Type 1 Diabetes Pathogenic T Cell Immunodiagnosis And Clinical Intervention Study Of DPP-IV Inhibitors

Part ?Five pivotal islet-specific epitopes improve pathogenic CD8+T cell immunoassay for diagnosis of type 1 diabetesObjective:Since autoreactive CD8+T cells play a central role in the destruction of pancreatic?-cells in type 1 diabetes,T-cell assays could contribute to both preclinical diagnosis and immune surrogate end points for clinical trials.This study was to explore a satisfactory islet-specific CD8+T-cell assay to more accurately diagnose type 1 diabetes.Research Design and Methods:Islet-specific CD8+T-cell IFN-y enzyme-linked immunospot(ELISpot)against 28 epitopes derived from seven ?-cell auto-antigens and radio-binding assay or ELISA for islet-autoantibodies were performed in 109 HLA-A2+ subjects.Results:New-onset autoantibody-positive type 1 diabetic patients responded to 16 epitopes among 28 epitopes by ELISpot in comparison with healthy controls.We,furthermore,determined ELISpot response against two epitopes was an optimal positive cutoff(75.0%sensitivity,94.4%specificity),and it was more sensitive in children(93.3%sensitivity,94.4%specificity).Islet-specific CD8+T cell response kept high accuracy(71.4%sensitivity,94.4%specificity)to reflect type 1 diabetes,even with 5 islet-specific epitopes.Notably,77.8%new-onset and 25.0%long-standing seronegative type 1 diabetic patients demonstrated positive response by ELISpot.Moreover,sensitivity to detect type 1 diabetes could reach 91.1%while ELISpot assay was complemented with autoantibody determinations.Conclusions:Islet-specific CD8+T-cell measurement could be a satisfactory application in clinical diagnosis and etiologic classification in type 1 diabetes.Part ?Clinical intervention study of DPP-? inhibitor in Type 1 Diabetic PatientsObjective:Type 1 diabetes mellitus is characterized by immune mediated ?-cell destruction.Due to the imbalance between glucagon and insulin,long-term type 1 diabetic patients experience frequent hypoglycaemia and high glucose variability despite of multiple daily injections of insulin.To testify the hypothesis that DPP-? inhibitor(saxagliptin)could reduce the fluctuation of glycemia and improve the glycemic control in type 1 diabetes through mechanisms of suppressing glucagon secretion,improving ? cell function,and re-regulating of the T cell immune system.Design and Setting:This study is a randomised,open-label,cohort study.108 type 1 diabetic patients were randomized 1:1 to receive insulin therapy with 5 mg/d saxagliptin(n=54)or without saxagliptin(n=54)for 24 weeks.Continous glucose montoring(CGM),mixed meal tolerance test,immune markers were performed at baseline and after 24 weeks of treatment,glycosylated hemoglobin(HbA1c)level were performed at baseline and after 12 weeks,24 weeks.Results:There were no differences in the clinical baseline data between the two groups.At baseline,CGM and CGM-derived results were comparable,mean amplitude of glycemic excursions(MAGE)was 7.0±2.7 vs 6.8±2.8 mmol/L in patients with saxagliptin or without saxagliptin(p>0.05).At 24 weeks,MAGE was 5.8±2.8 vs 6.5±2.3 mmol/L in patients with saxagliptin or without saxagliptin(p>0.05);low blood glucose index(LBGI)in patients with saxagliptin were lower than the controls(2.7±1.4 vs 5.5±3.7,p=0.011).At 24 weeks,there were no siginificant differences in HbAlc levels,insulin doses between the two groups(p>0.05).No patients had serious adverse events.Concluions:Preliminary study shown that type 1 diabetic patient with DPP-? inhibitor had lower glucose variability and risk of hypoglycemia.