Impact of Body Size on Preclinical Type 1 Diabetes Development and Progression

Abstract

Type 1 diabetes arises from the interplay of genetic susceptibility and environmental exposures, leading to autoimmune β-cell destruction. Although disease-modifying therapies (DMTs) can delay progression to clinical (stage 3) type 1 diabetes, treatment responses remain inconsistent and transient. The marked heterogeneity of type 1 diabetes, shaped by age, sex, race/ethnicity, and genetic background, underscores the need to elucidate distinct mechanistic pathways. Among environmental contributors, obesity stands out as a compelling modifiable target. Data from The Environmental Determinants of Diabetes in the Young (TEDDY), Type 1 Diabetes TrialNet, and other longitudinal cohorts link BMI and adiposity to the onset of islet autoimmunity, progression through preclinical stages, and development of stage 3 type 1 diabetes. These associations are not uniform; heightened susceptibility to adiposity-related risk is seen among younger children, Hispanic populations, and individuals with specific HLA genotypes. Despite robust epidemiologic evidence, the biological pathways connecting elevated BMI to autoimmune β-cell destruction remain incompletely defined. Emerging data implicate a network of immunologic and metabolic disturbances, including insulin resistance, β-cell stress, chronic adipose tissue inflammation, altered adipokine signaling, and gut microbiome changes, that collectively heighten β-cell vulnerability, amplify autoreactive immune responses, and drive metabolic decompensation toward clinical disease. Elucidating these mechanisms and identifying related biomarkers are critical to advancing precision prevention. In future studies, investigators should evaluate whether modifying elevated BMI or targeting obesity-associated immunologic and metabolic pathways can alter the preclinical trajectory of type 1 diabetes. Such mechanistic understanding may help curb type 1 diabetes incidence and improve outcomes for populations most vulnerable to obesity-related risk.