Imeglimin

Imeglimin is the first in a new tetrahydrotriazine-containing class of oral antidiabetic agents, the glimins. It has been shown to act on the liver, muscle and pancreatic β-cells to uniquely target the key defects of type 2 diabetes.

Imeglimin lowers glucose primarily by amplifying glucose-stimulated insulin secretion in high-fat-fed rodents.[Pubmed:27406738]

Am J Physiol Endocrinol Metab. 2016 Aug 1;311(2):E461-70.

Imeglimin is a promising new oral antihyperglycemic agent that has been studied in clinical trials as a possible monotherapy or add-on therapy to lower fasting plasma glucose and improve hemoglobin A1c (1-3, 9). Imeglimin was shown to improve both fasting and postprandial glycemia and to increase insulin secretion in response to glucose during a hyperglycemic clamp after 1-wk of treatment in type 2 diabetic patients. However, whether the beta-cell stimulatory effect of Imeglimin is solely or partially responsible for its effects on glycemia remains to be fully confirmed. Here, we show that Imeglimin directly activates beta-cell insulin secretion in awake rodents without affecting hepatic insulin sensitivity, body composition, or energy expenditure. These data identify a primary amplification rather than trigger the beta-cell mechanism that explains the acute, antidiabetic activity of Imeglimin.

Imeglimin: A Potential New Multi-Target Drug for Type 2 Diabetes.[Pubmed:26254210]

Drugs R D. 2015 Sep;15(3):227-32.

Imeglimin is a novel agent currently in development to treat type 2 diabetes. Laboratory studies have demonstrated that it has the potential to impact the three main pathophysiologic components of type 2 diabetes: impaired glucose uptake by muscle tissue, excess hepatic gluconeogenesis, and increased beta-cell apoptosis. Preliminary human studies that have been published within the last 2 years demonstrate that Imeglimin improves hemoglobin A1c and fasting plasma glucose similarly when compared with metformin and with sitagliptin. There has also been a low incidence of adverse effects, especially hypoglycemia, reported in these early human studies. Currently, Imeglimin is lacking long-term evidence to demonstrate any effects on its cardiovascular safety, and data on morbidity and mortality, though some studies are currently in progress. There is great potential for Imeglimin, if FDA approved, to play a significant role in the type 2 diabetes management algorithm.

Imeglimin increases glucose-dependent insulin secretion and improves beta-cell function in patients with type 2 diabetes.[Pubmed:25694060]

Diabetes Obes Metab. 2015 Jun;17(6):541-5.

AIMS: To assess the glucose-stimulated insulin secretion effect of Imeglimin in patients with type 2 diabetes. METHODS: We conducted a double-blind, randomized, placebo-controlled study in 33 patients with type 2 diabetes [glycated haemoglobin 6.8 +/- 0.1% (51 mmol/mol)], who were drug-naive or withdrawn from their previous metformin monotherapy for 2 weeks and received Imeglimin 1500 mg twice daily or placebo for 1 week. Glucose-stimulated insulin secretion was assessed using a hyperglycaemic clamp. The primary endpoint was insulin secretion as defined by total insulin response [incremental area under the curve (iAUC)0-45 min ] and insulin secretion rate (ISR) calculated from C-peptide deconvolution. beta-cell glucose sensitivity at steady state (second phase: 25-45 min), hepatic insulin extraction and insulin clearance were also calculated. RESULTS: Imeglimin treatment for 7 days raised the insulin secretory response to glucose by +112% (iAUC0-45 , p = 0.035), first-phase ISR by +110% (p = 0.034) and second-phase ISR by +29% (p = 0.031). Imeglimin improved beta-cell glucose sensitivity by +36% (p = 0.034) and tended to decrease hepatic insulin extraction (-13%; p = 0.056). Imeglimin did not affect glucagon secretion. CONCLUSIONS: In patients with type 2 diabetes, Imeglimin improves beta-cell function, which may contribute to the glucose-lowering effect observed with Imeglimin in clinical trials.

Imeglimin prevents human endothelial cell death by inhibiting mitochondrial permeability transition without inhibiting mitochondrial respiration.[Pubmed:27551496]

Cell Death Discov. 2016 Jan 18;2:15072.

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 beta-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.

Imeglimin (EMD 387008) is an oral glucose-lowering agent. Imeglimin improves insulin sensitivity. Imeglimin also reduces reactive oxygen species (ROS) production, increases mitochondrial DNA and improves mitochondrial function.

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