidence of PAD is 2 to 4 times higher in patients with type 2 diabetes compared to non-diabetic individuals( 9 ). As the duration of diabetes progresses, the prevalence of PAD also increases( 10 ). Furthermore, diabetes exacerbates the severity of PAD, augmenting the risk of severe complications such as amputation( 11 – 12 ). Epidemiological studies have shown that the global prevalence of diabetic retinopathy (DR) among diabetes patients is 22.27%. It is estimated that in 2020, there were approximately 103.12 million adults worldwide with DR, and this number is projected to increase to 165 million by 2045 ( 13 ). Almost all individuals with type 1 diabetes (T1D) and 60% of those with type 2 diabetes (T2D) will develop diabetic retinopathy within 20 years of having diabetes ( 14 ). DR can lead to progressive visual impairment and is one of the leading causes of preventable blindness among working-age populations. Additionally, DR increases the risk of severe systemic vascular complications such as stroke and coronary heart disease ( 15 ). Diabetic nephropathy (DN) is characterized by persistent albuminuria and subsequent decline in glomerular filtration rate. Ultimately, diabetic patients may progress to develop end-stage renal disease (ESRD) ( 16 ). Approximately 30% of individuals with type 1 diabetes and about 40% of those with type 2 diabetes will develop diabetic nephropathy ( 17 , 18 ). Diabetic nephropathy has become a major cause of end-stage renal disease globally and is also a risk factor for cardiovascular disease ( 19 ). Multiple studies have shown that DN patients have a significantly increased risk of adverse cardiovascular events, infections, and mortality ( 20 ). Diabetes and its complications not only significantly impact individuals and families but also have a profound economic impact on society ( 22 ). Therefore, it is crucial to explore innovative methods for early prevention and intervention of these complications. Tea is one of the most widely consumed beverages in the world.It has numerous health benefits, including antioxidant, anticancer, liver protection, heart health, anti-obesity, gut microbiota improvement, and anti-diabetic effects( 22 – 29 ). It contains many bioactive compounds, which may reduce the risk of diabetes and its complications( 30 ). A clinical case-control study showed that regular consumption of green tea can lower the risk of diabetic retinopathy by 50% compared to non-consumers( 31 ). Several studies have demonstrated the protective effects of tea intake against diabetic nephropathy( 32 – 34 ).A randomized controlled trial has demonstrated the therapeutic value of green tea extract in the treatment of diabetic peripheral neuropathy ( 35 ). Animal experimental results suggest that Epigallocatechin-3-O-gallate, a bioactive compound in green tea, has beneficial effects in lowering blood glucose, reducing blood lipids, and exhibiting antioxidative and anti-inflammatory properties. This may prevent the occurrence and development of diabetic neuropathic pain ( 36 ). Additionally, observational studies have found that drinking more than 150 milliliters of tea per day for at least one year may reduce arterial stiffness compared to non-tea drinkers ( 37 ). This may contribute to the alleviation of peripheral artery disease . Nevertheless, the research results regarding the causal relationship between tea consumption and vascular complications of diabetes are inconsistent. A longitudinal study conducted in Iran revealed that high consumption of tea leaves was not associated with an increased risk of chronic kidney disease ( 38 ). Another study also suggested that there was no significant correlation between tea intake and changes in estimated glomerular filtration rate (eGFR) ( 39 ). Furthermore, the results of a prospective cohort study further indicated that tea intake was unrelated to the risk of end-stage renal disease ( 40 ).A cohort study involving 12,428 older adults did not find a significant association between green or black tea consumption and glomerular filtration rate( 41 ).A cross-sectional study found no significant correlation between tea drinking frequency, type, and the risk of DR ( 42 ). A recent Mendelian randomization study did not provide genetic evidence for causality between tea intake and type 2 diabetes or several glycemic traits, including HbA1c, FPG, and HOMA-IR levels. Therefore, evidence supporting tea consumption as a preventive measure for T2D remains insufficient ( 43 ). The causal relationship between alcohol and complications of diabetes is also subject to debate. In the Mediterranean population, moderate alcohol consumption has been associated with a lower prevalence of peripheral artery disease (PAD) compared to non-drinkers. However, heavy alcohol consumption is associated with an increased risk of PAD ( 44 ). Yang et al. suggest that alcohol consumption may be a risk factor for lower limb arterial disease in patients with type 2 diabetes ( 45 ). On the other hand, a cross-sectional study found a negative correlation between alcohol consumption and peripheral artery disease in non-smoking men and women ( 46 ). A prospective study found that moderate alcohol consumption is negatively correlated with the risk of neuropathy and proliferative retinopathy in patients with type 1 diabetes ( 47 ). Another cross-sectional study found a significant association between moderate alcohol consumption and a reduced incidence of diabetic retinopathy in patients with type 2 diabetes compared to non-drinkers ( 48 ). However, a meta-analysis revealed no significant association between alcohol intake and the risk of diabetic retinopathy ( 49 ). Another observational study reported an increased risk of visual impairment associated with alcohol consumption in patients with type 2 diabetes but found no association with retinopathy ( 50 ). A cross-sectional study found that alcohol drinkers have a higher risk of diabetic nephropathy and severe retinopathy in patients with type 1 diabetes ( 51 ). Consequently, comprehending the causal relationship between tea, alcohol, and complications of diabetes is crucial for directing lifestyle interventions designed to mitigate diabetes-related complications in diabetic patients. Mendelian randomization (MR) is a statistical technique that uses single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) to infer causal relationships between exposures and outcomes. Since genetic variations are randomly allocated during gamete formation and are largely unaffected by environmental or lifestyle factors, MR can mitigate confounding factors and reverse causality in causal inference. In this study, a two-sample Mendelian randomization method was employed, utilizing publicly available large-scale genome-wide association study (GWAS) databases, to explore the causal relationships between tea consumption, alcohol intake, and diabetes, as well as its complications. 2 Materials and Methods 2.1 Data Collection GWAS data for Diabetic Nephropathy (DN), Diabetic Retinopathy (DR) and different subtypes of the disease based on previous studies were used as the outcome factors for this study, which can be found in the table below. The ending factors mainly include diabetes complicating peripheral circulatory system complications, diabetes complicating peripheral neuropathy, DN, DR and diabetes complicating various other complications. SNPs associated with alcohol intake were screened as instrumental table sizes using genome-wide association studies (GWAS) published in the https://gwas.mrcieu.ac.uk/ , Finland database as a reference. Both exposure and outcome cohorts were restricted to subjects of European ancestry to minimize population stratification bias. All original studies included in this MR have been approved by the ethics committees of their institutions, respectively. In addition, informed consent was already obtained from relevant participants in the original studies. Therefore, no further ethical approval was required for the present MR analysis. Table 1 Publicly available exposure data Disease categories Phenocode Ancestry num_cases num_controls Proliferative diabetic retinopathy finngen_R9_DM_RETINA_PROLIF European 9511 362581 Diabetes endpoints finngen_R9_DM_RETINOPATHY_EXMORE European 10413 308633 Type 1 diabetes with other specified/multiple/unspecified complications finngen_R9_E4_DM1NASCOMP European 6234 308280 Type 1 diabetes with neurological complications finngen_R9_E4_DM1NEU European 1077 308280 Type 1 diabetes with ophthalmic complications finngen_R9_E4_DM1OPTH European 5202 308280 Type 1 diabetes with peripheral circulatory complications finngen_R9_E4_DM1PERIPH European 669 308280 Type 1 diabetes with renal complications finngen_R9_E4_DM1REN European 1579 308280 Type 2 diabetes with other specified/multiple/unspecified complications finngen_R9_E4_DM2NASCOMP European 46373 308280 Type 2 diabetes with neurological complications finngen_R9_E4_DM2NEU European 1894 308280 Type 2 diabetes with ophthalmic complications finngen_R9_E4_DM2OPTH European 4172 308280 Type 2 diabetes with peripheral circulatory complications finngen_R9_E4_DM2PERIPH European 2179 308280 Type 2 diabetes with renal complications finngen_R9_E4_DM2REN European 2684 308280 Diabetic background retinopathy finngen_R9_H7_RETINOPATHYDIAB_BKG European 4011 344569 2.2 Study Design As shown in Fig. 1 , we used MR analysis to examine the causal relationship between alcohol intake and DN, DR, and different subtypes of the disease. The instrumental variables for MR analysis needed to fulfill three assumptions: i) causally related to exposure, ii) independent of confounders, and iii) affecting outcomes only through exposure ( 54 ). Instrumental variables were extracted from alcohol intake according to harmonized criteria set at a genome-wide significance level of p < 5 × 10 − 8 ( 55 ). The 71 SNPs were included in the alcohol intake dataset. Next, we performed linkage disequilibrium (LD) clustering analyses using the 1000 Genomes Project Phase III (EUR) as a reference panel to identify independent SNPs (r2 < 0.001 in the 10,000 kb range). The exposure dataset and the outcome dataset were harmonized by the R "harmonise_data" function and paired SNPs with intermediate allele frequencies were excluded. For SNPs that were not present in the outcome dataset, no substitution SNPs were sought. The F-statistic was used to assess the strength of the instrumental variables for each species, and instrumental variables were considered to be sufficiently strong if F was greater than 10 ( 56 , 57 ). None of the instrumental variables included in this study were "weak" instrumental variables (F statistic greater than 10). 