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

Abstract

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. Results Cross-sectionally, 90% of LADA cases were positive for only one antibody (10% multiple-antibodypositive). 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 (p0 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.

LADA and CARDS: A Prospective Study of Clinical Outcome in Established Adult-Onset Autoimmune Diabetes

“…The very low prevalence of both IA-2A or ZnT8A in this CARDS cohort with established diabetes contrasts with that in cohorts with recent-onset non-insulin-requiring diabetes, in line with the results from the second survey of the Norwegian HelseUndersøkelsen i Nord-Trøndelag Study (HUNT2), as well as the known tendency for both IA-2A and ZnT8A to disappear postdiagnosis (15,(18)(19)(20). In HUNT2, 59% of LADA patients lost GADA on follow-up, but of those who remained autoantibody positive all but one had GADA; IA-2A and ZnT8A showed a decrease in the titer over 10 years, but GADA titer did not decline (21). We would, therefore, not recommend testing of either IA-2A or ZnT8A in patients with established, compared with newly diagnosed, type 2 diabetes.…”

Smoking Is Associated With Reduced Risk of Autoimmune Diabetes in Adults Contrasting With Increased Risk in Overweight Men With Type 2 Diabetes

“…In this context, one cannot rule out the possibility that the association with GADA is restricted to alteration of the time dynamics of GADA. GADA levels are known to rise and then fall in pediatric patients with type 1 diabetes (23,24); however, evidence indicates that GADA are more persistent in LADA (25,26), at least in those who display high titers. In a previous study (25), it was shown that a majority of those who developed LADA between HUNT2 and HUNT3 were GADA-positive already at HUNT2 (i.e., during prediabetes) with no significant change in GADA between HUNT2 and 3.…”

Overweight, obesity and the risk of LADA: results from a Swedish case–control study and the Norwegian HUNT Study

“…Also, previous studies in the HUNT Study indicate a real impact of even low and transient levels of GADA, e.g. individuals with low GADA display lower fasting C-peptide levels than individuals with type 2 diabetes [44]. Still, the importance of GADA positivity for disease progression in very obese individuals with low GADA levels is unclear.…”

“…In the HUNT Study, some individuals had GADA measured several years after diagnosis. Because GADA can disappear after prolonged disease duration [44], it is possible that some individuals with LADA therefore appeared GADA negative and were classified as having type 2 diabetes. Notably, GADA tends to be more stable in LADA than in type 1 diabetes [12].…”