Appraisal of Clinical Explanatory Variables in Subtyping of Type 2 Diabetes Using Machine Learning Models

<b>Background</b>: Clustering type 2 diabetes (T2D) remains a challenge due to its clinical heterogeneity and multifactorial nature. We aimed to evaluate the validity and robustness of the clinical variables in defining T2D subtypes using a discovery-to-prediction design. <b>Methods</b>: Five explanatory clinical aetiology variables (fasting serum insulin, fasting blood glucose, body mass index, age at diagnosis and HbA1c) were assessed for clustering T2D subtypes using two independent patient datasets. Clustering was performed using the IBM-Modeler Auto-Cluster. The resulting cluster validity was tested by multinomial logistic regression. The variables' validity for direct unsupervised clustering was compared with machine learning (ML) predictive models. <b>Results</b>: Five distinct subtypes were consistently identified: severe insulin-resistant diabetes (SIRD), severe insulin-deficient diabetes (SIDD), mild obesity-related diabetes (MOD), mild age-related diabetes (MARD), and mild early-onset diabetes (MEOD). Using all five variables yielded the highest concordance between clustering methods. Concordance was strongest for SIRD and SIDD, reflecting their distinct clinical signatures in contrast to that in MARD, MOD and MEOD. <b>Conclusions</b>: These findings support the robustness of clinically defined T2D subtypes and demonstrate the value of probabilistic clustering combined with ML for advancing precision diabetes care.