Rationale. A consistent group of subjects with autoimmune diabetes (AD) is affected by a slowly progressive form of the disease, known as Latent Autoimmune Diabetes in Adults (LADA). This suggests that progression towards absolute insulin deficiency is not ineluctable. We hypothesize that LADA may offer a novel model to search for endogenous disease modifiers. These may be discovered by looking at differences between LADA and type 1 diabetes (T1D) in humoral features, proteomics, and in the clinical history of disease development.
Aim. To identify novel endogenous pathways of protection from disease progression in AD by carrying out a humoral, proteomic and phenotypic characterization of T1D and LADA.
Methods. In this cross-sectional study we will enroll two groups of subjects affected by AD representing the two extreme phenotypes of the disease: 100 subjects affected by T1D with no detectable C-peptide and 100 subjects affected by LADA with preserved ß-cell function after 5 years from the diagnosis. Novel candidate autoantibodies possibly related to lower autoimmune load (IA-2JM(601-630)) and quantitative proteomic profiles will be measured. Quantitative proteomic profiles will be compared between 50 T1D and 50 LADA matched for gender, kidney function and metabolic control by propensity score matching. Clinical history of the three years before diabetes development, including infectious diseases, allergies, surgery, pharmacotherapy, will be collected. Differences between the three groups will be evaluated and association with clinical features will be tested.
Novelty. We will investigate mechanisms of natural protection from AD by taking advantage from a population with the unique features of slow diabetes progression, free from insulin dependence, despite the presence of autoimmunity. This proposal is novel in that the heterogeneity of AD is proposed for the first time as an opportunity for understanding AD, with potential applications to precision medicine.
Expected outcomes:
We will investigate mechanisms of natural protection from AD by taking advantage from a population with the unique features of residual ß-cell function and slow diabetes progression, free from insulin dependence, despite the presence of autoimmunity. This proposal is novel in that the heterogeneity of AD is proposed for the first time as an opportunity for understanding and curing AD. We should expect to provide some robust means for dissecting the heterogeneity of AD susceptibility, pathophysiology and mechanisms of disease protection, with potential applications to precision medicine. The study of humoral features and proteome profiles of subjects with T1D and LADA will identify circulating proteins associated with immune response and/or reduced ßcell function and able to mark the differences between T1D and LADA and potentially associated to alterations in pancreatic islets. This project will also give the opportunity to create a unique biobank of liquid biopsies from subjects with AD at different stages of the disease in terms of ß-cell function and eventually of complications, to be used for future studies. The process towards a cure for AD should indeed encompass both a successful treatment supporting each patient with his own features and the identification of new pathways to prevent ß-cell failure to definitely clear patients from insulin-dependence. Strategies of preventing AD and slowing down ß-cell depletion will delay the need of insulin therapy and the onset of chronic complications, resulting in the reduction of both direct and indirect costs of AD, decreasing economic burden for health care system and for the whole society.
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