Biomarker Study Of Serum MiRNAs In Type 1 Diabetes

Background: The incidence of type 1 diabetes(T1D),a T cell-mediated beta cell destructive autoimmune disease,has been increasing about 3-4% annually for several decades.Individuals at risk for T1 D are diagnosed at a late stage when the possibility for disease prevention is absent.Autoantibodies(AA)to islet antigens such as islet antigen(IA)-2,IA-2b,and glutamate decarboxylase(GAD65)appear earlier before T1 D onset and are used for early T1 D prediction.However,the appearance of islet AA marks a relatively late stage of the autoimmune process and therefore is not suitable for early disease intervention.More importantly AA lack causal relationship with the pathogenesis of T1 D.Therefore,there is an urgent need for better(increased specificity/sensitivity)and earlier(predating autoantibodies)markers for the prediction of AA development.Micro RNAs(mi RNAs)have emerged as an important regulatory factors in pancreatic ?-cell development,homeostasis,function,and in a variety of immune cell development,differentiation and function.Our recent study showed that mi RNAs regulate T1 D development and serum mi RNAs are potential biomarkers for T1 D progression in mouse models.Our objective here is to identify specific serum mi RNA biomarkers for earlier and better prediction of individuals at risk for T1 D in human.Method: We performed serum mi RNA expressions profiles in 35 AA positive(IAA and ICA)non-T1 D subjects and 40 AA negative relative subjects from the Diabetes Prevention Trial-Type 1(DPT-1)cohort,using the Taq Man low-density arrays.Mi RNAs with changed expression level were further confirmed by a single Taq Man RT-PCR.Result: 9 mi RNAs(miR-146 a,mi R-561 and miR-548a-3p,mi R-184 and mi R-200a)were down-regulated and 1 mi RNA(mi R-30c)are up-regulated in the serum of AA+ non-T1 D subjects compared to that from AA-subjects(two-sample t-test P<0.05).In addition,a cluster of five mi RNAs(mi R-146 a,mi R-197,mi R-193 b,mi R-574-3p,and mi R-561)was identified to clearly separate AA+ subjects from AA-subjects with higher sensitivity and specificity(LASSO logistic regression).Mi RNA target and pathway prediction analyses revealed that some of these mi RNAs are related to immune function and beta-cell homeostasis and potentially involved in autoimmune processes.Conclusion: We have identified distinct serum mi RNA expressions profiles in AA+ subjects compared to AA-subjects.These serum mi RNAs could serve as potential biomarkers for early prediction of autoimmune processes in individuals at risk for T1 D,which need to be further confirmed in the future studies.Background :The incidence of type 1 diabetes(T1D),a T cell-mediated beta cell destructive autoimmune disease,has been increasing about 3-4% annually for several decades.Individuals at risk for T1 D are diagnosed at a late stage when the possibility for disease prevention is gone.New biomarkers are urgently needed to improve early risk characterization and to monitor the autoimmune disease process of T1 D.Micro RNAs have emerged as important regulatory factors in numerous biological processes and disease development and may be used as biomarkers for human diseases.Recently,we found that mi RNAs regulate T1 D development and serum mi RNAs are potential biomarkers for T1 D progression in a mouse model for T1 D.Our objective here is to identify specific serum mi RNA biomarkers for human T1 D.Method: Serum samples from 107 new onset(within 6 months of diagnosis)T1D patients and 107 non-progressors with autoantibody(IAA and ICA)positive(at high risk)were used to profile serum mi RNA expression.754 mi RNAs were profiled by using the Taq Man low-density arrays for initially screening.Candidate mi RNAs are confirmed by Real-time PCR.Putative targets of the mi RNAs were predicted using online software database Target Scan,mi RBase,polymi RTS and T1 dbase.Result: Three up-regulated human mi RNAs(hsa-mi R-218,hsa-mi R-381 and hsa-mi R-618)were significantly changed in T1 D patients compared to AA+ non-progressors(two sample t-test P<0.05).Several of these mi RNAs were linked to beta cell networks and apoptosis.Further explore analysis also revealed that the expression of mi R-218 is negatively associated with fasting C-peptide levels in new onset T1 D patients.Conclusion: The current study demonstrates that mi R-218 is expressed in higher level in new onset T1 D patients with ongoing beta cell destruction and may considered as a novel and promising convert biomarker for T1 D early prediction,progression and prognosis.