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Review
. 2016 Jan 27:5:F1000 Faculty Rev-110.
doi: 10.12688/f1000research.7356.1. eCollection 2016.

Recent advances in understanding Type 1 Diabetes

Gustaf Christoffersson  1 , Teresa Rodriguez-Calvo  1 , Matthias von Herrath  2
Affiliations
Review

Recent advances in understanding Type 1 Diabetes

Gustaf Christoffersson et al. F1000Res. .

Abstract

Type 1 diabetes is a multifactorial disease in which genetic and environmental factors play a key role. The triggering event is still obscure, and so are many of the immune events that follow. In this brief review, we discuss the possible role of potential environmental factors and which triggers are believed to have a role in the disease. In addition, as the disease evolves, beta cells are lost and this occurs in a very heterogeneous fashion. Our knowledge of how beta cell mass declines and our view of the disease's pathogenesis are also debated. We highlight the major hallmarks of disease, among which are MHC-I (major histocompatibility complex class I) expression and insulitis. The dependence versus independence of antigen for the immune infiltrate is also discussed, as both the influence from bystander T cells and the formation of neo-epitopes through post-translational modifications are thought to influence the course of the disease. As human studies are proliferating, our understanding of the disease's pathogenesis will increase exponentially. This article aims to shed light on some of the burning questions in type 1 diabetes research.

Keywords: Beta Cell Mass; Beta Cells; Environmental Triggers; Insulitis; MHC-I expression; Type 1 Diabetes.

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Conflict of interest statement

Competing interests: MGvH is an employee of Novo Nordisk. The other authors declare that they have no competing interests.

No competing interests were disclosed.

Figures

Figure 1.
Figure 1.. What does the type 1 diabetes scenario look like nowadays?
Genetically predisposed individuals are exposed to a triggering event, which induces inflammation and upregulation of major histocompatibility complex class I (MHC-I) molecules in endocrine cells. Autoantibodies against islet antigens appear in the circulation during the autoantibody-positive phase. In this period, blood glucose levels are normal and there are no evident symptoms of the disease. During this chimera of normality, autoreactive T cells proliferate and start to infiltrate the islets, causing waves of beta cell death. In this period, an imbalance between beta cell death and survival generates small fluctuations in beta cell mass. The immune infiltration becomes apparent during the pre-diabetic phase, in which infiltrating cells actively destroy beta cells at a faster pace, a phenomenon that cannot be overcome by endogenous regulatory elements. Dysregulation of glucose levels starts to appear because of the inability of the remaining beta cells to produce enough insulin. In addition, post-translational modifications (PTMs) might arise as a consequence of endoplasmic reticulum stress and inflammation, potentiating the activation of cytotoxic CD8 + T cells and further beta cell destruction. PTMs might expand into the diabetic period, as inflammation is still present. At diagnosis, the number of cells infiltrating the islets is large and insulitis becomes more apparent. The decline in beta cell mass makes it impossible to control glucose levels, and the first symptoms of disease start to appear. During the first years of the diabetic period, C-peptide might still be detectable as some beta cells manage to survive the immune attack. However, as beta cell mass diminishes, so do inflammation and infiltration. Overall, fluctuations in beta cell mass over the years create a continuous relapsing-remitting phenotype with a more abrupt fall around the time of diagnosis, when a critical beta cell mass is reached.
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Grants and funding

GC is supported by a postdoctoral fellowship from the Swedish Research Council.