Associations Between 25-hydroxyvitamin D3 And Digestive System Cancer-associated Tumor Markers In Different Glucose Tolerance States

BackgroundsThe prevalence of diabetes mellitus type 2(T2DM)has shown a steady increase alongside the upward socioeconomic mobility and the general improvement in the standards of living.Previous studies have shown that patients with T2DM are at a higher risk of developing malignant tumor as compared to non-diabetic individuals.The mechanism of the association between T2DM and risk of cancer is complex and multifaceted.Vitamin D is a fat-soluble vitamin that binds to the vitamin D receptor(VDR)for biological Vitamin D is not only an important hormone that regulates calcium and phosphorus metabolism,but also has a variety of biological functions such as regulating immunity,cell proliferation and differentiation,and regulating gene expression.The role of vitamin D(VD)in the process of tumorigenesis has increasingly been acknowledged in recent years.Colorectal cancer(CRC)is a malignant tumor that predominantly occurs in middle aged and elderly people.Patients typically exhibit no obvious clinical symptoms in the early stages of the disease.This study aimed to examine the risk factors associated with elevated serum markers of CRC in patients with T2DM.Our findings may help identify patients who may benefit from more frequent assessment of tumor marker levels.Vitamin D deficiency has been associated with increased risk of T2DM-associated complications.Patients with type 2 diabetes mellitus(T2DM)suffer not only hyperinsulinemia and hyperglycemia,but also associated complications such as albuminuria and colorectal cancer(CRC).In this study,we examined the associations between calcifediol level and p-cell function,and risk of CRC,in Chinese T2DM patients with different levels of albuminuria to gain insights into the protective effects of vitamin D in T2DM.Colorectal cancer is one of the most common gastrointestinal malignancies,and its high morbidity and mortality have seriously threatened the patients’ physical and mental health.More and more evidence has found that vitamin D can regulate the homeostasis of intestinal epithelial cells,affect the proliferation,differentiation,apoptosis and inflammatory state of intestinal epithelial cells,and reduce the occurrence and development of colorectal cancer.Serum 1,25-(OH)2D3 level is closely related to the incidence of colorectal cancer and the prognosis of patients.In recent years,researchers have found that l,25-(OH)2D3 can regulate the function of immune cell and inhibit apoptosis,thus protecting target cells.Currently,the role of vitamin D supplementation in patients with type 2 diabetes ’who are genetically positive for colorectal cancer is not clear,especially whether and how vitamin D changes the immune status of the body.Septin9 gene methylation has a relatively high detection rate in peripheral blood of patients with colorectal cancer and some precancerous lesions,and has become an important biomarker for colorectal cancer screening,diagnosis and treatment monitoring.In this study,Septin9 methylation positive patients with type 2 diabetes were treated with calcitriol,and the effects of vitamin D supplementation on the function of beta cells and the immune status of the patients were observed.Part 1 Risk factors for elevated serum colorectal cancer markers in patients with diabetes mellitus type 2:a retrospective case control studyObjective and methodsRecent years have witnessed an increase in the incidence of diabetes mellitus type 2(T2DM)and colorectal cancer(CRC).T2DM can increase the risk of CRC and detection of CRC-related tumor markers is an important screening tool for CRC.In this study,we examined the risk factors for increased CRC markers in patients with T2DM.Data pertaining to 229 patients with T2DM were retrospectively reviewed.The patients were categorized into 2 groups:CRC tumor marker-positive and-negative groups.Patients who tested positive for all three of the following CRC markers were included in the CRC tumor marker-positive group:serum carcinoembryonic antigen(CEA),carbohydrate antigen(CA)19-9 and Septin9 methylation(S9M).Gender,age,duration of T2DM,family history of T2DM,family history of CRC,smoking,drinking alcohol,body mass index(BMI),serum vitamin D(VD),glycated hemoglobin Ale(HbAlc),high-density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol(LDL-C),total cholesterol(Choi T),and triglyceride(TG)were included in the analysis.Univariate analysis was performed to identify variables that exhibited a significant association with CRC tumor marker status.Then,multivariate logistic regression was performed to determine the odds ratios(OR)with 95%confidence intervals(Cl).Pearson correlation analysis,partial correlation analysis and multiple linear regression analysis were used to detect the correlation between serum 25-OH-D level and colorectal cancer related tumor indicators In T2DM patients.ROC analysis was used to predict the correlation between negative and positive tumor markers and metabolic indicatorsResults1.Univariate analysis revealed that most CRC marker positive patients had higher age,family history of CRC,history of smoking and alcohol intake,overweight(BMI),longer history of T2DM,worse diabetes control(HbAlc),lower level VD and HDL-C,and higher level of Chol T and TG2.Logistic regression analysis showed that BMI,VD,HbA1c,and TG were independent predictors of CRC marker-positive status[OR,95%CIs and P values were 1.912(1.346-2.716),<0.001;0.773(0.633-0.943),0.011;9.082(3.52-23.433),<0.001;1 1.597(3.267-41.164),<0.001,respectively].3.Partial correlation analysis showed that after controlling for age,BMI,T2DM course,FBS,HbAle,TG,TC and lipoprotein,the level of 25-OH-D presented moderate or weak negative correlation with AFP,CA125,CA153,CA724,CEA and CA199.