Number of autoantibodies and HLA genotype, more than high titers of glutamic acid decarboxylase autoantibodies, predict insulin dependence in latent autoimmune diabetes of adults

Abstract

Objective: In latent autoimmune diabetes of adults (LADA), the progression into insulin-dependent diabetes is usually faster than in type 2 diabetes (T2D) but the factors influencing this progression are not completely known. In this study, we searched for sensitive markers associated with early development of insulin dependence. Design: The screening of 5568 T2D patients for glutamic acid decarboxylase autoantibodies (GAD65Ab) identified 276 LADA patients (MZ131; FZ145) and in 251 of them, tyrosine phosphatase-2 (IA-2Ab) and thyroperoxidase autoantibodies (TPOAbs), some clinical features and genotype variation of the main type 1 diabetes (T1D) disease susceptibility loci (HLA-DRB1 and HLA-DQB1) were analyzed. Results: Four years after the diagnosis of diabetes, high GAD65Ab titer was not significantly associated with faster progression toward insulin deficiency (PZ0.104). Patients with GAD65Ab and TPOAb or IA-2Ab or triple positivity for both islet and TPOAbs (GAD65Ab/IA-2Ab/TPOAb) showed a significantly faster disease progression (PZ0.002). Among 104 TPOAb-positive LADA patients, 10 received replacement therapy (L-thyroxine), 43 showed high TSH levels (62.7% developed insulin dependence), and 3 had hyperthyroidism treated with methimazole. Multivariate analysis revealed a significant effect on disease progression only for TPOAb (PZ0.022), female gender (PZ0.036), low body mass index (BMI; PZ0.001), and T1D high/intermediate risk HLA-DRB1/DQB1 genotypes grouped (PZ0.020). Conclusions: High GAD65Ab titers per se are not a major risk factor for disease progression in LADA, while the number of positive autoantibodies and HLA DRB1-DQB1 genotypes at high risk for T1D are significant predictors. Moreover, clinical characteristics such as low BMI and female gender are more likely to identify patients who will require insulin therapy within 4 years of diagnosis.

Distinct clinical and laboratory characteristics of latent autoimmune diabetes in adults in relation to type 1 and type 2 diabetes mellitus

“…On the other hand, other groups do not rely entirely on high anti-GAD65 titres, in order to predict the progression of LADA. Instead, strong predictors are considered the co-existence of positive autoantibodies and both HLA-DRB1 and HLA-DQB1, while, traits including female gender and low BMI and are highly likely to predict insulin requirement within 4 years post-diagnosis [43] . In mid-1990s, two independent groups will add an additional T1D specific autoantigen to the ICAs reactivity panel, the insulinoma antigen 2 (IA-2), a transmembrane molecule belonging to the family of protein tyrosine phosphatases [44][45][46] .…”

High GADA titer increases the risk of insulin requirement in LADA patients: a 7-year follow-up (NIRAD study 7)

“…During the early phase of disease, individuals with LADA can retain good metabolic control through diet alone or by taking oral hypoglycemic drugs, and this state can last from months to years. However, a percentage of LADA patients progress toward insulin requirement, indicating that LADA involves a slow and progressive loss of b-cells (5), although the factors influencing this progression are not completely known (6). The first evidence, demonstrating that a high GADA titer is a stronger predictor of insulin requirement than a general GADA positivity, was obtained from two studies with a limited number of LADA patients (7,8).…”

“…UKPDS 25 reported, in a larger population of LADA patients, that high GADA titer was associated with a significant higher risk of insulin requirement only among subjects older than 55 years at diagnosis (1). Afterwards, conflicting results were reported in the literature; some studies demonstrated that a high titer of GADA was associated with a shorter insulin-free period (9,10,11), whereas others did not support this hypothesis (6,12).…”

Multi-Component Vaccines for Suppression of Type 1 Diabetes

“…While most type 1 diabetes (T1D) cases develop in pre-adolescence, late onset diabetes (LADA), may appear generally from 40-60 yr of age and is often confused with type 2 diabetes. The progression of diabetes symptoms may be responsible for 10-15% of diabetes related heart disease mortality especially in low income socio-economic groups which are at greatest risk for diabetes related health disparities in the U.S (Kobayashi et al 2006;Maioli, Puddu, and Pes 2006). Diagnosis and treatment of hyperglycemia is poor, as islet -cell destruction is completely asymptomatic until more than half of the approximately 1x10 6 pancreatic islets have been destroyed or inactivated (Tang et al 2006).…”