Mechanism of Action of Imeglimin
Imeglimin is a first-in-class oral antidiabetic agent that targets mitochondrial bioenergetics to correct cellular energy metabolism dysfunction, working through dual mechanisms: amplifying glucose-stimulated insulin secretion while preserving β-cell mass, and enhancing insulin action by inhibiting hepatic glucose output and improving insulin signaling in liver and skeletal muscle. 1
Mitochondrial-Targeted Action
Imeglimin's underlying mechanism centers on correcting mitochondrial dysfunction, which is a fundamental pathophysiologic defect in type 2 diabetes 1:
- Rebalances respiratory chain activity by partially inhibiting Complex I while correcting deficient Complex III activity 1
- Reduces reactive oxygen species (ROS) formation, thereby decreasing oxidative stress that damages pancreatic β-cells 1
- Prevents mitochondrial permeability transition pore (PTP) opening, which is implicated in preventing cell death and preserving β-cell mass 1
Effects on Pancreatic β-Cells
The drug enhances pancreatic function through multiple pathways 1, 2:
- Enhances glucose-stimulated ATP generation in islets from diabetic models, improving the energy substrate needed for insulin secretion 1
- Induces synthesis of nicotinamide adenine dinucleotide (NAD+) via the salvage pathway, with NAD+ metabolites contributing to increased glucose-stimulated insulin secretion through enhanced calcium mobilization 1
- Preserves β-cell mass in rodent models of type 2 diabetes, potentially slowing disease progression 1
Effects on Insulin Sensitivity
Imeglimin improves insulin action through peripheral mechanisms 1, 2:
- Inhibits hepatic glucose output, reducing excessive glucose production by the liver 1
- Improves insulin signaling in both hepatocytes and skeletal muscle myocytes, addressing insulin resistance at key metabolic sites 1, 2
Unique Pharmacologic Profile
This mechanism of action distinguishes imeglimin from other antidiabetic drug classes 1:
- Unlike biguanides (metformin), which primarily decrease hepatic glucose output without direct β-cell effects 3
- Unlike sulfonylureas, which promote insulin secretion but do not address mitochondrial dysfunction or insulin resistance 3
- Unlike GLP-1 receptor agonists, imeglimin's action is independent of incretin pathways 1
The drug belongs to the tetrahydrotriazine chemical class and represents the first "glimin" compound 4, 2. Its targeting of mitochondrial bioenergetics addresses a root cause of type 2 diabetes rather than simply managing symptoms 1.
Clinical Implications
Imeglimin demonstrates glucose-lowering efficacy comparable to metformin (HbA1c reductions of 0.5-1.0% as monotherapy) with a favorable tolerability profile, particularly regarding gastrointestinal side effects 5, 6. The drug does not cause severe hypoglycemia due to its glucose-dependent mechanism of enhancing insulin secretion 1.