The heterogeneous pathogenesis of type 1 diabetes mellitus

Diabetes is a much more heterogeneous disease than the present subdivision into types 1 and 2 assumes; type 1 and type 2 diabetes probably represent extremes on a range of diabetic disorders. Both type 1 and type 2 diabetes seem to result from a collision between genes and environment. Although genetic predisposition establishes susceptibility, rapid changes in the environment (ie, lifestyle factors) are the most probable explanation for the increase in incidence of both forms of diabetes. Many patients have genetic predispositions to both forms of diabetes, resulting in hybrid forms of diabetes (eg, latent autoimmune diabetes in adults). Obesity is a strong modifier of diabetes risk, and can account for not only a large proportion of the epidemic of type 2 diabetes in Asia but also the ever-increasing number of adolescents with type 2 diabetes. With improved characterisation of patients with diabetes, the range of diabetic subgroups will become even more diverse in the future. Copyright © 2014 Elsevier Ltd. All rights reserved.

In the past 50 years, variants in the major histocompatibility complex (MHC) locus, also known as the human leukocyte antigen (HLA), have been reported as major risk factors for complex diseases. Recent advances, including large genetic screens, imputation, and analyses of non-additive and epistatic effects, have contributed to a better understanding of the shared and specific roles of MHC variants in different diseases. We review these advances and discuss the relationships between MHC variants involved in autoimmune and infectious diseases. Further work in this area will help to distinguish between alternative hypotheses for the role of pathogens in autoimmune disease development. Electronic supplementary material The online version of this article (doi:10.1186/s13059-017-1207-1) contains supplementary material, which is available to authorized users.

Type 1 diabetes mellitus (T1DM) is a chronic immune-mediated disease with a subclinical prodromal period, characterized by selective loss of insulin-producing-β cells in the pancreatic islets of genetically susceptible individuals. The incidence of T1DM has increased several fold in most developed countries since World War II, in conjunction with other immune-mediated diseases. Rapid environmental changes and modern lifestyles are probably the driving factors that underlie this increase. These effects might be mediated by changes in the human microbiota, particularly the intestinal microbiota. Research on the gut microbiome of individuals at risk of developing T1DM and in patients with established disease is still in its infancy, but initial findings indicate that the intestinal microbiome of individuals with prediabetes or diabetes mellitus is different to that of healthy individuals. The gut microbiota in individuals with preclinical T1DM is characterized by Bacteroidetes dominating at the phylum level, a dearth of butyrate-producing bacteria, reduced bacterial and functional diversity and low community stability. However, these changes seem to emerge after the appearance of autoantibodies that are predictive of T1DM, which suggests that the intestinal microbiota might be involved in the progression from β-cell autoimmunity to clinical disease rather than in the initiation of the disease process.