There is a significant number of patients with latent autoimmune diabetes in adults (LADA) in Japan, and a high level of GAD autoantibodies has a high predictive value for future insulin deficiency in such patients.
We aimed to improve the genetic characterisation of LADA and hypothesised that type 2 diabetes-associated gene variants also predispose to LADA, and that the associations would be strongest in LADA patients with low levels of GAD autoantibodies (GADA).
Proportion of responders , as well as levels of secreted IL-10, were significantly higher in LADA than T1DM group, following stimulation with both insulin (P=0.01) and GAD65 (P=0.03).
Proportion of responders , as well as levels of secreted IL-10, were significantly higher in LADA than T1DM group, following stimulation with both insulin (P=0.01) and GAD65 (P=0.03).
The SLC30A8 R325 W variant was associated with LADA with low GADA levels [SLC30A8 CC: OR (95% CI): 1.46 (1.00 - 2.13), p = 0.049], and reduced insulin secretion among the non-diabetic subjects and the patients with LADA.
Furthermore, the elevated beta-casein antibody levels found in LADA patients suggest that the antibody response to this protein may be relevant in autoimmune diabetes.
The data confirmed that sitagliptin altered the phenotype of T cells and downregulated the expression of T-BET and RORC in LADA patients, and ameliorated glycemic control in LADA patients.
Compared to healthy controls, the expression of histone acetyltransferases CREBBP in LADA patients was downregulated, and the expression of histone deacetylases HDAC1 and HDAC7 was upregulated.Conclusion.
The data confirmed that sitagliptin altered the phenotype of T cells and downregulated the expression of T-BET and RORC in LADA patients, and ameliorated glycemic control in LADA patients.
The expression of histone methyltransferase SUV39H2 for H3 lysine 9 methylation was downregulated in LADA patients, and the expression of histone demethylase KDM4C which made H3 lysine 9 demethylation was upregulated.<i>Conclusion</i>.
The aim of the study was 1) to establish the prevalence of GAD antibodies (GADab) in a population-based study of type 2 diabetes in western Finland, 2) to genetically and phenotypically characterize this subgroup, and 3) to provide a definition for latent autoimmune diabetes in adults (LADA).
The association was stronger in LADA with low GAD antibody (GADA; <median) (OR 4.25; 95% CI 2.76, 6.52) but present also in LADA with high GADA (OR 2.14; 95% CI 1.42, 3.24).
Genotype frequencies, measures of insulin secretion, and metabolic traits within LADA differed according to GAD antibody (GADA) quartiles, but even the highest quartile differed from type 1 diabetes.
Further logistic regression analysis demonstrated that positivity for TSPAN7A (OR 2.87, p = 0.034), disease duration (OR 1.83, p = 0.019) and GAD antibody titre (OR 2.67, p = 0.009) were risk factors for beta cell function in LADA, while BMI (OR 0.34, p = 0.001) was a protective factor.
The combination of overweight and high-risk genotypes of HLA, TCF7L2, and FTO was associated with pooled relative risk (RRpooled) of 7.59 (95% CI, 5.27 to 10.93), 2.65 (95% CI, 1.97 to 3.56), and 2.21 (95% CI, 1.60 to 3.07), respectively, for LADA, compared with normal-weight individuals with low/intermediate genetic risk.
Polymorphisms in HLA-DQB1, INS, PTPN22, and CTLA4 were genotyped in patients with LADA (n = 213), type 1 diabetes diagnosed at >35 years of age (T1D(>35y); n = 257) or <20 years of age (T1D(<20y); n = 158), and type 2 diabetes.
Interestingly, the most susceptible T1D haplotypes, DRB1*0901-DQA1*05-DQB1*0201, DRB1*0301-DQA1*03-DQB1*0201, and DRB1*0301-DQA1*03-DQB1*0303, are not associated with LADA.
The results of our study show that LADA is positively associated with the CTLA-4 A/G genotype, similarly to T1DM, thus providing further supporting evidence of the autoimmune origin of this form of diabetes mellitus of the adult.
Latent autoimmune diabetes in adults (LADA) is identified by the presence of GAD65 autoantibodies in diabetic patients who do not require insulin treatment for at least six months after the diagnosis.