2.3 Statistical Analysis Multiple methods have been used to assess whether there is a causal relationship between alcohol intake and DN, DR, and different subtypes of the disease, including the MR Egger method, the weighted median method, the inverse variance weighting method, the simple model method, and the weighted model method. The IVW method uses a meta-analysis approach to combine the Wald estimates of each SNP to derive an overall estimate of the effect of alcohol intake on disease ( 58 ). This method relies on all SNPs and is efficient in estimation which was chosen as the main method for this study ( 56 ). However, the results of IVW are stable only when there is no horizontal pleiotropy. Based on the assumption that instrumental strength is independent of direct effect (InSIDE), MR-Egger can utilize the intercept to assess horizontal pleiotropy ( 59 ). The MR egger method is preferred when horizontal pleiotropy is present. If more than 50% of the instrumental variables are invalid, the weighted median method is used to assess causality ( 60 ). The weighted median method was preferred when heterogeneity existed. In addition, these five methods must be oriented in the same direction. the MR-PRESSO analysis method assesses and reduces horizontal multidimensionality by detecting and excluding outliers ( 61 ). Cochran's IVW Q statistic is used to assess heterogeneity of instrumental variable ( 62 ). To identify potentially heterogeneous SNPs, we performed a "leave-one-out" analysis ( 63 ). By excluding each instrumental variable in turn, we observed stable results for the MR analysis.For dichotomous variables, the odds ratio was used as the outcome. For continuous variables, β values were used as the results. F statistical formula: F = beta^2/se^2. For each statistical test, we consider an overall significance level of P < 0.05 to be satisfactory. The data were analyzed using the R software (version 4.1.3). MR analyses were performed using the "TwosampleMR" R software package ( 64 ). 3 Result 3.1 Causal relationship between tea and alcohol intake and disease Alcohol intake was found to be causally associated with Type 2 diabetes with other specified/multiple/unspecified complications, Type 2 diabetes with ophthalmic complications and Type 2 diabetes with renal complications. A causal relationship was found between tea intake and Type 1 diabetes with neurological complications and Type 1 diabetes with peripheral circulatory complications (Fig. 2 ). IVW method to assess the existence of the causal relationship between Type 2 diabetes with other specified/multiple/unspecified complications (odds ratio = 0.80, 95% confidence interval: 0.66–0.97), Type 2 diabetes with ophthalmic complications (odds ratio = 0.62, 95% confidence interval: 0.43–0.88), Type 2 diabetes with renal complications (odds ratio = 0.52, 95% confidence interval: 0.35–0.78) and alcohol intake. IVW method to assess the existence of the causal relationship between Type 1 diabetes with neurological complications (odds ratio = 0.26, 95% confidence interval: 0.07–0.90), Type 1 diabetes with peripheral circulatory complications (odds ratio = 0.22, 95% confidence interval: 0.05–0.91) and tea intake. And there is no causal relationship between other diabetic complications and alcohol and tea intake. 3.2 Sensitivity analysis First, Cochran's Q test (P > 0.05) as well as the funnel plot suggested that there was no heterogeneity (Fig. 3 ). Leave-one-out assay reveals aberrant SNP loci for causal analysis of alcohol intake and type 2 diabetes with other specified/multiple/unspecified complications (Fig. 4 ). Meanwhile, the MR-PRESSO test found horizontal pleiotropy for both alcohol intake and all three exposure factors. Leave-one-out assay reveals aberrant SNP loci for causal analysis of tea intake and Type 1 diabetes with neurological complications, Type 1 diabetes with peripheral circulatory complications. However, the MR-PRESSO test and MR Egger's intercept analysis revealed no horizontal pleiotropy except for Type 1 diabetes with neurological complications and Type 1 diabetes with peripheral circulatory complications. Therefore, it was considered that there was no pleiotropy between Type 1 diabetes with neurological complications, Type 1 diabetes with peripheral circulatory complications, and tea intake. 4 Discussion To the best of our knowledge, this study represents the inaugural application of Mendelian randomization (MR) to evaluate the causal links between tea and alcohol consumption and the risk of diabetic complications.Our analysis revealed a causal association between alcohol consumption and various complications of T2D, including specified/multiple/unspecified, ocular, and renal complications.On the other hand, a causal link was observed between tea consumption and type 1 diabetes mellitus, specifically regarding neurological and peripheral circulatory complications.These findings suggest protective effects of tea intake.Furthermore, this Mendelian randomization study exhibited no evidence of selection bias or instrumental weaknesses. Resveratrol constitutes the primary bioactive compound present in wine.Studies have shown that treating animals with resveratrol can reduce hyperglycemia and hyperlipidemia, improve the integrity of kidney structure, and enhance renal function in diabetic nephropathy.Administration of resveratrol has been found to lower urinary albumin and serum creatinine levels in diabetic nephropathy mice, indicating an improvement in renal function.Additionally, the administration of resveratrol has been shown to decrease oxidative stress, reduce inflammatory cell infiltration, lower cytokine production, and diminish malondialdehyde (MAD) levels in the kidneys.Moreover, it enhances the activity of antioxidant enzymes and upregulates the expression of SIRT1.These results indicate that resveratrol treatment may exert protective effects against diabetic nephropathy ( 63 – 65 ).Diabetic retinopathy is characterized by an enhanced inflammatory response, ischemia, advancing degeneration of retinal pigment epithelial cells, blood-retinal barrier dysfunction, and subsequent vision loss ( 15 ).Studies on animals indicate that resveratrol potentially inhibits retinal neuronal apoptosis in diabetic rats ( 66 ).Supplementation with resveratrol significantly lowers blood glucose levels and reduces body weight in diabetic rats.Additionally, it elevates oxidative indices and superoxide dismutase activity in both blood and retina, ameliorates increased NF-κB activity and the rate of cell apoptosis in the retina ( 67 ), thereby offering protective effects against diabetic retinopathy (DR).Furthermore, resveratrol is capable of decelerating the progression of diabetic cataracts by mitigating oxidative damage to lens proteins ( 68 ). Flavonoids represent the primary phenolic compounds present in red wine.The flavonoid content in red wine encompasses flavanols (like catechins), flavonols (such as quercetin and myricetin), and anthocyanins (notably malvidin-3-glucoside) ( 69 ).In STZ-induced diabetic rats, treatment with different flavonoid compounds has been shown to improve the oxidative-reductive status of the retina, promoting an increase in glutathione and a decrease in lipid peroxidation.Observations also reveal that flavonoids can boost the levels of antioxidant enzymes, including SOD and CAT ( 70 ).Experimental findings suggest that flavanols exert a positive impact on retinal lesions and cataracts in diabetic rats.The underlying mechanisms are likely linked to the antioxidant properties of flavanols and their ability to inhibit VEGF, ERK1/2, p38MAPK, and aldose reductase ( 71 ).In conclusion, there is a notable potential for flavonoids present in red wine to offer protective effects against retinopathy in diabetic rats.A recent observational study has shown that increased consumption of flavonoids correlates with a lower risk of diabetic nephropathy ( 72 ).Studies have demonstrated that anthocyanins enhance kidney function in diabetic nephropathy patients by modulating amino acid metabolism ( 73 ).A systematic review and meta-analysis of animal research indicates that quercetin could enhance kidney function in diabetic nephropathy animal models, attributed to its antioxidant, anti-inflammatory, anti-fibrotic properties, and the regulation of renal lipid accumulation.This compound has the capability to diminish oxidative stress and inflammatory responses in the kidneys ( 74 ).Taken together, these studies suggest that flavonoids have protective effects against diabetic nephropathy.These findings