Fig. 3: Molecular signatures of distinct subgroups with impaired glucose control and comorbidities.
a, Circular heatmap showing the 502 metabolites consistently altered in the prediabetes and T2D groups versus the NGT group in both the discovery (D) and validation (V) cohorts (Wilcoxon rank-sum test; two-sided Padj < 0.1). b, Top 100 metabolites with significantly lower or higher ORs of CGI/T2D risks after adjusting for age and sex (logistic regression analyses; two-sided Padj < 0.1) c, Metabolites uniquely associated with specific prediabetes and T2D subgroups and those shared across groups. Metabolites associated with overweight or obesity (n = 117 of 165) in the NGT group of the discovery cohort, T2D (n = 150), HF (n = 99) and KD (n = 111) in the EPIC-Norfolk cohort, and ACS (n = 205) in Israelis are highlighted with colored lines if they were also T2D-associated in Swedes. d, Proportions of overweight-associated and obesity-associated metabolites over all prediabetes-associated, IFG-associated, IGT-associated, CGI-associated or T2D-associated metabolites. Groups labeled with different letters (a or b) indicate significant statistical differences (two-sided chi-squared test). e, Venn diagram showing that a total of 143 microbiome-associated metabolites (calculated by summing the three numbers highlighted in red) identified in Israelis (n = 104) or Swedes (n = 197) overlap with prediabetes-associated and T2D -associated metabolites (n = 502). f,g, Random forest classifiers in distinguishing CGIs and T2Ds from NGTs in the discovery (f) and validation (g) cohorts based on the FINDRISC, microbiome, 143 microbiome-associated and prediabetes-associated and diabetes-associated metabolites, the 32 most robust microbiome-associated metabolites identified in both the Swedish and Israeli cohorts, or all 501 of 502 prediabetes-associated and diabetes-associated metabolites excluding glucose. The performance of the classifiers is assessed by AUC; the cross-validation AUCs based on tenfold cross-validation repeated ten times in the discovery cohort and true prediction AUCs in the validation cohort were provided, respectively.
