Phd in MOLECULAR MEDICINE

Thesis title: Immuno-metabolic and phenotypic characterization of autoimmune diabetes and its complications

Background and objectives. Latent autoimmune diabetes in adults (LADA) is marked by a slower decline in β-cell reservoir over time than early-onset, “classical” type 1 diabetes (T1D). The endogenous mechanisms that slow down the β-cell demise are unknown and barely investigated. This research appraisal is aimed at (1) investigating the autoimmunity against interferon (IFN)-α as a possible protective mechanism to distinguish LADA from classical T1D, and (2) evaluating whether residual secretion of C-peptide is related to better metabolic control and less glycemic variability in people with young-onset T1D. Materials and methods. To pursue the first aim, levels of autoantibodies against IFN-α (AAb-IFN-α) were measured using a cell-based approach in 41 subjects with LADA and in 90 subjects with T1D. The primary and secondary outcomes were the difference between LADA and T1D in the proportion of participants testing positive for AAb against ≥2 and against 3 IFN-α isoforms, respectively. To achieve the second aim, random C-peptide was measured in 61 subjects with duration of T1D <15 years and linked to two weeks of continuous glucose monitoring (CGM) data corresponding to the date of blood sampling. The primary outcome was the difference in C-peptide levels between participants with high time below range (TBR) (n=15) and those with lower TBR (n=45). Results. In the first study, 7 (17.1%) and 5 (12.2%) participants with LADA, and 3 (3.3%) and 0 participants with T1D showed positivity for AAb against ≥2 and 3 IFN-α isoforms (p=0.011, and p=0.0025, respectively). Among LADA-positive individuals, levels of AAb against IFN-α2 isoform were inversely correlated with glutamic acid decarboxylase antibodies (GADA) titers (rho= -0.513; p=0.025). In the second study, random C-peptide levels were significantly higher among participants in the low-TBR group than in the high-TBR group (52.9 [19.5-176.3] vs 21.0 [9.4-106.6] pmol/l p=0.03, SMD=0.4 Persistence of C-peptide was associated with improved CGM-metrics (p<0.05). In logistic regression analysis exploring the relationship between TBR and C-peptide, β-coefficient of the regressions was similar before and after correction for disease duration (p=0.72). Conclusions. This project provides the first evidence of endogenous anti-IFN-α reactivity as an autoimmune response in LADA, a slowly progressive form of autoimmune diabetes (AD). This response is less commonly observed in people with the rapidly progressive form of AD, representing an endogenous defensive response against the rapid β-cell decay and the early need for insulin treatment at diagnosis. Therapeutic approaches aimed at maintaining C-peptide secretion have the potential to improve glycemic outcomes in people with AD, ultimately ameliorating the patients’ quality of life.