provide potential candidates for the development of new therapeutic approaches for diabetic nephropathy. Prior research has suggested that tea consumption provides protective benefits against complications related to diabetes.A randomized controlled trial has established the efficacy of green tea extract (GTE) intake in the treatment of mild to moderate diabetic peripheral neuropathy (DPN) ( 35 ).The flavonoids present in tea possess potent antioxidant properties and are capable of enhancing apoptotic and neurotrophic factors. They alleviate oxidative stress, thus safeguarding neurons from damage and potentially preventing diabetic retinopathy ( 75 – 82 ).Research has demonstrated that both pu-erh tea and green tea exert protective effects against diabetic nephropathy. These benefits may be attributed to various mechanisms, such as the reduction of advanced glycation end-product (AGE) accumulation, enhancement of energy metabolism, and mitigation of oxidative stress( 83 – 89 ).These findings offer promising avenues for potential pharmaceutical agents in the development of novel treatments for diabetic nephropathy. The varying impacts of tea and alcohol on complications in type 1 and type 2 diabetes can be attributed to the distinct pathogenic mechanisms of T1DM and T2DM.T1DM results from the extensive destruction of pancreatic beta cells, culminating in an absolute insulin deficiency.Conversely, T2DM primarily stems from insulin resistance and the progressive deterioration of insulin secretion ( 90 ).Owing to these divergent pathogenic mechanisms, the effects of tea and alcohol on complications may vary between these diabetes subtypes.Furthermore, in contrast to T2DM, which predominantly affects middle-aged and elderly individuals, T1DM typically develops in children and adolescents, who generally have limited exposure to tea and alcohol.This factor might also play a role in elucidating the disparities in their impacts across the different subtypes. Indeed, Mendelian randomization (MR) studies have yielded results that are inconsistent with those of prior observational studies.Several factors may account for this discrepancy.Firstly, the issues of reverse causality and residual confounding cannot be entirely ruled out in prior observational studies.Secondly, data in previous studies were derived from self-reported tea consumption, potentially leading to misclassification errors due to habitual tea drinking patterns.Consequently, the assessment of long-term tea consumption in observational studies may lack precision.Lastly, the demographic of habitual tea drinkers is not randomly distributed, being somewhat influenced by regional differences in tea consumption and closely linked to variables like age and gender.All these elements could potentially impact the outcomes of previous observational studies. 5 Conclusion In conclusion, our study elucidates the causal relationship between alcohol and tea consumption and the development of diabetes and its complications, as determined through Mendelian randomization (MR) analysis.This insight offers fresh perspectives for subsequent mechanistic research and promotes advocacy for healthier lifestyles. Declarations Acknowledgments: We thank the participants and researchers of the UK Biobank and FinnGen surveys. Their project is non-profit for public sharing of GWAS summary data. Institutional Review Board Statement: The UK Biobank and FinnGen R9 projects were approved by the Ethical Review Board and all participants signed an informed agreement. The study was conducted in accordance with the guidelines of the Declaration of Helsinki, and the utilization of summary level statistics did not require additional ethical review and approval. Funding: The article was not funded. Availability of data and materials: Exposure data were acquired from the GWAS summary dataset of the UK Biobank project incorporated by the MRCIEU GWAS database (https://gwas.mrcieu.ac.uk/) . Outcome data were obtained from the FinnGen R9 repository (https://r9.finngen.fi/). All data is publicly available. 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Consumption of Coffee but Not of Other Caffeine-Containing Beverages Reduces the Risk of End-Stage Renal Disease in the Singapore Chinese Health Study. J Nutr. 2018;148(8):1315-22. van Hasselt TJ, Pickles O, Midgley-Hunt A, Jiang CQ, Zhang WS, Cheng KK, et al. Effects of tea consumption on renal function in a metropolitan Chinese population: the Guangzhou biobank cohort study. J Ren Nutr. 2014;24(1):26-31. Xu C, Bi M, Jin X, Zhu M, Wang G, Zhao P, et al. Long-Term Tea Consumption Is Associated with Reduced Risk of Diabetic Retinopathy: A Cross-Sectional Survey among Elderly Chinese from Rural Communities. J Diabetes Res. 2020;2020:1860452. Zhang Y, Wang R, Tang X, Wang Y, Guo P, Wang S, et al. A Mendelian Randomization Study of the Effect of Tea Intake on Type 2 Diabetes. Front Genet. 2022;13:835917. Athyros VG, Liberopoulos EN, Mikhailidis DP, Papageorgiou AA, Ganotakis ES, Tziomalos K, et al. Association of drinking pattern and alcohol beverage type with the prevalence of metabolic syndrome, diabetes, coronary heart disease, stroke, and peripheral arterial disease in a Mediterranean cohort. Angiology. 2007;58(6):689-97. Yang S, Wang S, Yang B, Zheng J, Cai Y, Yang Z. Alcohol Consumption Is a Risk Factor for Lower Extremity Arterial Disease in Chinese Patients with T2DM. J Diabetes Res. 2017;2017:8756978. Vliegenthart R, Geleijnse JM, Hofman A, Meijer WT, van Rooij FJ, Grobbee DE, et al. Alcohol consumption and risk of peripheral arterial disease: the Rotterdam study. Am J Epidemiol. 2002;155(4):332-8. Beulens JW, Kruidhof JS, Grobbee DE, Chaturvedi N, Fuller JH, Soedamah-Muthu SS. Alcohol consumption and risk of microvascular complications in type 1 diabetes patients: the EURODIAB Prospective Complications Study. Diabetologia. 2008;51(9):1631-8. Fenwick EK, Xie J, Man RE, Lim LL, Flood VM, Finger RP, et al. Moderate consumption of white and fortified wine is associated with reduced odds of diabetic retinopathy. J Diabetes Complications. 2015;29(8):1009-14. Chen C, Sun Z, Xu W, Tan J, Li D, Wu Y, et al. Associations between alcohol intake and diabetic retinopathy risk: a systematic review and meta-analysis. BMC Endocr Disord. 2020;20(1):106. Lee CC, Stolk RP, Adler AI, Patel A, Chalmers J, Neal B, et al. Association between alcohol consumption and diabetic retinopathy and visual acuity-the AdRem Study. Diabet Med. 2010;27(10):1130-7. Harjutsalo V, Feodoroff M, Forsblom C, Groop PH. Patients with Type 1 diabetes consuming alcoholic spirits have an increased risk of microvascular complications. Diabet Med. 2014;31(2):156-64. Evans DM, Davey Smith G. Mendelian Randomization: New Applications in the Coming Age of Hypothesis-Free Causality. Annu Rev Genomics Hum Genet. 2015;16:327-50. Li P, Wang H, Guo L, Gou X, Chen G, Lin D, et al. Association between gut microbiota and preeclampsia-eclampsia: a two-sample Mendelian randomization study. BMC Med. 2022;20(1):443. Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol. 2013;37(7):658-65. Brion MJ, Shakhbazov K, Visscher PM. Calculating statistical power in Mendelian randomization studies. Int J Epidemiol. 2013;42(5):1497-501. Burgess S, Dudbridge F, Thompson SG. Combining information on multiple instrumental variables in Mendelian randomization: comparison of allele score and summarized data methods. Stat Med. 2016;35(11):1880-906. Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol. 2015;44(2):512-25. Bowden J, Davey Smith G, Haycock PC, Burgess S. Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator. Genet Epidemiol. 2016;40(4):304-14. Verbanck M, Chen CY, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet. 2018;50(5):693-8. Bowden J, Del Greco MF, Minelli C, Zhao Q, Lawlor DA, Sheehan NA, et al. Improving the accuracy of two-sample summary-data Mendelian randomization: moving beyond the NOME assumption. Int J Epidemiol. 2019;48(3):728-42. Hemani G, Bowden J, Davey Smith G. Evaluating the potential role of pleiotropy in Mendelian randomization studies. Hum Mol Genet. 2018;27(R2):R195-r208. Hemani G, Tilling K, Davey Smith G. Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet. 2017;13(11):e1007081. Den Hartogh DJ, Tsiani E. Health Benefits of Resveratrol in Kidney Disease: Evidence from In Vitro and In Vivo Studies. Nutrients. 2019;11(7). Zhang T, Chi Y, Kang Y, Lu H, Niu H, Liu W, et al. Resveratrol ameliorates podocyte damage in diabetic mice via SIRT1/PGC-1α mediated attenuation of mitochondrial oxidative stress. J Cell Physiol. 2019;234(4):5033-43. Kitada M, Kume S, Imaizumi N, Koya D. Resveratrol improves oxidative stress and protects against diabetic nephropathy through normalization of Mn-SOD dysfunction in AMPK/SIRT1-independent pathway. Diabetes. 2011;60(2):634-43. Zeng K, Wang Y, Huang L, Song Y, Yu X, Deng B, et al. Resveratrol inhibits neural apoptosis and regulates RAX/P-PKR expression in retina of diabetic rats. Nutr Neurosci. 2022;25(12):2560-9. Soufi FG, Mohammad-Nejad D, Ahmadieh H. Resveratrol improves diabetic retinopathy possibly through oxidative stress - nuclear factor κB - apoptosis pathway. Pharmacol Rep. 2012;64(6):1505-14. Higashi Y, Higashi K, Mori A, Sakamoto K, Ishii K, Nakahara T. Anti-cataract Effect of Resveratrol in High-Glucose-Treated Streptozotocin-Induced Diabetic Rats. Biol Pharm Bull. 2018;41(10):1586-92. Fernandes I, Pérez-Gregorio R, Soares S, Mateus N, de Freitas V. Wine Flavonoids in Health and Disease Prevention. Molecules. 2017;22(2). Rossino MG, Casini G. Nutraceuticals for the Treatment of Diabetic Retinopathy. Nutrients. 