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Despite the successful development of glucose-lowering drugs, such as glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 inhibitors recently, the proportion of patients achieving satisfactory glucose control has not risen as expected. The heterogeneity of diabetes determines that a one-size-fits-all strategy is not suitable for people with diabetes. Diabetes is undoubtedly more heterogeneous than the conventional subclassification, such as type 1, type 2, monogenic and gestational diabetes. The recent progress in genetics and epigenetics of diabetes has gradually unveiled the mechanisms underlying the heterogeneity of diabetes, and cluster analysis has shown promising results in the substratification of type 2 diabetes, which accounts for 95% of diabetic patients. 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