Effect Of Follicle Stimulating Hormone On Lipid Metabolism In Postmenopausal T2DM And Potential Mechanisms

Background: Diabetes mellitus(DM)is a chronic metabolic disease with elevated blood glucose as the basic feature.The rapidly developing economy and lifestyle changes have led to an increasing number of overweight and obese people,and the prevalence of DM is increasing year by year.In 2021,the prevalence of DM among people aged 20-79 years is 10.9%,and type 2 diabetes mellitus(T2DM)accounts for more than 90%.T2DM combined with disorder of lipid metabolism is an important risk factor for atherosclerosis(AS).Under the comprehensive influence of metabolic disorders such as insulin resistance,hyperglycemia and dyslipidemia,patients with T2DM are prone to atherosclerotic cardio-cerebrovascular diseases,and cardio-cerebrovascular diseases become the main cause of death.The occurrence of T2DM and its complications greatly increase the global population mortality and disability rate,and pose a major threat to human health.At present,most studies believe that estrogen has a protective effect on the heart,and the decrease of estrogen level is one of the main reasons for the significant increase in the risk of postmenopausal cardiovascular disease(CVD).However,after menopause,with the decrease of ovarian function and the decrease of estrogen,the negative feedback effect on follicle stimulating hormone(FSH)weakened,and the serum FSH increased significantly.It has been found that follicle stimulating hormone receptor(FSHR)is expressed in extra-gonadal tissues,such as bone tissue,adipocytes and so on.The results of epidemiological investigation and animal experiments show that there is a significant correlation between FSH level and blood glucose,lipid metabolism,bone metabolism,but the conclusion is not completely consistent,there is still a lot of controversy.Some studies have found that serum FSH is positively correlated with total cholesterol(TC)and low density lipoprotein cholesterol(LDL-C).On the contrary,some studies have found that FSH is negatively correlated with triglycerides(TG)and LDL-C.In this study,we observed the effect of FSH on lipid metabolism in postmenopausal T2DM patients,and predicted the potential molecular mechanism of postmenopausal T2DM dyslipidemia by searching the public database.Objectives: In this study,postmenopausal patients with T2DM were selected as subjects to analyze the relationship between serum FSH level and FBG,TC,TG,LDL-C,HDL-C and BMI in postmenopausal T2DM patients.Mining the relationship between FSH and dyslipidemia through web database,to further explore the potential molecular mechanism of the effect of FSH on postmenopausal T2DM lipid metabolism,and to provide clinicians with the research direction and treatment of T2DM complicated with lipid metabolism disorder.Methods: 1.The clinical data of 279 postmenopausal T2DM patients hospitalized in the Department of Endocrinology,Jining NO.1.people’s Hospital from October 2020 to October 2022 were collected retrospectively,including age,disease duration,height(HT),weight(WT),BMI,underlying diseases,FSH,E2,FBG,TC,TG,LDL-C,HDL-C,glycosylated hemoglobin(Hb A1c)and so on.Finally,226 patients were included according to the standard of nano-platoon.Graph Pad Prism9.3.1 software was used for statistical analysis.Patients were divided into 3 groups by age: 50-60 years,61-70 years,and >70years.One-way ANOVA was used to compare: 50-60 years old,61-70 years old and > 70 years old.One-way ANOVA was used to compare the indexes of BMI,sex hormone,blood lipid,FBG and Hb A1 c among the three age groups.The age group of 50-60 years was divided into low FSH group and high FSH group according to the median FSH,and E2 and lipids were analyzed.2.Bioinformatics analysis Search the Gene Cards database with keywords to screen the target genes of postmenopausal T2DM and lipid metabolism disorders.Construct the interaction between postmenopausal T2DM and lipid metabolism disorder,draw Wayne diagram to get the common action target.The common target genes were annotated by GO function annotation and KEGG enrichment analysis by R language cluster Profiler package,and the main biological functions and signal pathways involved in the co-expression genes were obtained.The PPI was established by using String database,and the Hub gene was obtained by network analysis of the target through the visualization of the coexpression of overlapping genes in the Cytoscape software module.By consulting a large number of literatures about the regulatory effect of FSH on body metabolism were indexed to predict the potential mechanism of postmenopausal T2DM lipid metabolism disorder caused by FSH.Results: A total of 226 patients,aged 50～84 years,with an average(62.40±7.36)years old.1.Three age groups: 50-60 years group(n = 105),61-70 years group(n = 87),>70 years group(n = 34).It was found that serum FSH in postmenopausal T2DM patients decreased gradually with the increase of age.The level of FSH was the highest in the group of50-60 years old.The levels of serum FSH,TC and LDL-C in the group of50-60 years old were significantly higher than those in the group of >70years old.There was no significant difference among WT,HT,BMI,FBG,E2,TG HDL-C,thyroid stimulating hormone(TSH),parathyroid hormone(PTH)and vitamin D.2.The age group aged 50-60 years was divided into low FSH group(FSH≤56.72 m IU/ml,n=53 cases)and high FSH group(FSH>56.72 m IU/ml,n=52 cases).The level of TG in high FSH group was significantly higher than that in low FSH group(P<0.05).There were no significant differences in E2,TC,LDL-C and HDL-C between the two groups.3.Bioinformatics analysis: the keywords "type2diabetesmellitus","postmenopause" and "dyslipidemia" were searched by Gene Cards database,and T2DM 2113 pathogenic targets,postmenopausal 878 targets and dyslipidemia 335 targets were selected.Finally,the gene information was integrated and weighed,and 97 common target genes(intersection genes)were obtained.The PPI network of 97 common genes was constructed by using String database,and the top 30 possible key regulatory genes were visually analyzed by Cytoscaspe software,among which INS,ALB,IL-6,TNF,PPARG,LEP,ADIPOQ,APOE,CRP and APOB were the top 10 nodes.Based on the enrichment analysis of 97 potential target genes that may lead to postmenopausal T2DM dyslipidemia,the first 20 GO functional annotations and KEGG signal pathways were obtained.Among them,the main biological function involved in GO enrichment is the activity of receptor ligands.The KEGG signal pathway is mainly AGE-RAGE signal pathway.The results of bioinformatics show that abnormal signal pathways of AGE-RAGE,AMPK and TNF may lead to dyslipidemia in postmenopausal T2DM.Combined with the results of bioinformatics analysis,this study found that there was a positive correlation between serum TG and FSH,TG and IL-6,IL-6 and FSH in 50-60-year-old postmenopausal T2DM patients.According to the results of statistical analysis,bioinformatics analysis and related literature search,this study speculated that FSH may affect the lipid metabolism of postmenopausal T2DM by stimulating the release of inflammatory cytokines in IL-6.Conclusion:1.The level of FSH reached the peak in 50-60 years old postmenopausal T2DM patients.2.There was a positive correlation between serum TG level and FSH in 50-60 years old postmenopausal T2DM patients.3.FSH may aggravate the disorder of lipid metabolism in50-60-year-old postmenopausal T2DM patients by activating inflammatory cytokines IL-6.4.AGE-RAGE,AMPK and TNF signal pathways may lead to dyslipidemia in postmenopausal T2DM.