2019;11(4). Liu F, Ma Y, Xu Y. Taxifolin Shows Anticataractogenesis and Attenuates Diabetic Retinopathy in STZ-Diabetic Rats via Suppression of Aldose Reductase, Oxidative Stress, and MAPK Signaling Pathway. Endocr Metab Immune Disord Drug Targets. 2020;20(4):599-608. Liu F, Nie J, Deng MG, Yang H, Feng Q, Yang Y, et al. Dietary flavonoid intake is associated with a lower risk of diabetic nephropathy in US adults: data from NHANES 2007-2008, 2009-2010, and 2017-2018. Food Funct. 2023;14(9):4183-90. Li YX, Lu YP, Tang D, Hu B, Zhang ZY, Wu HW, et al. Anthocyanin improves kidney function in diabetic kidney disease by regulating amino acid metabolism. J Transl Med. 2022;20(1):510. Hu T, Yue J, Tang Q, Cheng KW, Chen F, Peng M, et al. The effect of quercetin on diabetic nephropathy (DN): a systematic review and meta-analysis of animal studies. Food Funct. 2022;13(9):4789-803. Al-Dosari DI, Ahmed MM, Al-Rejaie SS, Alhomida AS, Ola MS. Flavonoid Naringenin Attenuates Oxidative Stress, Apoptosis and Improves Neurotrophic Effects in the Diabetic Rat Retina. Nutrients. 2017;9(10). Ola MS, Ahmed MM, Ahmad R, Abuohashish HM, Al-Rejaie SS, Alhomida AS. Neuroprotective Effects of Rutin in Streptozotocin-Induced Diabetic Rat Retina. J Mol Neurosci. 2015;56(2):440-8. Kumar B, Gupta SK, Srinivasan BP, Nag TC, Srivastava S, Saxena R, et al. Hesperetin rescues retinal oxidative stress, neuroinflammation and apoptosis in diabetic rats. Microvasc Res. 2013;87:65-74. Li D, Yang F, Cheng H, Liu C, Sun M, Wu K, et al. Protective effects of total flavonoids from Flos Puerariae on retinal neuronal damage in diabetic mice. Mol Vis. 2013;19:1999-2010. Silva KC, Rosales MA, Hamassaki DE, Saito KC, Faria AM, Ribeiro PA, et al. Green tea is neuroprotective in diabetic retinopathy. Invest Ophthalmol Vis Sci. 2013;54(2):1325-36. Al-Dosary DI, Alhomida AS, Ola MS. Protective Effects of Dietary Flavonoids in Diabetic Induced Retinal Neurodegeneration. Curr Drug Targets. 2017;18(13):1468-76. Ouyang H, Du A, Zhou L, Zhang T, Lu B, Wang Z, et al. Chlorogenic acid improves diabetic retinopathy by alleviating blood-retinal-barrier dysfunction via inducing Nrf2 activation. Phytother Res. 2022;36(3):1386-401. Mei X, Zhou L, Zhang T, Lu B, Sheng Y, Ji L. Chlorogenic acid attenuates diabetic retinopathy by reducing VEGF expression and inhibiting VEGF-mediated retinal neoangiogenesis. Vascul Pharmacol. 2018;101:29-37. Deng X, Sun L, Lai X, Xiang L, Li Q, Zhang W, et al. Tea Polypeptide Ameliorates Diabetic Nephropathy through RAGE and NF-κB Signaling Pathway in Type 2 Diabetes Mice. J Agric Food Chem. 2018;66(45):11957-67. Chen X, Sun L, Li D, Lai X, Wen S, Chen R, et al. Green tea peptides ameliorate diabetic nephropathy by inhibiting the TGF-β/Smad signaling pathway in mice. Food Funct. 2022;13(6):3258-70. Yokozawa T, Nakagawa T, Oya T, Okubo T, Juneja LR. Green tea polyphenols and dietary fibre protect against kidney damage in rats with diabetic nephropathy. J Pharm Pharmacol. 2005;57(6):773-80. Ladeira LCM, Dos Santos EC, Santos TA, da Silva J, Lima GDA, Machado-Neves M, et al. Green tea infusion prevents diabetic nephropathy aggravation in recent-onset type 1 diabetes regardless of glycemic control. J Ethnopharmacol. 2021;274:114032. Ribaldo PD, Souza DS, Biswas SK, Block K, Lopes de Faria JM, Lopes de Faria JB. Green tea (Camellia sinensis) attenuates nephropathy by downregulating Nox4 NADPH oxidase in diabetic spontaneously hypertensive rats. J Nutr. 2009;139(1):96-100. Yan SJ, Wang L, Li Z, Zhu DN, Guo SC, Xin WF, et al. Inhibition of advanced glycation end product formation by Pu-erh tea ameliorates progression of experimental diabetic nephropathy. J Agric Food Chem. 2012;60(16):4102-10. Sun W, Liu X, Zhang H, Song Y, Li T, Liu X, et al. Epigallocatechin gallate upregulates NRF2 to prevent diabetic nephropathy via disabling KEAP1. Free Radic Biol Med. 2017;108:840-57. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S17-s38. Additional Declarations No competing interests reported. Supplementary Files alcohol.csv tea.csv Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3767369","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":264615398,"identity":"78778ab2-9e7e-4bde-a62e-c7c507aa7030","order_by":0,"name":"Ming-Jie Jia","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA80lEQVRIiWNgGAWjYFACxuaHHyps5BjbGxsOfDCwsSNCC3ObscSZNGPmnsMHD84oSEsmQgt7gwRv2+FE9hluyYd5PhxibCCkweB4YoOBBBtzAu8MHoPDNgYHmBnYDx/dgFfLmYcNDwp42PIkZ/cYHM4xuMPHwJOWdgOvlhsgWyR4ig3nnAFpecbMIMFjRlCLBI+BROL+GzkGhy0MDjM2EKclwSCxcUZawmEGYrRInnkIDOQDCcaMPYcPHOwxSEtmI+QXvuPpjx9+/PcfFJXNH378sbHjZz98DK8WhQMJaCJs+JSDgHwDupZRMApGwSgYBegAAKNwWD2Or3h5AAAAAElFTkSuQmCC","orcid":"","institution":"The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine","correspondingAuthor":true,"prefix":"","firstName":"Ming-Jie","middleName":"","lastName":"Jia","suffix":""}],"badges":[],"createdAt":"2023-12-17 13:14:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3767369/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3767369/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":49135483,"identity":"71f11bb9-721c-4f0a-b1a7-394775b962f5","added_by":"auto","created_at":"2024-01-03 17:06:28","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":147825,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlow chart\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-3767369/v1/2daeadb8d6cba9e7c60f3d76.png"},{"id":49135481,"identity":"d94b05a1-6102-4247-8eff-3bc108108ca9","added_by":"auto","created_at":"2024-01-03 17:06:28","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":427094,"visible":true,"origin":"","legend":"\u003cp\u003eScatterplot of the causal relationship between tea and alcohol consumption and diabetes mellitus.\u003cstrong\u003e (A)\u003c/strong\u003e Scatterplot of MR analysis of alcohol intake and type 2 diabetes mellitus with other specified/multiple/unspecified comorbidities. \u003cstrong\u003e(B) \u003c/strong\u003eScatterplot of MR Analysis of Alcohol Intake and Type 2 Diabetes Mellitus with Ocular Complications.\u003cstrong\u003e (C) \u003c/strong\u003eScatterplot of MR Analysis of Alcohol Intake and Type 2 Diabetes Mellitus with Renal Complications.\u003cstrong\u003e (D)\u003c/strong\u003e Scatterplot of MR analysis of tea intake and type 1 diabetes mellitus with neurological complications.\u003cstrong\u003e (E) \u003c/strong\u003eScatterplot of MR analysis of tea intake and type 1 diabetes mellitus with peripheral circulatory complications.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-3767369/v1/d3137745d292dd75cdc3fb91.png"},{"id":49135479,"identity":"40554ee2-a3e9-4d47-983e-3b00785151fd","added_by":"auto","created_at":"2024-01-03 17:06:28","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":194520,"visible":true,"origin":"","legend":"\u003cp\u003eFunnel plots for assessing the degree of bias in instrumental variables.\u003cstrong\u003e (A) \u003c/strong\u003eFunnel plots of alcohol intake and type 2 diabetes mellitus with other specified/multiple/unspecified comorbidities. \u003cstrong\u003e(B) \u003c/strong\u003eFunnel plots of Alcohol Intake and Type 2 Diabetes Mellitus with Ocular Complications.\u003cstrong\u003e (C) \u003c/strong\u003eFunnel plots of Alcohol Intake and Type 2 Diabetes Mellitus with Renal Complications. \u003cstrong\u003e(D)\u003c/strong\u003e Funnel plots of tea intake and type 1 diabetes mellitus with neurological complications.\u003cstrong\u003e (E) \u003c/strong\u003eFunnel plots of tea intake and type 1 diabetes mellitus with peripheral circulatory complications.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-3767369/v1/b200c99c40e0383f5c3552a2.png"},{"id":49136035,"identity":"f8ea58e9-b78d-4b7e-8464-4b84407915fb","added_by":"auto","created_at":"2024-01-03 17:14:28","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":567390,"visible":true,"origin":"","legend":"\u003cp\u003eEvaluating MR results for the remaining instrumental variables after removing SNPs from the instrumental variables one by one.\u003cstrong\u003e (A)\u003c/strong\u003e Tree diagrams for alcohol intake and type 2 diabetes mellitus with other specified/multiple/unspecified comorbidities. \u003cstrong\u003e(B) \u003c/strong\u003eTree diagrams for Alcohol Intake and Type 2 Diabetes Mellitus with Ocular Complications.\u003cstrong\u003e (C) \u003c/strong\u003eTree diagrams for Alcohol Intake and Type 2 Diabetes Mellitus with Renal Complications.\u003cstrong\u003e (D)\u003c/strong\u003e Tree diagrams for tea intake and type 1 diabetes mellitus with neurological complications. \u003cstrong\u003e(E) \u003c/strong\u003eTree diagrams for tea intake and type 1 diabetes mellitus with peripheral circulatory complications.