Frequency, Immunogenetics, and Clinical Characteristics of Latent Autoimmune Diabetes in China (LADA China Study)

Abstract

Adult non–insulin requiring diabetes includes latent autoimmune diabetes of adults (LADA), distinguished from type 2 diabetes by the presence of islet autoantibodies. LADA China determined the characteristics of Chinese LADA. This nationwide, multicenter, clinic-based cross-sectional study was conducted in 46 university-affiliated hospitals in 25 Chinese cities. All 4,880 ketosis-free diabetic patients (<1 year postdiagnosis, without insulin therapy for >6 months, aged ≥30 years) had GAD antibody (GADA) and HLA-DQ genotype measured centrally with clinical data collected locally. GADA-positive subjects were classified as LADA. Of the patients, 5.9% were GADA positive with LADA. LADA showed a north-south gradient. Compared with GADA-negative type 2 diabetes, LADA patients were leaner, with lower fasting C-peptide and less metabolic syndrome. Patients with high GADA titers are phenotypically different from those with low GADA titers, while only a higher HDL distinguished the latter from those with type 2 diabetes. HLA diabetes–susceptible haplotypes were more frequent in LADA, even in those with low-titer GADA. HLA diabetes-protective haplotypes were less frequent in LADA. Our study implicates universal immunogenetic effects, with some ethnic differences, in adult-onset autoimmune diabetes. Autoantibody positivity and titer could be important for LADA risk stratification and accurate therapeutic choice in clinical practice.

Latent Autoimmune Diabetes in Adults With Low-Titer GAD Antibodies: Similar Disease Progression With Type 2 Diabetes

“…LADA was defined according to the Immunology of Diabetes Society 2004 definition, based on the diagnosis of diabetes at age $30 years old, independence of insulin therapy for at least 6 months, and GADA positivity (10). GADA levels $180 units/mL were defined as "high GADA level," whereas those between 18 and 180 units/mL were defined as "low GADA level" (16). The inclusion criteria were 1) diagnosis of diabetes (World Health Organization [WHO] 1999 criteria) at age $30 years, 2) duration of diabetes ,5 years, and 3) patients with residual islet function (fasting C-peptide…”

“…HLA-DQA1 and -DQB1 genotypes were defined by DNA analysis using PCR to amplify exon 2 of both DQA1 and DQB1 genes, followed by standard DNA sequencing-based typing (21). The definition of HLA protective haplotypes and HLA susceptibility haplotypes was according to that in LADA China Study reported by Zhou et al (16).…”

“…The apparent bimodal distribution of GADA titers can be used to classify LADA into two subgroups with distinct clinical, autoimmune, and genetic features (13)(14)(15). Studies of Chinese (16) and Caucasians (14) both showed that the characteristics of patients with low GADA titers were similar to those of antibody-negative type 2 diabetic patients, including sex and age at diagnosis, BMI, HbA 1c , b-cell function reserve, the metabolic syndrome, and insulin treatment. Therefore, whether a single autoantibody positive at low titers is sufficient evidence for autoimmune diabetes remains controversial (17,18).…”

“…Several cross-sectional studies have shown that GADA titers are associated with the phenotypic heterogeneity of clinical features in LADA patients (11)(12)(13)(14)(15)(16). The apparent bimodal distribution of GADA titers can be used to classify LADA into two subgroups with distinct clinical, autoimmune, and genetic features (13)(14)(15).…”

The heterogeneity of islet autoantibodies and the progression of islet failure in type 1 diabetic patients

“…However, the autoantibody assays were often negative in Asian T1DM patients. It might due to the unsensitive or unspecific assays, or testing far from diagnosis as antibody titers diminish, yet-to-beidentified auto-antigens, or foremost heterogeneity of islet autoantibodies in Chinese population (Lu et al, 2012;Wang et al, 2007;Zhou et al, 2013).…”