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

Abstract

OBJECTIVEThis study investigated the relationship between GAD autoantibody (GADA) titers and changing of b-cell function in patients with latent autoimmune diabetes in adults (LADA). RESEARCH DESIGN AND METHODSThis 3-year prospective study enrolled 95 subjects from 15 Chinese cities including 25 high-titer (GADA ‡180 units/mL) LADA patients, 42 low-titer (GADA <180 units/mL) LADA patients, and 28 type 2 diabetic patients, the latter two groups as controls of similar age, sex, and BMI. Clinical characteristics were determined annually, including glycosylated hemoglobin (HbA 1c ), fasting C-peptide (FCP), and 2-h postprandial C-peptide (PCP). RESULTSDespite similar initial FCP and PCP, FCP and PCP both decreased more in subjects with high GADA titer (FCP from mean 0.49 nmol/L at entry to 0.13 nmol/L at the third year; P < 0.05) than with low GADA titer (FCP from mean 0.48 to 0.38 nmol/L) and type 2 diabetes (FCP from mean 0.47 to 0.36 nmol/L); the latter two groups being similar. After 3 years, residual b-cell function (FCP >0.2 nmol/L) was detected in only 42% with an initial high GADA titer compared with 90% with a low GADA titer and 97% with type 2 diabetes (P < 0.01 for both). GADA positivity at the third year persisted more in subjects with initially high GADA (92%) than with low GADA (26%) titers (P < 0.01). CONCLUSIONSIn selected LADA patients, initial GADA titers identified subjects with different degrees of persistent autoimmunity and disease progression. LADA patients with a low GADA titer had metabolic phenotypes and loss of b-cell function similar to type 2 diabetic patients.

Response to Comment on Liu et al. Latent Autoimmune Diabetes in Adults With Low-Titer GAD Antibodies: Similar Disease Progression With Type 2 Diabetes: A Nationwide, Multicenter Prospective Study (LADA China Study 3). Diabetes Care 2015;38:16–21

“…Against the former, we have duplicated the assay by our Diabetes Autoantibody Standardization Program-standardized radioimmunoassay method, so false positivity rates are very low and the quantile-quantile plot indicates that the positive signal represents a distinct group of subjects (4). In support of the latter, compared with patients with type 2 diabetes, low-titer GADA patients had more total HLA-DQA1 susceptibility haplotypes and more were on insulin therapy at entry into the study (2,4).…”

“…We thank Shah and Yu (1) for their comments on our study (2) and for the opportunity to discuss some key points on the GAD antibody (GADA) pattern and its relation with progression of type 1 diabetes, especially for latent autoimmune diabetes in adults (LADA). They suggest that lowtiter GADA subjects in our study might have low-affinity GADA representing biologically "false positivity" and GADA affinity could be analyzed with an electrochemiluminescence (ECL)-based assay to determine if this was the case.…”

IgG4 subclass glutamic acid decarboxylase antibodies (GADA) are associated with a reduced risk of developing type 1 diabetes as well as increased C-peptide levels in GADA positive gestational diabetes

“…However, in LADA patients GADA titers have been reported to be of prognostic value for beta cell function [24][25][26], which makes it reasonable to assume that this would be the case also in GADA positive women with GDM. In most cases there was a good correlation between total GADA and GADA IgG 1 levels, suggesting that IgG 1 is the most abundant heavy chain in the circulation in GADA positive women.…”

Comment on Liu et al. Latent Autoimmune Diabetes in Adults With Low-Titer GAD Antibodies: Similar Disease Progression With Type 2 Diabetes: A Nationwide, Multicenter Prospective Study (LADA China Study 3). Diabetes Care 2015;38:16–21

“…We read with great interest the article by Liu et al (1) demonstrating that progression of diabetes among subjects with latent autoimmune diabetes in adults (LADA) having low titer of GAD antibody (GADA) is similar to that in subjects with type 2 diabetes over the period of 3 years. This is a large populationbased, prospective, well-controlled study with well-characterized subjects.…”