Time dynamics of autoantibodies are coupled to phenotypes and add to the heterogeneity of autoimmune diabetes in adults: the HUNT study, Norway

Aims The aetiology of latent autoimmune diabetes in adults (LADA), assessed by autoimmune markers, is insufficiently clarified. We cross-sectionally investigated the prevalence and prospectively the prediabetic and postdiabetic presence of antibodies to glutamic acid decarboxylase (GADA), insulinoma-associated protein 2 and zinc transporter 8 in LADA and in type 1 diabetes. Methods We included 208 'classic' type 1, 161 LADA and 302 type 2 diabetic cases from the second (HUNT2: 1995-1997) and third (HUNT3: 2006-2008) Nord-Trondelag health surveys. Prospective data were available for 59 type 1, 44 LADA and 302 type 2 diabetic cases followed from HUNT2 to HUNT3. From HUNT3, 24 type 1 diabetic and 31 LADA incident cases were available. Results Cross-sectionally, 90% of LADA cases were positive for only one antibody (10% multiple-antibody-positive). Prospectively, 59% of GADA-positive LADA patients in HUNT2 were no longer positive in HUNT3. LADA patients who became negative possessed less frequently risk HLA haplotypes and were phenotypically more akin to those with type 2 diabetes than to those who stayed positive. Still, those losing positivity differed from those with type 2 diabetes by lower C-peptide levels (p=0.009). Of incident LADA cases in HUNT3, 64% were already antibody-positive in HUNT2, i.e. before diabetes diagnosis. These incident LADA cases were phenotypically more akin to type 1 diabetes than were those who did not display positivity in HUNT2. Conclusion/interpretation The pattern of antibodies, the postdiabetic loss or persistence as well as the prediabetic absence or presence of antibodies influence LADA phenotypes. Time-dependent presence or absence of antibodies adds new modalities to the heterogeneity of LADA.