Declining insulin sensitivity is a key pathological contributor to dysglycemia: a longitudinal validation study in the Korean genome and epidemiology study

Background: The role of worsening insulin resistance (IR) in type 2 diabetes (T2D) progression among lean individuals is not well understood. We examined whether declining insulin sensitivity (IS), independent of beta-cell function (BCF), is associated with diabetes progression. Methods: In a 10-year longitudinal Korean cohort with normal glucose tolerance (N = 2,810; age 50 ± 8y; BMI 24.1 ± 2.8 kg/m²), participants underwent biannual oral glucose tolerance tests. Longitudinal changes in IS, BCF, BMI, and fat mass were evaluated. Participants were stratified by baseline BCF (low/high), diabetes progression status (non-progressors [Non-p], progressors to prediabetes [PreDM-p], or T2D [T2D-p] over time), and degree of IS decline (large/small). Results: Both T2D-p and PreDM-p showed greater IS decline than Non-p. At baseline, PreDM-p had IS comparable to T2D-p, but T2D-p declined more steeply. T2D-p and PreDM-p also had lower BCF at baseline, which remained low. Across baseline BCF groups (high/low), greater IS decline was consistently associated with higher risk of progression (all P