A substrate-competition hypothesis for type 2 diabetes driven by nutrient excess rather than a primary insulin-signaling defect

Type 2 diabetes (T2D) is most commonly framed within a dominant insulin-resistance paradigm characterized by reduced insulin-stimulated glucose disposal and inadequate suppression of hepatic glucose output. While this framework describes reproducible physiological phenotypes, the causal status and temporal ordering of insulin-signaling–associated changes in the development of chronic hyperglycemia remain debated. Clinical observations—including variable diabetes risk across BMI strata and frequent glycemic improvement with dietary change—motivate consideration of alternative causal models.

This article proposes an alternative hypothesis for the pathogenesis of T2D with an explicit causal sequence that does not invoke a primary insulin-signaling defect. In this framework, chronic dietary substrate surplus—particularly refined-carbohydrate exposure—exceeds an individual’s capacity to buffer and safely store lipid in adipose tissue (“personal fat threshold”). As adipose buffering becomes constrained, lipid overflow into the circulation and non-adipose tissues increases, leading to ectopic lipid accumulation in liver and skeletal muscle. This metabolic state promotes a preferential shift toward fatty-acid oxidation via substrate competition (the Randle cycle), functionally displacing glucose utilization. Within this framework, reduced insulin effectiveness emerges as a context-dependent physiological phenotype rather than as evidence of a required insulin-signaling defect or a necessary causal mediator of dysglycemia.

The model yields falsifiable predictions regarding temporal ordering and measurable intermediates and outlines cohort and controlled feeding-trial designs that allow direct empirical adjudication between this framework and insulin-resistance–first models, with implications for dietary strategies in T2D prevention and treatment.