Type 1 Diabetes: Disease Stratification

Abstract

Type 1 diabetes, a disorder characterized by immune-mediated loss of functional pancreatic beta cells, is a disease continuum with specific presymptomatic stages with defined risk of progression to symptomatic disease. Prognostic biomarkers have been developed for disease staging and for stratification of subjects that address the heterogeneity in rate of disease progression. Using biomarkers for stratification of subjects at different stages of type 1 diabetes will enable smaller and shorter intervention clinical trials with greater effect size. Addressing the heterogeneity of the disease will allow precision medicine-based approaches to prevention and interception of presymptomatic stages of disease and treatment and cure of symptomatic disease.

Keywords: Autoantibodies; Autoimmune process; Beta cell; Biomarkers; Dysglycemia; Staging; Stratification; Type 1 diabetes.

Fig. 1

Progression and staging of type 1 diabetes. Type 1 diabetes is characterized by a progressive loss of beta cell function (black dashed-dotted line) over time. As the disease progresses, beta cell function falls below the threshold (red dashed line) required to maintain glucose control creating a requirement for insulin replacement therapy. Type 1 diabetes may be staged over the course of its progression starting with stage 1 at which point 2 or more of the 4 commonly measured islet autoantibodies are detected with normoglycemia. Stage 2 is marked by the appearance of dysglycemia associated with loss of beta cell function in addition to the presence of autoantibodies. Stage 3 is defined by hyperglycemia requiring insulin. In the green boxes are categories of biomarkers which could be leveraged to refine the staging paradigm, improve prognostic predictions, or subset individuals within a given stage of disease. The specifics of these biomarkers are discussed in the text related to the relevant stage.