Liraglutide reprograms vascular smooth muscle cell metabolism to suppress extracellular matrix remodeling in diabetic atherosclerosis

This study found that liraglutide counteracted diabetes-related changes in vascular smooth muscle cells and atherosclerotic plaques in mice. It did so by improving mitochondrial function and shifting cell metabolism and extracellular matrix remodeling. The findings point to a mechanism by which liraglutide could promote more stable plaques in diabetic atherosclerosis.

Journal article — Preclinical in vitro and in vivo mouse study. Population: Primary vascular smooth muscle cells exposed to high glucose and diabetic ApoE -/- mice. Follow-up: 12 weeks. Interventions: Liraglutide.

Compared with normal glucose, high glucose impaired mitochondrial respiration, enhanced glycolysis, reduced mitochondrial membrane potential, increased mitochondrial reactive oxygen species, and promoted mitochondrial fragmentation and extracellular matrix remodeling. Liraglutide restored mitochondrial function, activated AMPK/PGC-1α signaling, suppressed mTOR activation and HIF-1α accumulation, reduced collagen I, MMP-2, and MMP-9 expression, and partially restored elastin levels. In diabetic ApoE -/- mice treated with liraglutide for 12 weeks, systemic metabolic parameters improved, atherosclerotic plaque burden and lipid accumulation decreased, plaque collagen content increased, plaque p-AMPK expression was restored, and HIF-1α and MMP-9 expression were reduced.

Researchers studying liraglutide in diabetic atherosclerosis would care about this paper because it links the drug's effects on plaques to AMPK/PGC-1α signaling, mitochondrial function, and extracellular matrix remodeling in vascular smooth muscle cells. It does not establish whether these mechanisms operate in humans or whether liraglutide changes clinical outcomes in diabetic patients.

Key findings

• High glucose impaired mitochondrial respiration and increased glycolysis in vascular smooth muscle cells compared with normal glucose.
• Liraglutide restored mitochondrial function and mitochondrial membrane potential in vascular smooth muscle cells exposed to high glucose.
• Liraglutide reduced collagen I, MMP-2, and MMP-9 expression and partially restored elastin levels in high-glucose-treated cells.
• In diabetic ApoE -/- mice, 12 weeks of liraglutide reduced atherosclerotic plaque burden and lipid accumulation while increasing plaque collagen content.
• Liraglutide activated AMPK/PGC-1α signaling and suppressed mTOR activation and HIF-1α accumulation in high-glucose cells.
• In diabetic ApoE -/- mice, liraglutide restored plaque p-AMPK expression and reduced HIF-1α and MMP-9 expression.

Limitations

• Authors did not report study limitations.
• In vitro and mouse findings may not translate to humans.
• No human data or clinical outcomes were assessed.
• No dose-response relationship or dosing information was reported.

The record

• Journal: Journal of diabetes investigation
• Published: 2026-08-04
• PMID: 42549609 — DOI: 10.1111/jdi.70398
• Funding: Science and Technology Innovation Team Project of Shaanxi Provincial Department of Science and Technology; Traditional Chinese Medicine Scientific Research and Innovation Talent Project of Shaanxi Provincial Administration of Traditional Chinese Medicine
• Author countries: China

Peptide profiles: Liraglutide.

All indexed evidence: Liraglutide trials & papers.

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