Worsening Insulin Resistance Is Key Pathological Contributor to Dysglycemia in Lean Koreans-A Longitudinal Validation Study in the Korean Genome and Epidemiology Study (KoGES)

Insulin resistance (IR) is a modest but important pathophysiological factor in the development of type 2 diabetes (T2D) in East Asians and manageable through lifestyle intervention. The degree to which worsening insulin resistance independent of beta cell dysfunction, contributes to diabetes progression in lean Koreans is unknown. With a 10-year longitudinal study from a Korean cohort, we investigated whether worsening insulin resistance contributes to disease progression in individuals who had normal glucose tolerance at baseline (N=3700, Age=50.1±8.3 y, BMI= 24.1±2.9 kg/m2). We identified metabolic characteristics of progressors and non-progressors to prediabetes (PreDM) or T2D at baseline and 10 year-longitudinal changes in IR and BMI. To assess whether longitudinal changes of IR, independent of beta-cell function (BCF), contributed to progression, the cohort was divided into low and high BCF groups, using group median at baseline. Progressors to PreDM or T2D had weaker BCF and more insulin resistance, compared to non-progressors (Panel A) at baseline. Insulin sensitivity declined more, 30.7 vs 46.5 vs 16.7% and BMI increased in progressors to PreDM or T2D, but not in nonprogressor (Panels A and B). Conclusion: Worsening insulin resistance even for lean people is a key pathological factor to PreDM and T2D progression. Disclosure D.Kim: None. H.Kang: None. A.Sherman: None. S.T.Chung: None. S.Kim: None. J.Ha: None. J.Kim: None. M.Im: None. S.Ryang: None. W.Yi: None. M.Kim: None. Y.Kim: None. I.Kim: None. Y.Kim: None. Funding Busan Economic Promotion Agency; National Research Foundation of Korea (2022H1D3A2A01063552); Korea Health Industry Development Institute (HI18C2383); dkNET New Investigator Pilot Program in Bioinformatics; National Institute of Diabetes and Digestive and Kidney Diseases