Time-dependent effects on circulating cytokines in patients with LADA: A decrease in IL1-ra and IL-1 beta is associated with progressive disease.

BACKGROUND: Cytokines and chemokines participate in autoimmune processes at cellular targets which include insulin-producing beta cells. To which extent such participation is reflected in the circulation has not been conclusively resolved. AIM: We compared the time course of cytokines/chemokines in Latent Autoimmune Diabetes in Adults (LADA) patients heterogeneous for high or low autoimmune activity as determined by levels of antibodies against glutamic acid decarboxylase (GADA). METHODS: Serum samples to be measured were from a two-armed randomized controlled trial (RCT) in 68 LADA patients. The study encompassed 21 months with C-peptide as primary endpoint. We measured 27 immune mediators at baseline, at 9 and at 21 months (end of study). Results of measurements were analyzed by multiple linear regression. RESULTS: At baseline, a high body mass index (BMI) (>26 kg/m2) was associated with elevated levels of the interleukins (IL) IL-1 beta, IL-1ra, IL-2, IL-5, IL-6 and IL-13. Treatment during RCT (sitagliptin vs. insulin) did not affect the time course (21 months) of levels of cytokines/chemokines (by univariate analyses). However, levels of the cytokines IL-1ra and IL-1 beta decreased significantly (p < 0.04 or less) in patients with high vs. low GADA when adjusted for BMI, age, gender (male/female), treatment (insulin/sitagliptin) and study site (Norwegian/Swedish). CONCLUSIONS: In LADA, high levels of GADA, a proxy for high autoimmune activity and linked to a decline in C-peptide, was associated with a decrease of selected cytokines over time. This implies that the decline of IL-1ra and IL-1 beta in the circulation reflects autoimmune activity and beta cell demise in LADA.

Investigating optimal ß-cell-preserving treatment in latent autoimmune diabetes in adults: Results from a 21-month randomized trial.

AIMS: To compare outcomes of glucagon-stimulated C-peptide tests (GSCTs) in people with latent autoimmune diabetes in adults (LADA) after a 21-month intervention with either insulin or the dipeptidyl peptidase-4 inhibitor sitagliptin. RESEARCH DESIGN AND METHODS: We included 64 glutamic acid decarboxylase (GAD) antibody-positive individuals, who were diagnosed with diabetes <3 years before the study, aged 30 to 70 years, and without clinical need for insulin treatment. We stratified participants by age and body mass index (BMI) and evaluated ß-cell function by GSCT after a 48-hour temporary withdrawal of study medication. RESULTS: Age at randomization (mean 53 years), BMI (mean 27 kg/m2 ) and metabolic markers were similar between treatment arms. Glycated haemoglobin concentrations during intervention did not differ between arms. Fasting C-peptide concentrations after the intervention were similar, as were stimulated C-peptide levels (0.82 ± 0.63 nmol/L after insulin, 0.82 ± 0.46 nmol/L after sitagliptin; nonsignificant). Autoimmunity in the study population (estimated from GAD antibody titres and positivity/no positivity for zinc transporter 8 and islet antigen 2 antibodies) affected the evolution of the GSCT results significantly, which deteriorated in participants with high but not in those with low autoimmunity. Adjustment using analysis of covariance for the degree of autoimmunity did not alter the findings of no difference between treatment arms. CONCLUSIONS: ß-cell function after intervention was similar in patients with insulin- and sitagliptin-treated LADA, regardless of the strength of autoimmunity. Further, participants with low levels of GAD antibodies did not experience progressive deterioration of ß-cell function over a 21-month period. Taken together, these findings could be useful for clinicians' choices of treatment in people with LADA.