ArticleDiabetologia2026
Genetic subtyping of MASLD reveals a glucose-lowering axis linked to GCKR alternative splicing.
Article in Diabetologia, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
aims/hypothesisMetabolic dysfunction-associated steatotic liver disease (MASLD) is a global metabolic condition with a complex relationship to type 2 diabetes. Yet human genetic studies suggest the existence of a MASLD subtype with favourable glycaemic effects, raising a clinically important question: how can hepatic steatosis coexist with improved glycaemic outcomes? We aimed to determine whether MASLD comprises genetically distinct subtypes with divergent glycaemic consequences, and to define the genetic basis of a glucose-lowering MASLD subtype.
methodsWe integrated genetic and triglyceride-related metabolomic profiles to cluster 18 established MASLD-associated variants and construct mutually adjusted partitioned polygenic risk scores (PRSs) in the UK Biobank. We tested associations with hepatic biomarkers, liver outcomes and type 2 diabetes, and replicated glycaemic findings in an independent Chinese cohort (the Taizhou Longitudinal Study [TZL]). We prioritised candidate loci using colocalisation and fine-mapping and performed allele-specific functional assays and structural modelling to investigate the underlying mechanism at the lead locus.
resultsPartitioned PRSs revealed bidirectional glycaemic axes: one PRS lowered fasting glucose and type 2 diabetes risk, whereas the remaining PRSs increased both, despite all associating with higher liver injury markers and adverse liver outcomes. The divergent glycaemic effects were replicated in the TZL. To pinpoint the genetic basis of the glucose-lowering axis, colocalisation and fine-mapping prioritised GCKR rs1260326 (C>T) as a shared MASLD-type 2 diabetes signal and the lead cis-pQTL for circulating glucokinase regulatory protein (GKRP). Functional experiments showed that the rs1260326 T allele promotes exon-15 skipping in GCKR, reduces the abundance of full-length GKRP and yields a truncated protein. In silico structural modelling suggested that the truncated GKRP isoform may have reduced binding affinity for glucokinase, although this predicted effect requires experimental validation. CONCLUSIONS/
interpretationMASLD comprises genetically distinct subtypes with opposing glycaemic and type 2 diabetes risk profiles. Within the glucose-lowering subtype, rs1260326-mediated alternative splicing of GCKR provides a potential mechanistic link to reduced GKRP abundance and glycaemic protection. These findings support a more granular view of MASLD heterogeneity and may inform future subtype-specific risk stratification and prevention.
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