Clinical and experimental treatment of type 1 diabetes

Abstract

Type 1 diabetes (T1D) is an autoimmune disease resulting in the destruction of the insulin-producing pancreatic beta cells. Disease progression occurs along a trajectory from genetic risk, the development of islet autoantibodies, and autoreactive T cells ultimately progressing to clinical disease. Natural history studies and mechanistic studies linked to clinical trials have provided insight into the role of the immune system in disease pathogenesis. Here, we review our current understanding of the underlying etiology of T1D, focusing on the immune cell types that have been implicated in progression from pre-symptomatic T1D to clinical diagnosis and established disease. This knowledge has been foundational for the development of immunotherapies aimed at the prevention and treatment of T1D.

Keywords: autoantibodies; autoimmunity; cellular immunology; diabetes; immunotherapy.

Graphical Abstract

Figure 1:

Predisposition, natural history, and staging of T1D. Disease progression occurs along a trajectory from genetic risk, initiation, and progression to clinical diagnosis. During initiation and progression, there is immune activation and immune response, respectively, with the development of islet autoantibodies. Disease progression is sequential but the rate of progression is variable among individuals. There are three stages of pre-symptomatic disease as defined by JDRF, the Endocrine Society, and the American Diabetes Association [7]: Stage 1 is defined by two or more islet autoantibodies with normal blood glucose levels; Stage 2 is two or more islet autoantibodies with dysglycemia; and Stage 3 is clinical diagnosis with symptomatic T1D. Ongoing research seeks to define the environmental triggers that initiate and promote disease progression.

Figure 2:

Balance of innate and adaptive fixed and acquired immune phenotypes during the trajectory of T1D. Early fixed phenotypes in orange, early dynamic phenotypes in light blue, phenotypes acquired during progression in purple, and phenotypes acquired at clinical disease onset in red.

Figure 3:

HLA, age, and immune features distinguish fast disease progression from slow disease progression. Beta cell function as measured by C-peptide loss. Fast progressors are defined by complete loss of beta cell function within 2 years of diagnosis.