The Effects And Mechanisms Of Sweet Beverage Consumptions On Cardiometabolic Diseases

Background: With the acceleration of population aging,cardiometabolic diseases(CMD,including coronary heart disease,hypertension,stroke,and diabetes in our study)have become the leading cause of the global disease burden.The coexistence of two or more CMD is increasingly common,forming cardiometabolic multimorbidity(CMM),which seriously threatens patient prognosis.Sweet beverages,including sugar-sweetened beverages(SSB),artificially-sweetened beverages(ASB),and pure vegetable/fruit juices,have been found to be associated with various CMD.However,previous studies mainly focused on the association between sweet beverages consumption and separate CMD risks in healthy populations.The study on the role of sweet beverages consumption in the entire disease process of CMD is lack.The main sugar ingredient in SSB is high-fructose corn syrup(HFCS),which consists of 55% fructose and 45% glucose.Previous studies have suggested that potential mechanism underlying the association between SSB consumption and CMD risks may be related to the simultaneous consumption of glucose and fructose,but the molecular mechanisms are not fully understood.Method: Our study population was from a large-scale,population-based prospective cohort UK Biobank(UKB),which enrolled over 500,000 individuals aged 40 to 69 among UK.The consumption of sweet beverages was obtained from five 24-hour dietary recall questionnaires completed by participants.Participants were divided into three groups according to their sweet beverages’ consumption: 0serving/day,0-1 serving/day and >1 serving/day.Our study explored the association between sweet beverages and CMD risks through epidemiological study and mechanism study:(1)Using competing risk model,we analyzed the associations between three types of sweet beverages and the risk of first single CMD among participants without any history of CMD.We investigated the role of sweet beverages in the process from healthy to first single CMD.(2)Using competing risk model,we also analyzed the associations between three types of sweet beverages and the risk of CMM among participants with their first single CMD.We investigated the role of sweet beverages in the process from first single CMD to CMM.(3)Using multivariable Cox regression model,we analyzed the associations between three types of sweet beverages and all-cause mortality,cardiovascular mortality and cancer mortality among CMM patients.We investigated the role of sweet beverages in the process from CMM to death.(4)We established a model simulating high SSB intake by adding glucose and fructose to drinking water as an HFCS solution in C57BL6/J male mice.Phenotype changes,tissue staining,serum lipid profiling and gene expression profiling were detected to investigate the effect of HFCS intake on the cardiometabolic system.Human umbilical vein endothelial cells(HUVEC)or cardiomyocytes(H9C2)were treated with mixed monosaccharides(glucose and fructose)with concentrations of 0 m M,10 m M,20 m M and 30 m M.The effects of high concentrations of monosaccharides on endothelial cells or cardiomyocytes were observed through RT-PCR,Western blotting and fluorescent gene reporter experiments.Results:(1)Among participants without any history of CMD,SSB >1serving/day had a 16% higher risk of first single CMD incidence.The highest intake of ASB(>1 serving/day)was associated with a 16%increased risk of first single CMD incidence.Lower levels of pure fruit/vegetable juice intake(0-1 serving/day)were associated with a 6%decreased risk of first single CMD incidence,while higher levels of pure fruit/vegetable juice intake(>1 serving/day)had a marginal association with the risk of first single CMD incidence.(2)Among participants with their first single CMD,SSB consumption of >1 serving/day had a 19% higher risk of CMM incidence.ASB consumption of >1 serving/day was associated with a 15%increased risk of CMM incidence.Both lower and higher levels of pure fruit/vegetable juice intake were associated with a 10% decreased risk of CMM incidence.(3)Among CMM patients,SSB >1 serving/day had a 52% increased risk of cardiovascular death.We did not observe statistically significant associations between intake of ASB and pure fruit/vegetable juices and the risk of cardiovascular or cancer mortality.(4)Mice drinking water with added HFCS solution showed significant weight gain,increased weight of visceral adipose tissue and liver.Histological staining of tissue showed thickening of the intima of the arteries,connective tissue proliferation and scattered foam cells in mice with HFCS solution.Serum lipid profiling analysis revealed increased levels of serum triglycerides,total cholesterol and low-density lipoprotein cholesterol and decreased high-density lipoprotein cholesterol levels.Gene expression chip analysis showed that 41 genes were significantly upregulated and 37 genes were significantly downregulated in the heart tissue of mice with HFCS solution.After treating HUVECs with high concentrations of monosaccharides,we found that they had a certain inhibitory effect on endothelial cell proliferation,targeting MAPK pathway.High concentrations of monosaccharides treatment could also induce apoptosis in endothelial cells and apoptosis in a mitochondrial-dependent manner.Glucose and fructose treatment promoted the production of reactive oxygen species(ROS)in endothelial cells and activated the Nrf2 signaling pathway to participate in oxidative stress damage in endothelial cells.Additionally,it enhanced the transcriptional activity of AP-1 and NF-κB in endothelial cells,which promoted the expression of inflammatory cytokines such as IL-1β and IL-6.High concentration of monosaccharidess could inhibit the cardiomyocytes and induce apoptosis of cardiomyocytes.High concentration of monosaccharides could induce cardiomyocytes to produce ROS and regulated oxidative stress pathway in the cardiomyocytes.Conclusion:(1)Highest SSB consumption is associated with an increased risk of first single CMD in healthy individuals,as well as an increased risk of CMM in patients with their first single CMD and higher risk of cardiovascular mortality in CMM patients.SSB show adverse effects in the entire process of CMD trajectory.ASB consumption also linked to an increased risk of first single CMD in healthy individuals and an increased CMM risks in those with first single CMD.ASB may not be a healthier substitution for SSB.Pure fruit/vegetable juices,on the other hand,have been shown to decrease the risk of first single CMD and CMM.Pure fruit/vegetable juices might be a more suitable SSB substitution.(2)The mechanism underlying the associations between SSB consumption and CMD risks may be linked to intervention in lipid metabolism and injury to endothelial cells and cardiomyocytes.High levels of HFCS treatment can raise blood lipid levels,inhibit the proliferations of endothelial cells and cardiomyocytes,promote cell apoptosis,lead to oxidative stress injuries of endothelial cells and cardiomyocytes,meanwhile,High levels of HFCS treatment can promote the expressions of endothelial cell inflammatory factors and generate an inflammatory response.