Imeglimin prevents human endothelial cell death by inhibiting mitochondrial permeability transition without inhibiting mitochondrial respiration
Open accessAbstract
Imeglimin is the first in a new class of oral glucose-lowering agents, having recently completed its phase 2b trial. As Imeglimin did show a full prevention of β-cell apoptosis, and since angiopathy represents a major complication of diabetes, we studied Imeglimin protective effects on hyperglycemia-induced death of human endothelial cells (HMEC-1). These cells were incubated in several oxidative stress environments (exposure to high glucose and oxidizing agent tert -butylhydroperoxide) which led to mitochondrial permeability transition pore (PTP) opening, cytochrome c release and cell death. These events were fully prevented by Imeglimin treatment. This protective effect on cell death occurred without any effect on oxygen consumption rate, on lactate production and on cytosolic redox or phosphate potentials. Imeglimin also dramatically decreased reactive oxygen species production, inhibiting specifically reverse electron transfer through complex I. We conclude that Imeglimin prevents hyperglycemia-induced cell death in HMEC-1 through inhibition of PTP opening without inhibiting mitochondrial respiration nor affecting cellular energy status. Considering the high prevalence of macrovascular and microvascular complications in type 2 diabetic subjects, these results together suggest a potential benefit of Imeglimin in diabetic angiopathy.
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Imeglimin decreases reactive oxygen species production and prevents hyperglycaemia-induced cell death via complex I by inhibiting reverse electron transfer-mediated reactive oxygen species in preclinical studies.
“Interestingly, a newly reported molecule, imeglimin, a tetrahydrotriazine-containing oral glucose-lowering agent, decreased ROS production and prevented hyperglycaemia-induced cell death via complex l by inhibiting reverse electron transfer-mediated ROS production in preclinical studies240, and its efficacy and favourable safety and tolerability profile have been confirmed in patients with T2DM241”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [240]
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References 50 · Cited by 99
- Authors
- Detaille, D., Vial, G., Borel, A.-L., Cottet-Rouselle, C., Hallakou-Bozec, S., Bolze, S., Fouqueray, P., & Fontaine, E.
- Affiliations
- Inserm (FR)
- Poxel SA (France) (FR)
- Corresponding author
- Fontaine, E
- Venue
- Cell Death Discovery
- Published
- 2016-01-18
- Volume
- 2
- Issue
- 1
- Pages
- 15072-15072
- ISSN
- 2058-7716 (ISSN-L)
- PMC
- PMC4979505
- OpenAlex
- W2515784845
- Cited by
- 99
- References
- 50
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 14 · 2023: 13 · 2022: 16 · 2021: 8 · 2020: 15 · 2019: 4 · 2018: 3 · 2017: 2 · 2016: 1
- FWCI
- 1.73
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death Discovery (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- imeglimin, mitochondrial permeability transition, endothelial cell death, HMEC-1 cells, hyperglycemia, tert-butyl hydroperoxide, oxidative stress, cytochrome c release, reactive oxygen species, reverse electron transfer, complex I, mitochondrial respiration, diabetic vascular disease, type 2 diabetes, glucose-lowering agents
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