Introducing the Endotype Concept to Address the Challenge of Disease Heterogeneity in Type 1 Diabetes

Abstract

The clinical diagnosis of new-onset type 1 diabetes has, for many years, been considered relatively straightforward. Recently, however, there is increasing awareness that within this single clinical phenotype exists considerable heterogeneity: disease onset spans the complete age range; genetic susceptibility is complex; rates of progression differ markedly, as does insulin secretory capacity; and complication rates, glycemic control, and therapeutic intervention efficacy vary widely. Mechanistic and immunopathological studies typically show considerable patchiness across subjects, undermining conclusions regarding disease pathways. Without better understanding, type 1 diabetes heterogeneity represents a major barrier both to deciphering pathogenesis and to the translational effort of designing, conducting, and interpreting clinical trials of disease-modifying agents. This realization comes during a period of unprecedented change in clinical medicine, with increasing emphasis on greater individualization and precision. For complex disorders such as type 1 diabetes, the option of maintaining the "single disease" approach appears untenable, as does the notion of individualizing each single patient's care, obliging us to conceptualize type 1 diabetes less in terms of phenotypes (observable characteristics) and more in terms of disease endotypes (underlying biological mechanisms). Here, we provide our view on an approach to dissect heterogeneity in type 1 diabetes. Using lessons from other diseases and the data gathered to date, we aim to delineate a roadmap through which the field can incorporate the endotype concept into laboratory and clinical practice. We predict that such an effort will accelerate the implementation of precision medicine and has the potential for impact on our approach to translational research, trial design, and clinical management.Describing aspects of biology as "heterogeneous" often has a negative connotation. It is a term that is used when we do not understand a measured or observed aspect of disease or when we need to explain data that are not consistent. However, it is evident that recognizing that there are "different kinds" of cells, genes, types of response, and severity of disease could offer a set of opportunities for therapies to work and biomarkers to be meaningful. Thus, it may be time to exploit heterogeneity rather than curse it and to use the opportunity to carve out endotypes of type 1 diabetes that have traction both in the clinic and in the laboratory.The introduction of the term "endotype" can largely be attributed to developments in the field of asthma (1) when it became apparent in the late 1990s that different pathogenic mechanisms induce a similar symptom cluster and manifest as a

Type 1 diabetes in Africa: an immunogenetic study in the Amhara of North-West Ethiopia

“…GADAnegative patients demonstrated an association with HLA-DRB1*04 and protection with HLA-DRB1*15. In short, they have some of the immunogenic features of the autoimmune diabetes of adolescent and adult European-origin and Chinese populations [41], while the diabetes-associated autoantibody, GADA, was similarly the dominant autoantibody and associated with HLA-DRB1*03:01, consistent with heterogeneity of type 1 diabetes endotypes [42,43]. Our observations imply a widespread commonality in GADA-dominant, HLAassociated adult-onset autoimmune diabetes, despite global variation in the precise HLA-associated genotypes.…”

Efficacy of GAD-alum immunotherapy associated with HLA-DR3-DQ2 in recently diagnosed type 1 diabetes

“…We further show that the effect is most pronounced in individuals who are simultaneously negative for genotypes that include the HLA-DR4-DQ8 haplotype. Interestingly, recent research highlights the existence of different phenotypes of type 1 diabetes based on autoantibody seroconversion that, in turn, are linked to HLA risk haplotypes [7,9,10]. More specifically and as noted above, as HLA-DR3-DQ2 has been associated with seroconversion to GAD65 autoantibodies and DR4-DQ8 with seroconversion to insulin autoantibodies [7,10], our results suggest that the best efficacy of antigen-specific immunotherapy may be achieved when targeting individuals that show a specific HLA type that is linked to the tolerising antigen.…”

“…The effect of GAD-alum on preserving endogenous insulin production has been evaluated in several placebo-controlled, randomised trials in individuals recently diagnosed with type 1 diabetes, albeit with inconclusive results [1][2][3][4]. It is becoming increasingly clear that factors such as genetic background in the form of HLA genotype affect both the risk of diabetes affliction and the pathogenesis of the disease [5][6][7][8][9][10][11][12][13]. It is conceivable that HLA may also influence the effect of antigen-specific immunotherapies like GAD-alum and while this possibility has been considered incidentally in prior clinical trials [2,3], this hypothesis has not been extensively evaluated.…”

Studies of insulin and proinsulin in pancreas and serum support the existence of aetiopathological endotypes of type 1 diabetes associated with age at diagnosis

“…Therefore, to address this, we have made use of both the Network of Pancreatic Organ Donors (nPOD) biobank of organ donor pancreas samples collected in the USA and a separate, unique, collection of pancreases recovered from young people close to the clinical onset of type 1 diabetes from the UK [5,6]. In particular, we have adopted a histological approach to consider an important question raised by emerging data (reviewed recently by Battaglia et al [7]) which imply that type 1 diabetes may not represent a single disease but that distinct endotypes exist. This concept is of critical importance since, if verified, it suggests that different immunotherapeutic approaches will be required to achieve successful intervention in specific groups of patients.…”