Markers of autoimmunity in Latent Autoimmune Diabetes in Adults (LADA) and non-diabetic adults: Impact in phenotype and genetic predisposition: Results from the Nord-Trøndelag health study

Abstract

Diabetes is mainly classified: type 1 and type 2 diabetes. Type 1 diabetes is an autoimmune disease in which the body's immune system attacks and destroys the beta cells that produce insulin. Patients with type 2 diabetes have somewhat reduced insulin production which coupled to poor insulin efficiency leads to increased levels of blood glucose. In 1986 a group of patients who deviated from the classical type 2 diabetes diagnosis was reported. These patients showed signs of autoimmunity in form of detectable antibodies (mainly antiGAD) against the insulin-producing beta cells, antibodies which are commonly found in type 1 diabetes. The patients had still considerable good betacell function and were initially diet and/or orally treated like type 2 diabetes. However, as a group they developed insulin dependency faster than type 2 diabetes. This patient group was later called Latent Autoimmune Diabetes in Adult (LADA). As with type 2 diabetes the LADA patients are older at diagnosis and often overweight. Nevertheless, the LADA patients display a high risk for progression to insulin dependency. This suggests that the etiology of LADA is a mix of type 1 and type 2 diabetes. The prevalence of LADA is similar to that of type 1 diabetes; however the etiology and phenotype of LADA is less characterized than type 1 and type 2 diabetes. The aim of this study was therefore primarily to investigate the genetic and phenotypic background of LADA. We also looked at the presence and clinical implications of antiGAD positivity in a general adult non-diabetic population. The study was based on data from the second (HUNT2: 1995-1997) and third (HUNT3:2006-2008) Nord-Trøndelag health surveys. Paper I: The aim was to identify genetic risk factors that could affect the development of LADA. This was done by looking at known risk genes for both type 1 and type 2 diabetes and their link to LADA. Genetic similarities were found with both type 1 and type 2 diabetes. Further, the type 1 diabetes genes were associated with LADA with higher degree of autoimmunity (high titres of antiGAD), while type 2 diabetes genes were associated with LADA with lower autoimmunity. Overall, the data suggest that LADA patients with high autoimmunity are genetically more similar to type 1 diabetes, and LADA patients with low autoimmunity are genetically more similar to type 2 diabetes. Paper II: The aim was to study the autoimmune process in LADA patients, both before and after diagnosis of diabetes. We followed the LADA patients who had participated in both HUNT2 and HUNT3 by measuring antibodies that are known to be related to autoimmunity in patients with type 1 diabetes (anti-GAD, anti-IA-2 and anti-ZnT8). Over 50% of the LADA patients, who had participated in both HUNT2 and HUNT3, were antibody negative after the 10-year period between HUNT2 and HUNT3. LADA patients who were antibody negative were more type 2 diabetes like; i.e. they were more obese and older when they developed diabetes, than those who kept their positivity. However, the antibody negative LADA patients had significantly lower C-peptide values than patients with type 2 diabetes. This suggests that even a short period of antibody positivity is of clinical importance. Samples analysed for antiGAD also showed that many of the LADA patients who developed LADA after HUNT2 had detectable antibody in the blood at HUNT2, i.e. before the onset of the disease. Thus, for some LADA patients there is a long period of pre-diabetes in the form of an ongoing autoimmune process. LADA patients with positivity for antibodies at HUNT2 were more type 1 diabetes like compared with those who were antibody negative. These findings show that the antibody patterns in LADA patients affect the LADA patients' disease progression and phenotype. Paper III: The presence and clinical implications of antiGAD positivity in non-diabetic populations are poorly elucidated. We examined these aspects prospectively in a cohort of adult non-diabetic patients (n = 4496) who had participated in both HUNT2 and HUNT3. AntiGAD positivity was found in 1.7% of the group. Positivity was not associated with gender, first-degree family history of diabetes (FHD), smoking, glucose or BMI. However, the HLA-DQA1/DQB1 haplotype, a known risk haplotype for type 1 diabetes was associated with antiGAD positivity. Association was also found with positivity for antiTPO, an antibody found in hypothyroidism. Approximately 50% of the patients who were positive by antiGAD at HUNT2 had turned antiGAD negative at HUNT3. We conclude that antiGAD positivity in persistently non-diabetic individuals is partly consistent, is not associated with clinical parameters related to diabetes, but is associated with high risk HLA haplotypes and autoimmunity in the thyroid gland.