Correlation analysis between cytokines’ profile, autoimmune antibodies and the duration of type 1 diabetes: A case control study in a specialized children’s centre in Riyadh

Abstract

Objective: The aim of this study was to investigate the role of cytokines in children with T1D living in Saudi Arabia and their correlation with disease duration and autoimmune antibody markers. Methods: A case-control study was conducted in the endocrine clinic of King Abdullah Specialized Children’s Hospital in Riyadh. A total of 274 T1D and healthy control children were enrolled in the study. 5 mL of venous blood samples were collected in the morning after 9 to 12 h of fasting in BD Vacutainer® EDTA tubes and centrifuged at 250 g for 15 min at. Plasma was then stored at −20°C for detection of anti-islet, anti-GAD antibodies (Abs), and C-peptide using commercial ELISA kits from Thermo Fisher Scientific. The levels of cytokines were measured using commercial sandwich ELISA kits from Abcam. Results: Median differences in cytokine levels (IFN-γ, TNF-α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-13, IL-18, IL-21, IL-35, and IL-37) were significantly higher in T1D patients compared with healthy controls ( p-value < .001). Spearman’s Rho correlation indicated that TNFα, IL-1β, IL-4, IL-10, IL-13, and IL-21 correlated significantly with T1D Abs ( p-value = .01). HbA1C correlated negatively with IL-35 and IL-37, and positively with IL-18 ( p-value = .01). Linear regression analysis showed a significant increase in anti-glutamic acid antibodies (GAD) in patients with >3 years of T1D duration. Conclusion: Autoantibodies remained positive at high levels in our patients over a 3-year duration of the disease and correlated with specific cytokines. The clear correlations with disease duration and profile of specific cytokines could be targets for future therapeutic interventions.

The Impact of Metabolic Memory on Immune Profile in Young Patients with Uncomplicated Type 1 Diabetes

“…Although the A1 and A2 subgroups of patients with diabetes were statistically different in terms of the duration of the disease, the current HbA 1c levels were comparable between the subgroups. Our data are in agreement with the findings of Al-Dubayee et al [ 49 ] while others have shown that a longer duration of diabetes is associated with higher HbA 1c levels [ 65 , 66 ]. In our study, we have shown ( Table 2 ) that there were no differences in the levels of pro-inflammatory cytokines, IL-12 and IL-18, between all subgroups.…”

“…This finding is in line with a study by Overgaard et al, which has demonstrated that in pediatric patients with type 1 diabetes, TNF-α correlates with residual beta-cell function and may serve as a prognostic marker of disease progression [ 67 ]. Other studies have also shown elevated levels of TNF-α in patients with T1D [ 26 , 27 , 33 , 49 ]. Our study results demonstrated that glycemic control in the first year of disease (HbA 1c onset, HbA 1c 1st year) has a significant impact on inflammation even years later.…”

“…Some authors have shown a significant positive correlation between TNF-α and HbA 1c [ 65 ]. On the other hand, some studies have demonstrated a significant negative correlation between the levels of IL-12 [ 63 ], IL-35 [ 49 ], and HbA 1c levels. Similarly to our results, Al-Dubayee et al found no significant relationship between higher levels of HbA 1c and TNF-α IL-4 or IL-10 and the HbA 1c level [ 49 ].…”

“…This cytokine may play a crucial role in reducing inflammation and improve insulin sensitivity in T1D. In contrast, IL-18 had been shown to have a positive correlation with HbA1c levels [ 49 ]. Harms et al demonstrated a positive correlation between IL-18, IL-18 BP, and HbA1c levels in patients with T1D.…”

“…IL-4, IL-10, and IL-13 cytokines have been proposed to activate the humoral immune response by stimulating B cells to release autoantibodies against islet cells and GAD molecules. Serum levels of cytokines such as IFN-γ, TNF-α, IL-6, IL-1β, IL-4, and IL-10 were significantly higher in patients with T1D compared to healthy individuals [ 41 , 49 , 53 ]. These findings suggest that hyperglycemia may upregulate inflammatory pathways and increase pro-inflammatory cytokine secretion in patients with T1D [ 54 ].…”