Type 1 diabetes and obesity in children : Focus on inflammation

Abstract

Type 1 diabetes (T1D) is an inflammatory disorder as is obesity. This thesis addresses inflammatory features in both conditions, with focus on inflammatory mediators and the role of adipose tissue (AT). The first part, specific aspects of immune tolerance in T1D,focuses on immune (dys) regulation and biomarkers for the immune responses elicited in T1D. Recognition of pan HLA-DR binding HSP-60 epitopes in paediatric new-onset T1D patients is studied and compared with longstanding T1D patients as well as healthy controls. Although HSP60 peptides induced low peptide-specific proliferative responses we detected some, mainly intracellular, peptide-specific cytokine production in T1D patients. Biomarkers for the remission period could not be identified. Next, we report our finding that autoreactive CD8 T cells, recognizing preproinsulin (PPI) peptides binding with very low affinity to HLA molecules, appear to escape thymic selection while numbers of PPI specific CD8 T cells are decreased for peptides with intermediate and high HLA-A2-binding affinity. Therefore, very low affinity binding peptides might play an important role in mediating loss of tolerance. The second part, AT inflammation and the role of adipokines in T1D and obesity, focuses on AT inflammation, more specifically on the role of adipokines in T1D and obesity by studying adipokine levels as well as adipocyte differentiation under various conditions in new-onset paediatric T1D patients. Results were compared to healthy controls (HC) and patients with longstanding T1D. In T1D patients increased adipokine levels where found, while some adipokines further increased with longer duration of T1D. Furthermore, plasma factors (but not glucose and free fatty acids) in T1D patients were shown to in vitro influence adipocyte differentiation as well as secretion of adipokines by these adipocytes.Next, the role of vitamin D deficiency with regard to inflammation and insulin sensitivity in obese children was analysed and compared to healthy controls by performing comprehensive profiling of inflammatory mediators. Vitamin D deficiency was shown to be an independent factor influencing systemic inflammation, while vitamin D sufficiency is associated with better insulin sensitivity in obesity. The final part, inflammatory mediators in pancreatic β cell transplantation in T1D,describes an exploratory study to identify prognostic or descriptive biomarkers of disease remission, recurrence and progression in T1D patients transplanted with pancreatic islets, during the first year after transplantation. Interestingly, inflammatory mediator levels varied more between individual patients than being influenced by transplantation and concomitant immune suppression. Nonetheless, distinct immune correlates could be identified in serum that associated with clinical outcome. These findings are then discussed in a broader perspective. Anti-inflammatory therapies, including vitamin D, treatment with HSP60 peptides and cytokine blockade, have the potential to positively affect β cell function while AT inflammation might further compromise β cell function. Next, the role of inflammatory mediators as biomarkers in paediatric T1D and obesity is discussed. Although, in our studies, no single inflammatory mediator was identified predicting outcome of various interventions in T1D, combining inflammatory mediators to evaluate interventions may hold promise, specifically in a personalised approach.