The Screening Strategy For Latent Autoimmune Diabetes In Adults (LADA) Using 4 Islet Autoantibodies

Objective:To explore the sceening strategy for latent autoimmune diabetes in adults (LADA) using four islet autoantibodies, and to provide the basis for LADA screening strategy confirming to the realistic situation of China.Subjects and Methods:A total of 3062 phenotypic type 2 diabetic patients, who were randomly selected from patients participating LADA-China study, were devided into two groups:non-insulin treating group (n=2388) and insulin treating group (n=674), according to different treatment.405 healthy cases were also included as controls. We screened glutamic acid decarboxylase antibody (GADA), protein tyrosine phosphatase-2 antibody (IA-2A) and zinc transporter 8 autoantibody (ZnT8A) by radioligand assay (RLA) in all the patients. In addition, insulin autoantibody (IAA) were determined by microtiter plate radioimmune assay (RIA) in 2388 non-insulin treating T2DM patients. We have examined the prevalence of the four islet autoantibodies, and explored the value of combined or isolated determination of the four autoantibodies in phenotypic T2DM patients. Giving consideration to both the diagnostic sensitivity and clinical characteristics, we studied the optimal screening strategy for LADA.Results:1. The positive prevalence of GADA, IA-2A and ZnT8A in 3062 phenotypic T2DM patients was 6.43%(197/3062),1.96%(60/3062), 1.99%(61/3062) respectively, and in 405 health controls was 1.23% (5/405),0.49%(2/405),0.99%(4/405) respectively. The frequencies of IA-2A and ZnT8A were both lower than that of GADA (both P＜0.001).2. In non-insulin treating group, the positive prevalence of GADA, IA-2A, ZnT8A and IAA was 5.78%(138/2388),1.51%(36/2388),1.84% (44/2388),1.26%(30/2388) respectively. The positive prevalence of IA-2A, ZnT8A and IAA were all lower than that of GADA (all P＜0.001). In insulin treating group, the positive prevalence of IA-2A (24/674, 3.56%) and ZnT8A (17/674,2.52%) had no significant differences (P>0.05), but both of them were lower than that of GADA (59/674, 8.75%, both P<0.001).3. In non-insulin treating group, the overlapping positive rate between IAA and GADA was 13.33%(4/30), being significantly lower than that between IA-2A and GADA or ZnT8A and GADA [vs.38.89% (14/36) & 38.64%(17/44), both P＜0.05]. In insulin treating group, the overlapping positive rate between IA-2A and GADA was 29.17%(7/24), being not significantly different with that between ZnT8A and GADA (4/17,P>0.05).4. In non-insulin treating group, conbined with GADA and IA-2A determination, the diagnostic sensitivity of LADA was 6.70%; then combined with ZnT8A detection; it could reach 7.58%; it could reach up to 8.63% if continued to be combined with IAA detection. In insulin treating group, based on testing of GADA and IA-2A, combination determination of ZnT8A could increase the diagnostic sensitivity of LADA from 10.68% to 12.31%.5. In non-insulin treating group, compared with autoantibodies negative T2DM patients:the GADA positive alone patients had lower fasting C peptide (FCP) (P=0.000), the IA-2A positive alone patients had lower body mass index (BMI) but higher HbA1c (both P=0.000), the ZnT8A positive alone patients had higher FCP, total cholesterol (TC), triglycerides, low density lipoprotein cholesterol (LDL-C) (all P=0.000), the IAA positive alone patients had lower BMI and HbA1c (both P=0.000). In non-insulin treating group, compared with autoantibodies negative T2DM patients:the GADA positive alone patients had lower FCP (P=0.003); the ZnT8A positive alone patients were with higher proportion of family history of type 2dibeties (P=0.012); the IA-2A positive alone patients had higher FCP than the GADA positive alone patients (P=0.016).6. In non-insulin treating group, patients who were positive for GADA and IA-2A had lower BMI but higher HbA1c levels (both P＜0.05). In insulin treating group, patients who were positive for GADA and IA-2A had lower triglycerides than GADA positive alone patients (P=0.017). 7. Whether in non-insulin treating group or insulin treating group, the HbA1c level of ZnT8A,GADA and IA-2A all positive patients showed an upward trend when compared with patients who were positive for GADA and IA-2A, but the differences was not statistically significant (P>0.05).Conclusions:Combination determination of GADA, IA-2A, ZnT8A and IAA can increase diagnostic sensitivity of LADA. Combination determination of GADA and IA-2A is an optimized strategy for LADA screening. The determination of ZnT8A at the basis of GADA and IA-2A can not only increase diagnostic sensitivity of LADA, but also confirm clinical characteristics of the patients.The value of IAA in LADA screening should be confirmed by further follow-up study.