We studied nPOD donors with type 1 diabetes and demonstrated a significant positive association between residual ICI%≥5 and the type 2 diabetes-associated TCF7L2 rs7903146 T allele (i.e. CT or TT genotype). This association was significantly stronger in AA donors than in other racial groups. Unsurprisingly, shorter diabetes duration was also a predictor of residual ICI%≥5.

Overall, these data support the presence of a type 1 diabetes endotype associated with a genetic factor influencing metabolic pathways that predispose to type 2 diabetes [4], and donors in this category exhibited less severe beta cell loss. It is possible that the disease pathogenesis may include type 2 diabetes-associated mechanisms, and this may provide an explanation for the poor response to immunotherapies to prevent type 1 diabetes or its progression in a subset of individuals. If so, strategies that target both type 1 diabetes and type 2 diabetes-associated factors when they are present may increase the success of prevention and treatment.

Although the association between AA race and ICI%≥5 after adjusting for age, diabetes duration, sex, BMI and TCF7L2 variant did not reach statistical significance (p=0.053), the association between TCF7L2 variants and higher ICI% was significantly stronger in AA donors than in other races (p=0.0167). Potential explanations for the differences between ancestries include both genetic and environmental factors. Although genetic differences among ancestries are starting to be known, the notable type 1 diabetes genetic heterogeneity within populations of African ancestry and the influence of genetics on beta cell function warrant further study. Our knowledge on the environmental factors that affect residual beta cell function is even more limited. Obesity modifies the progression of islet autoimmunity [10] and increases the risk of type 1 diabetes [5], but this increase is almost four times higher for Hispanic than NHW autoantibody-positive adolescents and adults [11]. Although this association is yet to be tested in AA individuals, the observation that racial and ethnic minorities in the USA have a higher prevalence of obesity and, simultaneously, are experiencing higher increases in type 1 diabetes incidence than NHW individuals supports the impact of obesity on the development of type 1 diabetes. Thus, it will be important to test whether prevention of obesity lowers type 1 diabetes risk in cohorts from racially and ethnically diverse backgrounds.

Shorter diabetes duration was associated with a higher ICI%, predictably as beta cell loss continues after diabetes onset [12]. Similarly, individuals presenting at an older age have slower rates of C-peptide decline and, thus, retain higher residual beta cell function. As we adjusted for age and diabetes duration, these factors are unlikely to explain the differences seen.

Limitations of the study include its retrospective design, the use of a data-driven definition of high ICI% and that there were more than twice as many donors with a low ICI%. Additionally, our analysis was limited to nPOD donors with sufficient tissue sample for testing. While these analyses should be considered exploratory, they generate intriguing hypotheses that warrant further investigation. Studying gene expression profiles at beta cell level, along with proteomic and metabolic profiles, may further our knowledge of the mechanisms underlying our observations. Altogether, our study sheds light on the variability of residual beta cell function in type 1 diabetes. This knowledge will help dissect the heterogeneity within and between diabetes types and further our understanding of the aetiopathogenesis of type 1 diabetes.