Study On Risk Factors And Transcriptomics And Metabolomics Of Depressive Disorder In Type 2 Diabetes Mellitus

Objective:Depressive disorder(MDD)has become one of the common neuropsychiatric complications of type 2 diabetes mellitus(T2DM),which is an important reason for the decrease of living standards and life expectancy in diabetic patients.Therefore,to explore the pathogenesis of type 2 diabetic complicated with depressive disorder(T2DM-MDD)is particularly important for the early diagnosis and subsequent treatment of the disease.At the same time,this study explores the risk factors of type 2 diabetes combined with depressive disorder,and combines transcriptomics and metabolomics to explore the potential pathogenesis of type 2 diabetes combined with depressive disorder from the two levels of genes and metabolites,providing a basis for the diagnosis of the disease and subsequent treatment targets.Methods:In this cross-sectional study,122 patients with type 2 diabetes admitted to the Department of Endocrinology,the Second Hospital of Shandong University from July 2021 to February 2023 were selected.Participants ranged in age from 40 to 82.The Hamilton Depression Scale(HAMD)was used to assess depressive status.According to the HAMD score,59 patients were classified into T2DM-MDD group with HAMD≥7,and 63 patients were classified into T2DM simple diabetes group with HAMD<6.Meanwhile,demographic information,disease characteristics and clinical laboratory indicators of patients were collected for risk factor analysis of this population.In transcriptomic analysis,data sets related to type 2 diabetes and depression were retrieved through Gene Expression Omnibus(GEO)to conduct differential gene screening and network analysis,so as to find the hub genes and corresponding biological processes associated with type 2 diabetic complicated with depressive disorder.In metabolomics analysis,10 patients in each T2DM-MDD group and T2DM group were selected,and serum samples were collected.LC-MS/MS(liquid chromatography-mass spectrometry)was used to screen different metabolites between groups,so as to explore the characteristic metabolic spectrum of T2DM-MDD.Finally,transcriptomics and metabolomics were combined to conduct a joint study on transcriptomic differential genes and metabolomic differential compounds and pathways,and to analyze the changes in genes,metabolites and pathways associated with type 2 diabetic complicated with depressive disorder in order to explore its possible pathogenesis.Results:1.Differences between groups and risk factors:Subjects were divided into T2DM-MDD and T2DM groups based on HAMD score for intergroup comparison.Results showed that gender(42/21 vs 21/38,P<0.001),smoking history(36.5%vs 13.6%,P=0.04),vascular plaques in lower extremities(74.6%vs 61.0%,P=0.36)and anxiety score(5 vs 14,P<0.001).Binary Logistic regression analysis was performed for the aforementioned variables,and the results suggested that higher anxiety score,vascular plaques of lower extremities was an independent risk factor for depression in type 2 diabetes patients.2.A total of 193 differential genes(69 up-regulated genes,124 down-regulated genes)related to type 2 diabetes combined with depressive disorder were identified in transcriptomics.GO concentration is mainly related to biological processes and molecular functions such as natural killer cell differentiation,negative regulation of immune system processes,autophagy regulation,neuroinflammatory response,neuronal death,amyloid clearance,lyase activity,peptide binding,etc.KEGG pathway is mainly concentrated in leukocyte transendothelial migration,DNA replication,phagosomes,mismatch repair and other pathways.It is speculated that the regulation of immune inflammation and the aging process may be the common mechanism of MDD and T2DM.3.In metabolomics,19 differential metabolites(12 up-regulated metabolites and 7 down-regulated metabolites)of diabetic comorbidities were screened,covering many categories such as lipids,purines,steroids,amino acids,etc.Enrichment analysis showed that there were significant differences between steroid hormone biosynthesis and fatty acid biosynthesis pathways.4.The combined analysis of transcriptomics and metabolomics showed that steroid hormone biosynthesis pathway and fatty acid biosynthesis pathway were correlated with type 2 diabetes combined with depressive disorder.Among them,steroid hormone synthesis pathway was activated in both T2DM and MDD transcriptome data.However,the expression of fatty acid synthesis pathway was different in the two data sets,showing inhibition in the T2DM phenotype data set and activation in the MDD phenotype data set.Conclusions:There are differences between T2DM and T2DM-MDD patients in gender,smoking history,presence or absence of vascular plaques in lower extremities,and anxiety scores.Higher anxiety scores and vascular plaques of lower extremities are independent risk factors for depression in type 2 diabetes patients.Multiple omics combined analysis showed that steroid hormone biosynthesis pathway and fatty acid biosynthesis pathway are correlated with the occurrence of type 2 diabetes combined with depressive disorder.In the future,it is necessary to further explore the specific regulatory status of these two pathways in type 2 diabetes comorbidity depression based on T2DM-MDD phenotype model.