Distinct multi-omics signatures of clinical subgroups of type 2 diabetes define heterogeneous responses to an insulin sensitizer.

Type 2 diabetes (T2D) subgroups defined by clinical variables differ in disease progression and treatment response. To uncover potential molecular drivers of this heterogeneity, we performed a multi-omics analysis of 826 drug-naïve T2D patients from two phase 3 trials of the insulin sensitizer chiglitazar. Here we show that severe insulin-resistant diabetes (SIRD) is characterized by distinct miRNA profiles (e.g., miR-122-5p) correlated with liver injury, and metabolic shifts in amino acids and primary bile acids. Mild obesity-related diabetes (MOD) showed the lowest level of phenylacetylglutamine, a metabolite known to promote cardiovascular disease. Severe insulin-deficient diabetes (SIDD) exhibited high pancreas-specific miR-7-5p, while mild age-related diabetes (MARD) presented the mildest abnormalities. Finally, integrating these multi-omics signatures into machine learning models enhanced prediction of insulin sensitizer efficacy over clinical data alone. Our findings define the distinct molecular signatures of T2D subgroups, facilitating the prediction of heterogeneous treatment responses and supporting personalized clinical management.