(r>-0.60,P<0.05).4.Multiple linear regression analysis showed that 25-OH-D as the independent variable and CA125,CA153,CEA and CA199 as the dependent variable respectively,25-OH-D would significantly reduce the above-mentioned serum indicators(P<0.05).5.ROC analysis showed that 25-OH-D was negatively correlated with tumor markers,with the optimal cut-off value of 31.95 ng/mL.BMI HbA1c and TG were the risk factors for positive tumor markers,and the optimal cut-off values were 24.00kg/m2,8.55%and 2.18 mmol/L,respectively.ConclussionIn this retrospective study,high level of BMI,HbAlc,TG and low level of VD were correlated with CRC tumor marker-positive status in T2DM patients.Patients with these risk factors may benefit from more frequent screening for CRC tumor markers.Part 2 Associations between vitamin D and β-cell function and colorectal cancer-associated tumor markers in type 2 diabetic patients with albuminuriaObjective and methodsPatients with type 2 diabetes mellitus(T2DM)suffer not only hyperinsulinemia and hyperglycemia,but also associated complications such as albuminuria and colorectal cancer(CRC).Vitamin D is an essential nutrient and precursor hormone that regulates numerous physiological processes in the body,and its deficiency is associated with microalbuminuria,β-cell dysfunction,and increased risk of CRC in T2DM patients.To investigate the significance of vitamin D in T2DM,we compared serum calcifediol levels(an indicator of vitamin D)among healthy individuals and T2DM patients stratified by albumin/creatinine ratio(ACR),and analyzed correlations with β-cell function(BCF)and risk of CRC.Results1.Compared with the healthy control group,the FPG,FINS,and HbA1c levels were significantly elevated in these T2DM groups.In particular,the FPG,FINS,and HbA1c levels in the microalbuminuria and macroalbuminuria groups were also significantly higher than the normoalbuminuria group.2.The β-cell function was then analyzed and compared.Our results showed that,HOMA-IR in the healthy control group was significantly lower than the T2DM groups.Moreover,HOMA-IR in the normoalbuminuria group was significantly lower than the microalbuminuria group,which was also significantly lower than the macroalbuminuria group(Table 2).HOMA-BCF and insulin secretion in the normoalbuminuria group were significantly higher than the macroalbuminuria group.3.The CRC-associated tumor markers,ACR,and serum calcifediol level,in T2DM were investigated and analyzed.Our results showed that,the serum levels of AFP,CEA,CA199,and CA125,as well as the rate of septin 9 methylation,in the microalbuminuria and macroalbuminuria groups,were significantly higher than the healthy control group(Table 3).Moreover,among the T2DM patients,the rates of septin 9 methylation in the microalbuminuria and macroalbuminuria groups were significantly higher than the normoalbuminuria group.However,the rate of septin 9 methylation in the macroalbuminuria group was only slightly higher than the microalbuminuria group.4.Serum calcifediol level was significantly higher in the healthy controls than in T2DM patients.In T2DM patients,calcifediol level was inversely associated with ACR,HOMA-IR,AFP,CEA and septin 9 methylation,but positively with HOMA-BCF and insulin secretion.5.The multivariate stepwise principal component regression analysis indicated that calcifediol,hemoglobin Ale,and serum creatinine are independent risk factors for elevated CEA in T2DM.ConclussionOur results suggest that vitamin D may have a suppressive effect on T2DM-associated complications and may therefore be a potential prophylactic treatment against β-cell dysfunction and cancer development in T2DM patients with albuminuria.Part 3 Effects of vitamin D supplementation on β-cell function and immune status in type 2 diabetic patients with colorectal cancer positive genesObjective and methodsTo observe the effect of vitamin D on β-cell function and immune status in type 2 diabetes mellitus patients with colorectal cancer gene positive.Fifty Septin9 methylation positive patients with type 2 diabetes were enrolled and received oral treatment with calcitriol(0.25μ/day)for 3 months.Blood glucose control,insulin resistance,tumor markers,and serum cytokine levels were measured or assessed.Pearson correlation analysis and partial correlation analysis were used to detect the correlation between serum 25-OH-D level and various indicators.ResultsThe baseline level of serum 25-OH-D in patients with type 2 diabetes was 17.15±4.82 ng/mL.After 3 months of vitanin D supplementation,serum 25-OH-D3 level was significantly increased to 27.54±4.80 ng/mL,and the difference was statistically significant(P<0.001).After calcitriol treatment,1)the levels of FPG,HbAlc and FINS significantly decreased compared with that before treatment,and the insulin resistance index HOMA-IR value significantly decreased(P<0.001).2)Serum CEA and CA199 values of the patients were significantly reduced,and the difference was statistically compared with that before treatment(P<0.001).3)Serum IL-2 and γ-interferon levels of the patients were significantly higher than before treatment(P<0.001).Serum IL-6,IL-10 and TNF-α levels were significantly lower than before treatment,with significant differences(P<0.001).Pearson correlation analysis showed that the 25-OH-D-difference was significantly negatively correlated with the IL-6 difference(r=-0.306,P<0.05).After controlling the difference of PFG-difference and HbA1c-difference,partial correlation analysis showed the 25-OH-D-difference was significantly negatively correlated with the IL-6-difference(r=-0.298,P<0.05).Pearson correlation analysis showed a significant positive correlation between 25-OH-D and gamma-interferon(r=0.373,P<0.05).After controlling variables age,FPG,and HbA1c,partial correlation analysis showed that a significant positive correlation between 25-OH-D and gamma-interferon(r=0.409,P<0.05).ConclussionVitamin D supplementation helps improve β-cell function and immune status in patients with type 2 diabetes who are genetically positive for colorectal cancer.