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-3767369/v1/41938a5b0188eac04aadbacf.png"},{"id":49348119,"identity":"9a93885e-91bd-4d99-ab91-f218d28bd820","added_by":"auto","created_at":"2024-01-09 05:37:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":949703,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3767369/v1/53cf5450-8964-4815-9f4d-5aa133068199.pdf"},{"id":49135485,"identity":"427ff13a-1ce0-4396-a4a1-ca3ff01c4904","added_by":"auto","created_at":"2024-01-03 17:06:28","extension":"csv","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":10654,"visible":true,"origin":"","legend":"","description":"","filename":"alcohol.csv","url":"https://assets-eu.researchsquare.com/files/rs-3767369/v1/cb65b7a0bf475036c11ea80d.csv"},{"id":49136036,"identity":"d8ceaa30-a0d2-4d6d-a53a-4d851e0efa33","added_by":"auto","created_at":"2024-01-03 17:14:28","extension":"csv","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":4554,"visible":true,"origin":"","legend":"","description":"","filename":"tea.csv","url":"https://assets-eu.researchsquare.com/files/rs-3767369/v1/b5f1bc6e31ff2bf604866098.csv"}],"financialInterests":"No competing interests reported.","formattedTitle":"Association between tea intake and alcohol consumption and diabetes complications: A two sample Mendelian randomization study","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eDiabetes is a serious metabolic disorder with an increasing incidence rate. It is estimated that by 2030, there will be over 578\u0026nbsp;million people worldwide affected by diabetes(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). As the diabetes progresses, patients may gradually develop various vascular complications, including macrovascular diseases such as cerebrovascular disease, cardiovascular disease, and peripheral vascular disease, as well as microvascular diseases such as diabetic nephropathy, retinopathy, and neuropathy(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Among adults (aged 20\u0026ndash;79) with diabetes worldwide, diabetic vascular complications are the leading cause of death(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).Among the numerous complications associated with diabetes, diabetic neuropathy caused by damage to the peripheral and autonomic nervous systems is the most common (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). According to the International Diabetes Federation, it is estimated that by 2050, half of the individuals with type 2 diabetes will develop some form of neuropathy without effective intervention (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). The main types of nerve damage in diabetic neuropathy include distal symmetric polyneuropathy, small-fiber-predominant neuropathy, radiculoplexopathy, and mononeuropathy (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). These syndromes lead to a high incidence of morbidity, increased mortality, and pain in patients (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).Peripheral artery disease (PAD) is a chronic arterial occlusive disease of the lower limbs, and it is particularly closely associated with diabetes. Approximately 20\u0026ndash;30% of individuals with PAD also have diabetes(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). The incidence of PAD is 2 to 4 times higher in patients with type 2 diabetes compared to non-diabetic individuals(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). As the duration of diabetes progresses, the prevalence of PAD also increases(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Furthermore, diabetes exacerbates the severity of PAD, augmenting the risk of severe complications such as amputation(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eEpidemiological studies have shown that the global prevalence of diabetic retinopathy (DR) among diabetes patients is 22.27%. It is estimated that in 2020, there were approximately 103.12\u0026nbsp;million adults worldwide with DR, and this number is projected to increase to 165\u0026nbsp;million by 2045 (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Almost all individuals with type 1 diabetes (T1D) and 60% of those with type 2 diabetes (T2D) will develop diabetic retinopathy within 20 years of having diabetes (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). DR can lead to progressive visual impairment and is one of the leading causes of preventable blindness among working-age populations. Additionally, DR increases the risk of severe systemic vascular complications such as stroke and coronary heart disease (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Diabetic nephropathy (DN) is characterized by persistent albuminuria and subsequent decline in glomerular filtration rate. Ultimately, diabetic patients may progress to develop end-stage renal disease (ESRD) (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Approximately 30% of individuals with type 1 diabetes and about 40% of those with type 2 diabetes will develop diabetic nephropathy (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Diabetic nephropathy has become a major cause of end-stage renal disease globally and is also a risk factor for cardiovascular disease (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Multiple studies have shown that DN patients have a significantly increased risk of adverse cardiovascular events, infections, and mortality (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDiabetes and its complications not only significantly impact individuals and families but also have a profound economic impact on society (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Therefore, it is crucial to explore innovative methods for early prevention and intervention of these complications.\u003c/p\u003e \u003cp\u003eTea is one of the most widely consumed beverages in the world.It has numerous health benefits, including antioxidant, anticancer, liver protection, heart health, anti-obesity, gut microbiota improvement, and anti-diabetic effects(\u003cspan additionalcitationids=\"CR23 CR24 CR25 CR26 CR27 CR28\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). It contains many bioactive compounds, which may reduce the risk of diabetes and its complications(\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). A clinical case-control study showed that regular consumption of green tea can lower the risk of diabetic retinopathy by 50% compared to non-consumers(\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). Several studies have demonstrated the protective effects of tea intake against diabetic nephropathy(\u003cspan additionalcitationids=\"CR33\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e).A randomized controlled trial has demonstrated the therapeutic value of green tea extract in the treatment of diabetic peripheral neuropathy (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). Animal experimental results suggest that Epigallocatechin-3-O-gallate, a bioactive compound in green tea, has beneficial effects in lowering blood glucose, reducing blood lipids, and exhibiting antioxidative and anti-inflammatory properties. This may prevent the occurrence and development of diabetic neuropathic pain (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). Additionally, observational studies have found that drinking more than 150 milliliters of tea per day for at least one year may reduce arterial stiffness compared to non-tea drinkers (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e). This may contribute to the alleviation of peripheral artery disease .\u003c/p\u003e \u003cp\u003eNevertheless, the research results regarding the causal relationship between tea consumption and vascular complications of diabetes are inconsistent. A longitudinal study conducted in Iran revealed that high consumption of tea leaves was not associated with an increased risk of chronic kidney disease (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e). Another study also suggested that there was no significant correlation between tea intake and changes in estimated glomerular filtration rate (eGFR) (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). Furthermore, the results of a prospective cohort study further indicated that tea intake was unrelated to the risk of end-stage renal disease (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e).A cohort study involving 12,428 older adults did not find a significant association between green or black tea consumption and glomerular filtration rate(\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e).A cross-sectional study found no significant correlation between tea drinking frequency, type, and the risk of DR (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e). A recent Mendelian randomization study did not provide genetic evidence for causality between tea intake and type 2 diabetes or several glycemic traits, including HbA1c, FPG, and HOMA-IR levels. Therefore, evidence supporting tea consumption as a preventive measure for T2D remains insufficient (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe causal relationship between alcohol and complications of diabetes is also subject to debate. In the Mediterranean population, moderate alcohol consumption has been associated with a lower prevalence of peripheral artery disease (PAD) compared to non-drinkers. However, heavy alcohol consumption is associated with an increased risk of PAD (\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e). Yang et al. suggest that alcohol consumption may be a risk factor for lower limb arterial disease in patients with type 2 diabetes (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e). On the other hand, a cross-sectional study found a negative correlation between alcohol consumption and peripheral artery disease in non-smoking men and women (\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e). A prospective study found that moderate alcohol consumption is negatively correlated with the risk of neuropathy and proliferative retinopathy in patients with type 1 diabetes (\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e). Another cross-sectional study found a significant association between moderate alcohol consumption and a reduced incidence of diabetic retinopathy in patients with type 2 diabetes compared to non-drinkers (\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e). However, a meta-analysis revealed no significant association between alcohol intake and the risk of diabetic retinopathy (\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e). Another observational study reported an increased risk of visual impairment associated with alcohol consumption in patients with type 2 diabetes but found no association with retinopathy (\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e). A cross-sectional study found that alcohol drinkers have a higher risk of diabetic nephropathy and severe retinopathy in patients with type 1 diabetes (\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e). Consequently, comprehending the causal relationship between tea, alcohol, and complications of diabetes is crucial for directing lifestyle interventions designed to mitigate diabetes-related complications in diabetic patients.