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Body Fat Distribution and Ectopic Fat Accumulation as Mediator of Diabetogenic Action of Lipid-Modifying Drugs: A

Yuanlong Hu1, Xinhai Cui2, Mengkai Lu3

  • 1First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China.

Mayo Clinic Proceedings
|February 7, 2025
PubMed
Abstract

Insights

Lipid-modifying drugs like HMGCR and APOB inhibitors increase type 2 diabetes risk, mediated by liver and gluteofemoral fat. LPL enhancers reduce risk, also mediated by these fat depots.

Area of Science:

  • Genetics and Pharmacology
  • Metabolic Diseases
  • Causal Inference

Background:

  • Lipid-modifying drugs are crucial for cardiovascular disease prevention.
  • The relationship between these drugs and new-onset diabetes requires further elucidation.
  • Ectopic fat accumulation is implicated in metabolic dysregulation.

Purpose of the Study:

  • To investigate the causal links between lipid-modifying drug targets and type 2 diabetes (T2D).
  • To identify mediating factors, specifically ectopic fat, in the drug-T2D association.
  • To differentiate prodiabetic and antidiabetic effects based on drug targets.

Main Methods:

  • Mediation Mendelian randomization analysis was employed.
  • Genetic variants for 11 lipid-modifying drug targets were analyzed.
  • Causal effects and mediation proportions were statistically evaluated.

Main Results:

  • HMGCR and APOB inhibition showed a causal association with increased T2D risk.
  • LPL enhancement demonstrated a causal association with reduced T2D risk.
  • Liver fat and gluteofemoral adipose tissue mediated these associations.

Conclusions:

  • Liver fat and gluteofemoral adipose tissue mediate the prodiabetic effects of HMGCR and APOB inhibition.
  • These fat depots also mediate the antidiabetic effects of LPL enhancement.
  • Findings highlight the role of fat accumulation in drug-induced diabetes risk.

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