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The increasing incidence of type 1 diabetes observed in the past 60 years has spawned massive efforts in multiple research fields to elucidate the aetiology of this disease. While GWAS studies provide a good genetic basis for the current knowledge, it is clear that environmental triggers and their influence in disease prevalence and origin are highly important. The realization of disease heterogeneity has created a requirement for better biomarkers to complement the known autoantibody markers and to more successfully predict the severity and onset time of the disease. Such biomarkers would be needed both for prevention as well as for monitoring disease activity and response to preventive and therapeutic measures. Systematic holistic approaches concentrating on the triggering molecular mechanisms, pancreatic beta cells, immune response, as well as the influence of diet and environment, are necessary to understand the disease pathogenesis and find a cure. The current genomic knowledge is being broadened with accompanying studies in epigenetics and transcriptomic regulation, metabolomics, proteomics and lipidomics, covering the whole system from beta cells, the profile and cellular balance of the infiltrating lymphocytes, to gut microbiota and viral infections. Here we highlight interesting recent findings in type 1 diabetes research. [ABSTRACT FROM AUTHOR]

The therapeutic capacity of an antibody directed against the T cell receptor (anti-TCR) of the TCR/CD3 complex alone or in combination with fingolimod (FTY720) to reverse the diabetic metabolic state through suppression of autoimmunity and stimulation of β cell regeneration was analyzed in the LEW.1AR1- iddm (IDDM) rat, an animal model of human type 1 diabetes. Animals were treated with anti-TCR (0.5 mg/kg body weight for 5 days) monotherapy or in combination with fingolimod (1 mg/kg body weight for 40 days). Metabolic changes and β cell morphology were analyzed before, immediately after, and 60 days after end of therapy. Both therapies were started early after disease manifestation and led to normoglycemia in parallel with an increase of the C-peptide concentration. Combination therapy increased the β cell mass reaching a range of normoglycemic controls, decreased the apoptosis rate fivefold, and increased the proliferation rate threefold. Additionally, at 60 days after therapy, islets were virtually free of T cells, macrophages, and cytokine expression. In contrast, after anti-TCR monotherapy, β cell mass remained low with an activated immune cell infiltrate. A concomitant fivefold increased β cell apoptosis rate resulted in a complete loss of β cells. Only combination therapy yielded sustained normoglycemia with full reversal of islet infiltration and restoration of pancreatic β cell mass. Key Message: [ABSTRACT FROM AUTHOR]