\u003c/p\u003e \u003cp\u003eMendelian randomization (MR) is a statistical technique that uses single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) to infer causal relationships between exposures and outcomes. Since genetic variations are randomly allocated during gamete formation and are largely unaffected by environmental or lifestyle factors, MR can mitigate confounding factors and reverse causality in causal inference. In this study, a two-sample Mendelian randomization method was employed, utilizing publicly available large-scale genome-wide association study (GWAS) databases, to explore the causal relationships between tea consumption, alcohol intake, and diabetes, as well as its complications.\u003c/p\u003e"},{"header":"2 Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n\u003ch2\u003e2.1 Data Collection\u003c/h2\u003e\n\u003cp\u003eGWAS data for Diabetic Nephropathy (DN), Diabetic Retinopathy (DR) and different subtypes of the disease based on previous studies were used as the outcome factors for this study, which can be found in the table below. The ending factors mainly include diabetes complicating peripheral circulatory system complications, diabetes complicating peripheral neuropathy, DN, DR and diabetes complicating various other complications. SNPs associated with alcohol intake were screened as instrumental table sizes using genome-wide association studies (GWAS) published in the \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://gwas.mrcieu.ac.uk/\u003c/span\u003e\u003c/span\u003e, Finland database as a reference. Both exposure and outcome cohorts were restricted to subjects of European ancestry to minimize population stratification bias. All original studies included in this MR have been approved by the ethics committees of their institutions, respectively. In addition, informed consent was already obtained from relevant participants in the original studies. Therefore, no further ethical approval was required for the present MR analysis.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003ePublicly available exposure data\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eDisease categories\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ePhenocode\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eAncestry\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003enum_cases\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003enum_controls\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eProliferative diabetic retinopathy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003efinngen_R9_DM_RETINA_PROLIF\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEuropean\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e9511\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e362581\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDiabetes endpoints\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003efinngen_R9_DM_RETINOPATHY_EXMORE\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEuropean\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e10413\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e308633\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eType 1 diabetes with other specified/multiple/unspecified complications\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003efinngen_R9_E4_DM1NASCOMP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEuropean\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e6234\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e308280\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eType 1 diabetes with neurological complications\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003efinngen_R9_E4_DM1NEU\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEuropean\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1077\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e308280\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eType 1 diabetes with ophthalmic complications\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003efinngen_R9_E4_DM1OPTH\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEuropean\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e5202\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e308280\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eType 1 diabetes with peripheral circulatory complications\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003efinngen_R9_E4_DM1PERIPH\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEuropean\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e669\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e308280\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eType 1 diabetes with renal complications\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003efinngen_R9_E4_DM1REN\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEuropean\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1579\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e308280\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eType 2 diabetes with other specified/multiple/unspecified complications\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003efinngen_R9_E4_DM2NASCOMP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEuropean\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e46373\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e308280\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eType 2 diabetes with neurological complications\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003efinngen_R9_E4_DM2NEU\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEuropean\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1894\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e308280\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eType 2 diabetes with ophthalmic complications\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003efinngen_R9_E4_DM2OPTH\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEuropean\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e4172\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e308280\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eType 2 diabetes with peripheral circulatory complications\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003efinngen_R9_E4_DM2PERIPH\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEuropean\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2179\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e308280\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eType 2 diabetes with renal complications\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003efinngen_R9_E4_DM2REN\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEuropean\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2684\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e308280\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDiabetic background retinopathy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003efinngen_R9_H7_RETINOPATHYDIAB_BKG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEuropean\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e4011\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e344569\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003ch2\u003e2.2 Study Design\u003c/h2\u003e\n\u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, we used MR analysis to examine the causal relationship between alcohol intake and DN, DR, and different subtypes of the disease. The instrumental variables for MR analysis needed to fulfill three assumptions: i) causally related to exposure, ii) independent of confounders, and iii) affecting outcomes only through exposure (\u003cspan class=\"CitationRef\"\u003e54\u003c/span\u003e). Instrumental variables were extracted from alcohol intake according to harmonized criteria set at a genome-wide significance level of p\u0026thinsp;\u0026lt;\u0026thinsp;5 \u0026times; 10\u0026thinsp;\u0026minus;\u0026thinsp;8 (\u003cspan class=\"CitationRef\"\u003e55\u003c/span\u003e). The 71 SNPs were included in the alcohol intake dataset. Next, we performed linkage disequilibrium (LD) clustering analyses using the 1000 Genomes Project Phase III (EUR) as a reference panel to identify independent SNPs (r2\u0026thinsp;\u0026lt;\u0026thinsp;0.001 in the 10,000 kb range). The exposure dataset and the outcome dataset were harmonized by the R \"harmonise_data\" function and paired SNPs with intermediate allele frequencies were excluded. For SNPs that were not present in the outcome dataset, no substitution SNPs were sought. The F-statistic was used to assess the strength of the instrumental variables for each species, and instrumental variables were considered to be sufficiently strong if F was greater than 10 (\u003cspan class=\"CitationRef\"\u003e56\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e57\u003c/span\u003e). None of the instrumental variables included in this study were \"weak\" instrumental variables (F statistic greater than 10).