Plasma metabolite association profiles for type 2 diabetes genetic clusters in Finnish men.

AIMS/HYPOTHESIS: A recent study has suggested eight clusters of genetic variants associated with type 2 diabetes. We aimed to characterise metabolite associations for these eight clusters.

METHODS

We constructed type 2 diabetes overall and cluster-partitioned polygenic risk scores (PRSs) in 10,015 Finnish men with 979 named plasma metabolites measured in Metabolon HD4 mass spectrometry platform. We evaluated metabolite-PRS associations using linear regression. We also performed a mediation analysis to examine whether metabolites statistically accounted for part of the association between genetic risk and incident type 2 diabetes that developed in a mean of 13.6 years' follow-up.

RESULTS

We identified 337 metabolites significantly associated with type 2 diabetes genetic risk, including 242 exclusive to cluster-partitioned PRSs. Of the significant metabolites, 26 exhibited significantly heterogeneous associations across clusters. We identified significant enrichment for 33 metabolic pathways among the cluster-associated metabolites. Notably, metabolites for the two pancreatic beta cell-related clusters exhibited enrichment in distinct pathways: the beta cell + proinsulin (PI) cluster in fructose, mannose and galactose metabolism; and the beta cell - PI cluster in branched-chain amino acid metabolism. Mediation analysis suggested that >50% of the associated metabolites showed patterns statistically consistent with a mediating role in the associations between PRSs and incident type 2 diabetes.

CONCLUSIONS/INTERPRETATION: This study underscores the value of type 2 diabetes clustering and highlights metabolic heterogeneity across clusters. The findings have the potential to guide personalised interventions.

DATA AVAILABILITY: The datasets generated during and/or analysed in the current study are available in dbGaP (accession ID: phs000743.v4.p1 and phs004033.v1.p1).