What is the clinical evidence from this study?

Study design: Observational. Population: Vascular dysfunction. Intervention: Genetically proxied AMPK activation (GP-AMPK) and metformin. Primary outcome: Pulse wave velocity (PWV) and carotid intima-media thickness (cIMT).

What question did this study set out to answer?

The study aims to investigate the protective vascular effects of metformin through AMPK activation using both genetic epidemiology and an experimental model.

June 12, 2026Open Access

AMPK‐mediated prevention of vascular dysfunction with metformin: Experimental and population‐based evidence

Key Result

Genetically proxied AMPK activation was associated with lower pulse wave velocity, and ex vivo metformin restored endothelial relaxation in Angiotensin II-treated vessels.

Key Points

The study aims to investigate the protective vascular effects of metformin through AMPK activation using both genetic epidemiology and an experimental model.
Combined population-based genetic epidemiology with an ex vivo vascular model.
Utilized genetically proxied AMPK activation (GP-AMPK) based on 20 SNPs.
Conducted a two-sample Mendelian randomisation to assess the effect on inflammatory markers.
Higher GP-AMPK activation linked to lower pulse wave velocity (PWV).
Metformin improved endothelial relaxation in Ang II-treated vessels, dependent on AMPK activation.
Molecular analyses indicated decreased markers of matrix remodeling and inflammation with metformin treatment.

Study Design

Type

Observational

Structured PICO

Does AMPK activation by metformin improve vascular function and reduce arterial stiffness?

Population

Population-based genetic epidemiology analysis (mean age 64.3 years, 43.8% female) combined with an ex vivo porcine coronary artery model to assess the vascular effects of AMPK activation.

Exposure

Genetically proxied AMPK activation (GP-AMPK) using 20 SNPs, and ex vivo metformin treatment.

Comparator

Lower GP-AMPK activation, and Angiotensin II-treated vessels without metformin.

Outcome

Pulse wave velocity (PWV), carotid intima-media thickness (cIMT), and ex vivo endothelial relaxation.surrogate

Metformin may improve early vascular dysfunction and reduce arterial stiffness through an AMPK-endothelium-dependent hyperpolarisation axis, independent of its glycaemic effects.

Abstract

Abstract Background and Purpose Metformin is increasingly recognised for its vasculoprotective effects, primarily through activation of AMP‐activated protein kinase (AMPK). We combined population‐based genetic epidemiology, with an ex vivo vascular model, to investigate the beneficial vascular effects of AMPK activation by metformin. Experimental Approach We used genetically proxied AMPK activation (GP‐AMPK), based on 20 genome‐wide significant single‐nucleotide polymorphisms (SNPs), to assess associations with pulse wave velocity (PWV) and carotid intima‐media thickness (cIMT). A two‐sample Mendelian randomisation (MR) was performed to test the effect of GP‐AMPK on a panel of inflammatory markers. We also developed a porcine coronary artery model of endothelial dysfunction to test the restorative effects of metformin on vascular function and related molecular signalling pathways. Key Results Higher GP‐AMPK activation was associated with lower PWV, but not cIMT, in our epidemiological analysis (mean age 64.3 years, 43.8% female). Ex vivo, metformin restored endothelial relaxation in Angiotensin (Ang) II–treated vessels via endothelium‐dependent hyperpolarisation (EDH) mechanisms, an effect abolished by AMPK inhibition. Western blotting confirmed the activation of AMPK (alpha 1 subunit) with metformin treatment. Inhibitor studies demonstrated a shift from NO‐mediated to EDH‐mediated relaxation with metformin. Molecular analyses showed reduced Ang II–induced expression of matrix remodelling (MMP1, MMP2) and senescence (P21) markers, as well as suppression of pro‐inflammatory cytokines (Il‐1β, Il‐6, TNF‐α), consistent with MR results. Conclusion and Implications Metformin restored endothelial function and reduced vascular stiffness through an AMPK–EDH axis, highlighting a novel, potential therapeutic mechanism for early vascular dysfunction independent of glycaemic effects.