\u003c/p\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n\u003ch2\u003e2.3\u0026nbsp;\u003cem\u003eStatistical Analysis\u003c/em\u003e\u003c/h2\u003e\n\u003cp\u003eMultiple methods have been used to assess whether there is a causal relationship between alcohol intake and DN, DR, and different subtypes of the disease, including the MR Egger method, the weighted median method, the inverse variance weighting method, the simple model method, and the weighted model method. The IVW method uses a meta-analysis approach to combine the Wald estimates of each SNP to derive an overall estimate of the effect of alcohol intake on disease (\u003cspan class=\"CitationRef\"\u003e58\u003c/span\u003e). This method relies on all SNPs and is efficient in estimation which was chosen as the main method for this study (\u003cspan class=\"CitationRef\"\u003e56\u003c/span\u003e). However, the results of IVW are stable only when there is no horizontal pleiotropy. Based on the assumption that instrumental strength is independent of direct effect (InSIDE), MR-Egger can utilize the intercept to assess horizontal pleiotropy (\u003cspan class=\"CitationRef\"\u003e59\u003c/span\u003e). The MR egger method is preferred when horizontal pleiotropy is present. If more than 50% of the instrumental variables are invalid, the weighted median method is used to assess causality (\u003cspan class=\"CitationRef\"\u003e60\u003c/span\u003e). The weighted median method was preferred when heterogeneity existed. In addition, these five methods must be oriented in the same direction. the MR-PRESSO analysis method assesses and reduces horizontal multidimensionality by detecting and excluding outliers (\u003cspan class=\"CitationRef\"\u003e61\u003c/span\u003e). Cochran's IVW Q statistic is used to assess heterogeneity of instrumental variable (\u003cspan class=\"CitationRef\"\u003e62\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eTo identify potentially heterogeneous SNPs, we performed a \"leave-one-out\" analysis (\u003cspan class=\"CitationRef\"\u003e63\u003c/span\u003e). By excluding each instrumental variable in turn, we observed stable results for the MR analysis.For dichotomous variables, the odds ratio was used as the outcome. For continuous variables, \u0026beta; values were used as the results. F statistical formula: F\u0026thinsp;=\u0026thinsp;beta^2/se^2. For each statistical test, we consider an overall significance level of P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 to be satisfactory. The data were analyzed using the R software (version 4.1.3). MR analyses were performed using the \"TwosampleMR\" R software package (\u003cspan class=\"CitationRef\"\u003e64\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"3 Result","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n\u003ch2\u003e3.1 Causal relationship between tea and alcohol intake and disease\u003c/h2\u003e\n\u003cp\u003eAlcohol intake was found to be causally associated with Type 2 diabetes with other specified/multiple/unspecified complications, Type 2 diabetes with ophthalmic complications and Type 2 diabetes with renal complications. A causal relationship was found between tea intake and Type 1 diabetes with neurological complications and Type 1 diabetes with peripheral circulatory complications (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). IVW method to assess the existence of the causal relationship between Type 2 diabetes with other specified/multiple/unspecified complications (odds ratio\u0026thinsp;=\u0026thinsp;0.80, 95% confidence interval: 0.66\u0026ndash;0.97), Type 2 diabetes with ophthalmic complications (odds ratio\u0026thinsp;=\u0026thinsp;0.62, 95% confidence interval: 0.43\u0026ndash;0.88), Type 2 diabetes with renal complications (odds ratio\u0026thinsp;=\u0026thinsp;0.52, 95% confidence interval: 0.35\u0026ndash;0.78) and alcohol intake. IVW method to assess the existence of the causal relationship between Type 1 diabetes with neurological complications (odds ratio\u0026thinsp;=\u0026thinsp;0.26, 95% confidence interval: 0.07\u0026ndash;0.90), Type 1 diabetes with peripheral circulatory complications (odds ratio\u0026thinsp;=\u0026thinsp;0.22, 95% confidence interval: 0.05\u0026ndash;0.91) and tea intake. And there is no causal relationship between other diabetic complications and alcohol and tea intake.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n\u003ch2\u003e3.2 Sensitivity analysis\u003c/h2\u003e\n\u003cp\u003eFirst, Cochran's Q test (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05) as well as the funnel plot suggested that there was no heterogeneity (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Leave-one-out assay reveals aberrant SNP loci for causal analysis of alcohol intake and type 2 diabetes with other specified/multiple/unspecified complications (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). Meanwhile, the MR-PRESSO test found horizontal pleiotropy for both alcohol intake and all three exposure factors. Leave-one-out assay reveals aberrant SNP loci for causal analysis of tea intake and Type 1 diabetes with neurological complications, Type 1 diabetes with peripheral circulatory complications. However, the MR-PRESSO test and MR Egger's intercept analysis revealed no horizontal pleiotropy except for Type 1 diabetes with neurological complications and Type 1 diabetes with peripheral circulatory complications. Therefore, it was considered that there was no pleiotropy between Type 1 diabetes with neurological complications, Type 1 diabetes with peripheral circulatory complications, and tea intake.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eTo the best of our knowledge, this study represents the inaugural application of Mendelian randomization (MR) to evaluate the causal links between tea and alcohol consumption and the risk of diabetic complications.Our analysis revealed a causal association between alcohol consumption and various complications of T2D, including specified/multiple/unspecified, ocular, and renal complications.On the other hand, a causal link was observed between tea consumption and type 1 diabetes mellitus, specifically regarding neurological and peripheral circulatory complications.These findings suggest protective effects of tea intake.Furthermore, this Mendelian randomization study exhibited no evidence of selection bias or instrumental weaknesses.\u003c/p\u003e \u003cp\u003eResveratrol constitutes the primary bioactive compound present in wine.Studies have shown that treating animals with resveratrol can reduce hyperglycemia and hyperlipidemia, improve the integrity of kidney structure, and enhance renal function in diabetic nephropathy.Administration of resveratrol has been found to lower urinary albumin and serum creatinine levels in diabetic nephropathy mice, indicating an improvement in renal function.Additionally, the administration of resveratrol has been shown to decrease oxidative stress, reduce inflammatory cell infiltration, lower cytokine production, and diminish malondialdehyde (MAD) levels in the kidneys.Moreover, it enhances the activity of antioxidant enzymes and upregulates the expression of SIRT1.These results indicate that resveratrol treatment may exert protective effects against diabetic nephropathy (\u003cspan additionalcitationids=\"CR64\" citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e).Diabetic retinopathy is characterized by an enhanced inflammatory response, ischemia, advancing degeneration of retinal pigment epithelial cells, blood-retinal barrier dysfunction, and subsequent vision loss (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).Studies on animals indicate that resveratrol potentially inhibits retinal neuronal apoptosis in diabetic rats (\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e).Supplementation with resveratrol significantly lowers blood glucose levels and reduces body weight in diabetic rats.Additionally, it elevates oxidative indices and superoxide dismutase activity in both blood and retina, ameliorates increased NF-κB activity and the rate of cell apoptosis in the retina (\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e), thereby offering protective effects against diabetic retinopathy (DR).Furthermore, resveratrol is capable of decelerating the progression of diabetic cataracts by mitigating oxidative damage to lens proteins (\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFlavonoids represent the primary phenolic compounds present in red wine.The flavonoid content in red wine encompasses flavanols (like catechins), flavonols (such as quercetin and myricetin), and anthocyanins (notably malvidin-3-glucoside) (\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e).In STZ-induced diabetic rats, treatment with different flavonoid compounds has been shown to improve the oxidative-reductive status of the retina, promoting an increase in glutathione and a decrease in lipid peroxidation.Observations also reveal that flavonoids can boost the levels of antioxidant enzymes, including SOD and CAT (\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e).Experimental findings suggest that flavanols exert a positive impact on retinal lesions and cataracts in diabetic rats.The underlying mechanisms are likely linked to the antioxidant properties of flavanols and their ability to inhibit VEGF, ERK1/2, p38MAPK, and aldose reductase (\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e).In conclusion, there is a notable potential for flavonoids present in red wine to offer protective effects against retinopathy in diabetic rats.A recent observational study has shown that increased consumption of flavonoids correlates with a lower risk of diabetic nephropathy (\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e).Studies have demonstrated that anthocyanins enhance kidney function in diabetic nephropathy patients by modulating amino acid metabolism (\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e).A systematic review and meta-analysis of animal research indicates that quercetin could enhance kidney function in diabetic nephropathy animal models, attributed to its antioxidant, anti-inflammatory, anti-fibrotic properties, and the regulation of renal lipid accumulation.This compound has the capability to diminish oxidative stress and inflammatory responses in the kidneys (\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e).Taken together, these studies suggest that flavonoids have protective effects against diabetic nephropathy.These findings provide potential candidates for the development of new therapeutic approaches for diabetic nephropathy.