Efficacy and Mechanisms of Imeglimin in Type 2 Diabetes Management

Imeglimin is a novel oral hypoglycaemic agent that targets mitochondrial bioenergetics to improve glucose homeostasis. Its dual mechanism involves enhancement of glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells and amelioration of insulin resistance in peripheral tissues. By modulating mitochondrial function, preventing the accumulation of dysfunctional organelles through mitophagy, and maintaining mitochondrial integrity, imeglimin reduces oxidative stress and apoptosis in β-cells, thereby preserving β-cell mass. Concurrently, it exerts a mild, competitive constraint on respiratory chain activity in hepatocytes to decrease hepatic gluconeogenesis without impairing maximal mitochondrial respiration. Clinical trials have demonstrated modest but sustained reductions in HbA1c and fasting plasma glucose, along with improvements in insulinogenic index and insulin sensitivity indices. Preclinical investigations further reveal vascular benefits, including attenuation of atherosclerotic plaque development and preservation of endothelial function. Across diverse models, imeglimin has shown a consistent safety profile, positioning it as a promising adjunct or monotherapy for global management of type 2 diabetes mellitus.

Research from Nature Portfolio

Recent studies have elucidated novel cellular mechanisms by which imeglimin sustains β-cell function, hepatic metabolism and mitochondrial quality control. One investigation employing diabetic mouse models revealed that chronic treatment improved β-cell ultrastructure, increased insulin granule density and decreased apoptotic markers, culminating in enhanced insulin release in response to glucose. In hepatocyte culture, imeglimin was shown to selectively constrain ATP-coupled oxygen consumption, modestly activate AMP-activated protein kinase (AMPK) and induce expression of respiratory complex I and III subunits, indicating a transcriptional reprogramming distinct from metformin. More recently, work in diabetic β-cells demonstrated that imeglimin alleviates the buildup of dysfunctional mitochondria by normalising mitophagic flux, reducing reactive oxygen species and restoring glucose-stimulated insulin secretion without the effects observed with metformin, underscoring its unique mode of action.

Efficacy and Mechanisms of Imeglimin in Type 2 Diabetes Management publication trend

The graph below shows the total number of articles in efficacy and mechanisms of imeglimin in type 2 diabetes management across all publications each year (not limited to Nature Index journals).

Technical terms

Glucose-stimulated insulin secretion (GSIS): Release of insulin by pancreatic β-cells in response to elevated glucose concentrations.

Mitophagy: Selective autophagic removal of damaged or dysfunctional mitochondria to maintain cellular mitochondrial quality control.

AMP-activated protein kinase (AMPK): A central energy sensor kinase activated by increased AMP/ATP ratio that regulates metabolic pathways.

Insulinogenic index: A measure of early-phase β-cell insulin secretion calculated from the ratio of insulin to glucose during an oral glucose tolerance test.

Hepatic gluconeogenesis: Endogenous production of glucose by the liver from non-carbohydrate substrates.

Reactive oxygen species (ROS): Highly reactive oxygen-containing molecules that can induce oxidative stress within cells.

References

1. Imeglimin mitigates the accumulation of dysfunctional mitochondria to restore insulin secretion and suppress apoptosis of pancreatic β-cells from db/db mice. Scientific Reports (2024).
2. The mechanism by which imeglimin inhibits gluconeogenesis in rat liver cells. Endocrinology Diabetes & Metabolism (2021).
3. The Efficacy and Safety of Imeglimin as Add-on Therapy in Patients With Type 2 Diabetes Inadequately Controlled With Sitagliptin Monotherapy. Diabetes Care (2014).
4. Phase 2 trial with imeglimin in patients with Type 2 diabetes indicates effects on insulin secretion and sensitivity. Endocrinology Diabetes & Metabolism (2022).
5. Protective effects of imeglimin on the development of atherosclerosis in ApoE KO mice treated with STZ. Cardiovascular Diabetology (2024).
6. Imeglimin prevents human endothelial cell death by inhibiting mitochondrial permeability transition without inhibiting mitochondrial respiration. Cell Death Discovery (2016).
7. Imeglimin exerts favorable effects on pancreatic β-cells by improving morphology in mitochondria and increasing the number of insulin granules. Scientific Reports (2022).
8. Effects of imeglimin on mitochondrial function, AMPK activity, and gene expression in hepatocytes. Scientific Reports (2023).
9. Comparative evaluation of clinical glycemic control markers treated with imeglimin and its effect on erythrocytes in patients with type 2 diabetes mellitus: study protocol of a single-arm, open-label, prospective, exploratory trial. Frontiers in Pharmacology (2023).