Cluster Analysis of Younger-Onset Type 2 Diabetes in an Asian Cohort Reveals Distinct Subgroups With Differential Pathophysiology and Outcomes

To understand the heterogeneity of younger-onset type 2 diabetes (T2D), clinical data-driven clustering was performed, which identified three distinct subgroups that were replicated in an independent cohort. Compared with the mild obesity-related diabetes (MOD) subgroup, both severe insulin-deficient diabetes (SIDD) and severe insulin-resistant diabetes with insulin insufficiency (SIRD-II) subgroups had higher risk of developing diabetes-related complications. Differential molecular signatures confirmed the biological distinctiveness of younger-onset T2D subgroups and highlight potential mechanisms, such as glucolipotoxicity stress that may drive complications in the SIRD-II subgroup. Proteomic analyses validated previously reported biomarkers and identified novel candidates, providing a foundation for future mechanistic studies.