\u003c/p\u003e \u003cp\u003ePrior research has suggested that tea consumption provides protective benefits against complications related to diabetes.A randomized controlled trial has established the efficacy of green tea extract (GTE) intake in the treatment of mild to moderate diabetic peripheral neuropathy (DPN) (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e).The flavonoids present in tea possess potent antioxidant properties and are capable of enhancing apoptotic and neurotrophic factors. They alleviate oxidative stress, thus safeguarding neurons from damage and potentially preventing diabetic retinopathy (\u003cspan additionalcitationids=\"CR76 CR77 CR78 CR79 CR80 CR81\" citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e).Research has demonstrated that both pu-erh tea and green tea exert protective effects against diabetic nephropathy. These benefits may be attributed to various mechanisms, such as the reduction of advanced glycation end-product (AGE) accumulation, enhancement of energy metabolism, and mitigation of oxidative stress(\u003cspan additionalcitationids=\"CR84 CR85 CR86 CR87 CR88\" citationid=\"CR83\" class=\"CitationRef\"\u003e83\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e).These findings offer promising avenues for potential pharmaceutical agents in the development of novel treatments for diabetic nephropathy.\u003c/p\u003e \u003cp\u003eThe varying impacts of tea and alcohol on complications in type 1 and type 2 diabetes can be attributed to the distinct pathogenic mechanisms of T1DM and T2DM.T1DM results from the extensive destruction of pancreatic beta cells, culminating in an absolute insulin deficiency.Conversely, T2DM primarily stems from insulin resistance and the progressive deterioration of insulin secretion (\u003cspan citationid=\"CR90\" class=\"CitationRef\"\u003e90\u003c/span\u003e).Owing to these divergent pathogenic mechanisms, the effects of tea and alcohol on complications may vary between these diabetes subtypes.Furthermore, in contrast to T2DM, which predominantly affects middle-aged and elderly individuals, T1DM typically develops in children and adolescents, who generally have limited exposure to tea and alcohol.This factor might also play a role in elucidating the disparities in their impacts across the different subtypes.\u003c/p\u003e \u003cp\u003eIndeed, Mendelian randomization (MR) studies have yielded results that are inconsistent with those of prior observational studies.Several factors may account for this discrepancy.Firstly, the issues of reverse causality and residual confounding cannot be entirely ruled out in prior observational studies.Secondly, data in previous studies were derived from self-reported tea consumption, potentially leading to misclassification errors due to habitual tea drinking patterns.Consequently, the assessment of long-term tea consumption in observational studies may lack precision.Lastly, the demographic of habitual tea drinkers is not randomly distributed, being somewhat influenced by regional differences in tea consumption and closely linked to variables like age and gender.All these elements could potentially impact the outcomes of previous observational studies.\u003c/p\u003e"},{"header":"5 Conclusion","content":"\u003cp\u003eIn conclusion, our study elucidates the causal relationship between alcohol and tea consumption and the development of diabetes and its complications, as determined through Mendelian randomization (MR) analysis.This insight offers fresh perspectives for subsequent mechanistic research and promotes advocacy for healthier lifestyles.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the participants and researchers of the UK Biobank and FinnGen surveys. Their project is non-profit for public sharing of GWAS summary data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInstitutional Review Board Statement:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe UK Biobank and FinnGen R9 projects were approved by the Ethical Review Board and all participants signed an informed agreement. The study was conducted in accordance with the guidelines of the Declaration of Helsinki, and the utilization of summary level statistics did not require additional ethical review and approval.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe article was not funded.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eExposure data were acquired from the GWAS summary dataset of the UK Biobank project incorporated by the MRCIEU GWAS database (https://gwas.mrcieu.ac.uk/) . Outcome data were obtained from the FinnGen R9 repository (https://r9.finngen.fi/). All data is publicly available.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eM.J. independently completed the experimental design, data collection and manuscript writing.All author have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDuh EJ, Sun JK, Stitt AW. Diabetic retinopathy: current understanding, mechanisms, and treatment strategies. JCI Insight. 2017;2(14).\u003c/li\u003e\n\u003cli\u003eDal Canto E, Ceriello A, Ryd\u0026eacute;n L, Ferrini M, Hansen TB, Schnell O, et al. Diabetes as a cardiovascular risk factor: An overview of global trends of macro and micro vascular complications. 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Diabetes Care. 2022;45(Suppl 1):S17-s38.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"tea, alcohol, diabetes complication, diabetes mellitus, type 1 diabetes, type 2 diabetes","lastPublishedDoi":"10.21203/rs.3.rs-3767369/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3767369/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eStudies have indicated that there is a relationship between tea drinking, alcohol consumption, and a reduced risk of diabetes and its complications. However, there is currently no consensus on the potential relationships between tea drinking, alcohol consumption, and diabetes as well as its complications. In this study, we employed a two-sample Mendelian randomization (MR) analysis for the first time to systematically explore the causal relationships between tea intake, alcohol consumption, and diabetes as well as its complications.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eGenetic instruments for tea drinking were identified from a genome-wide association study (GWAS) involving 447,485 individuals. Genetic instruments for alcohol intake were identified from a GWAS involving 462,346 individuals. Summary data for diabetes and its complications were obtained from various GWAS meta-analyses. Causal effects between tea drinking, alcohol consumption, and diabetes as well as its complications were examined. Inverse variance-weighted Mendelian randomization (MR) analysis was conducted as the primary method for causal inference. Further sensitivity analyses were performed to ensure the robustness of the results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThe IVW assessment showed a causal relationship between alcohol intake and three diabetic complications. Type 2 diabetes with other specified/multiple/unspecified complications , Type 2 diabetes with ophthalmic complications and Type 2 diabetes with renal complications indicated an association with alcohol intake. However, there was horizontal pleiotropy in the study of alcohol intake and three diabetic complications, making the conclusions unreliable. The IVW assessment showed a causal relationship between tea intake and two diabetic complications. Type 1 diabetes with neurological complications, Type 1 diabetes with peripheral circulatory complications showed an association with tea intake.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eOur research shows that tea and alcohol consumption have a protective effect against diabetic complications.This research contributes to a deeper understanding of dietary influences on diabetes, offering potential directions for future research and public health advocacy.\u003c/p\u003e","manuscriptTitle":"Association between tea intake and alcohol consumption and diabetes complications: A two sample Mendelian randomization study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-03 17:06:23","doi":"10.21203/rs.3.rs-3767369/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cabd0227-b1ec-4dcb-b39c-67e7ff4a1a3e","owner":[],"postedDate":"January 3rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":27884170,"name":"Health sciences/Endocrinology"},{"id":27884171,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2024-01-09T05:29:19+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-03 17:06:23","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3767369","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3767369","identity":"rs-3767369","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}