Abstract
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.
Highlights
Imeglimin is the first in a new tetrahydrotriazine-containing class of oral glucose-lowering agents – the Glimins – and has just completed a phase 2b clinical trial (US/EU EudraCT number 2012004045-33)
We demonstrate that Imeglimin prevents hyperglycemia-induced cell death in human endothelial cells (HMEC-1) cells by inhibiting permeability transition pore (PTP) opening without inhibiting mitochondrial respiration and strongly decreases reactive oxygen species (ROS) produced by reverse electron transport at the mitochondrial complex I level
In order to establish whether Imeglimin can prevent human endothelial cell death, HMEC-1 cells were exposed either to tertbutylhydroperoxide or high concentration of glucose, two conditions known to induce PTP opening and cell death.[20]
Summary
Imeglimin is the first in a new tetrahydrotriazine-containing class of oral glucose-lowering agents – the Glimins – and has just completed a phase 2b clinical trial (US/EU EudraCT number 2012004045-33). Several clinical trials evidenced Imeglimin efficacy on HbA1c as a mono and add-on therapy,[1,2,3] being well tolerated. Imeglimin has effects on the liver, muscle and the pancreas,[4] three key organs involved in type 2 diabetes pathophysiology, through suspected mechanisms involving the mitochondria and reduced oxidative stress. Imeglimin decreases hepatic glucose production and increases muscle glucose uptake.[4] Imeglimin demonstrated increased insulin secretion in response to glucose in diabetic patients during a hyperglycemic clamp study.[5] Recently, it was demonstrated in high fat high sucrose diet mice that
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