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Cross-ethnic Molecular Signatures Underpin the Adverse Impact of Statin Use on Type 2 Diabetes

Fengzhe Xu1, Min Yang1, Wei Hu2

  • 1Westlake Center for Intelligent Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China.

Genomics, Proteomics & Bioinformatics
|November 9, 2025
PubMed

Insights

Statins may increase type 2 diabetes (T2D) risk. This study found elevated gastric inhibitory polypeptide (GIP) levels, linked to statin use, may explain this T2D risk in diverse populations.

Area of Science:

  • Genetics and Molecular Biology
  • Metabolomics and Proteomics
  • Endocrinology and Diabetes Research

Background:

  • Statins are primary therapies for lowering LDL cholesterol but are associated with an increased risk of type 2 diabetes (T2D).
  • The precise mechanisms underlying statin-induced T2D remain largely unidentified, necessitating further investigation into molecular pathways.
  • Understanding these mechanisms is crucial for mitigating adverse effects and optimizing lipid-lowering therapies.

Purpose of the Study:

  • To elucidate the molecular etiology of statin-induced type 2 diabetes (T2D) using a multi-omics approach.
  • To identify specific metabolites and proteins influenced by statin use that may contribute to T2D risk.
  • To investigate the role of gastric inhibitory polypeptide (GIP) in the association between statin use and T2D.

Main Methods:

  • Systematic screening of gut microbial features, blood metabolites, and circulating proteins in East Asian and European cohorts.
  • Utilized Mendelian randomization analyses to assess causal relationships between genetically proxied statin use, molecular signatures, and T2D risk.
  • Integrated multi-omics data to establish molecular signatures associated with statin-induced T2D.

Main Results:

  • Identified a panel of blood metabolites and proteins potentially affected by genetically proxied statin use across different ethnicities.
  • Mendelian randomization analysis revealed a significant association between elevated circulating gastric inhibitory polypeptide (GIP) levels and increased T2D risk.
  • The link between genetically proxied statin use and GIP was consistent in both East Asian and European populations, underscoring GIP's role.

Conclusions:

  • Gastric inhibitory polypeptide (GIP) plays a key role in mediating the risk of type 2 diabetes associated with statin therapy.
  • This study provides a comprehensive multi-omics atlas of molecular signatures linked to statin-induced T2D.
  • The findings offer valuable insights for identifying potential therapeutic targets to prevent or manage statin-associated T2D.
Keywords:
Cross-ethnicMendelian randomizationMulti-omicsStatinT2D

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