Biology and Natural History of Type 1 Diabetes Mellitus

Abstract: Type 1 diabetes mellitus is a clinical condition characterized by insufficient insulin pro-duction due to progressive loss of pancreatic islet β-cells mediated by an autoimmune response. This deregulation of the immune system is caused by the action of genetic, epigenetic, and envi-ronmental factors in varying combinations for each individual. Although the inflammation of the islets with immune cell infiltration, known as insulitis, is an important element in pathogenesis, oth-er factors are necessary for disease initiation. Associations with variants of HLA and other genes related to immune system function, mainly haplotypes HLA-DR3-DQ2 and HLA-DR4-DQ8, are more evident. The influence of polymorphisms and epigenetic modifications, as well as the micro-biome, is convincing proof of the existence of a complex interaction between genetic, immune, and environmental factors in the etiology and pathogenesis of this metabolic disorder. Loss of self-tolerance to autoimmunity is a critical point in the development of the disease, and regulatory T cells play a key role in this process. Thus, any failure of these cells, either due to an insufficient number or altered expression of cytokines and transcription factors, may be the trigger for the onset of the disease. The protective action of regulatory T cells is controlled by gene expression that is modulated by epigenetic modifications, including the dysregulation of noncoding RNAs. This re-view takes an updated approach to the natural history of type 1 diabetes, focusing on the factors in-volved in the etiology and pathogenesis.