The prevalence and incidence of type 2 diabetes (T2D) are sharply increasing across the world. Recent topics have attracted attention for novel anti-diabetic agents [1]. From diabetic situation, a need for novel and adequate oral hypoglycemic agents (OHAs) has been expected for long. One possible ideal OHA may be imeglimin, which is antidiabetic agents-glucokinase activators [2]. As an allosteric activator of glucokinase, it stimulates insulin secretion from beta cell and suppresses hepatic glucose production, which is an oral low molecular weight agent. Imeglimin has been used mainly in Japan, China, India for Asian countries, This specific OHA will add some valuable efficacy for diabetic treatment in the near future.

Authors and collaborators have continued diabetic research and practice with OHAs for years, such as imeglimin (Twymeeg) [3]. It showed clinically effective results in various T2D cases [4]. In this article, latest topics concerning imeglimin will be described. Imeglimin is included in the glimins group, and acts by enhancing glucose-stimulated insulin secretion (GSIS) mechanism and preserving beta cell mass, which leads to increased insulin secretion [5]. Further, it raises insulin action by changing in insulin signaling in both skeletal muscle and liver. This is a unique action targeting insulin resistance and secretion by controlling the mitochondrial dysfunction. Imeglimin hydrochloride as Twymeeg has been an OHA for T2D, that was approved in Japan with dual mechanism mode of functioning actions, for the first time in the world [6]. From in vivo studies, imeglimin has enhanced the insulin sensitivity and modulated also mitochondrial function, where it decreased Complex I activity and reactive oxygen species (ROS) production and restored the deficient Complex III. These mechanisms contributed the improvement of glucose variability in skeletal muscles and liver cells. Since imeglimin has both effects for insulin resistance and secretion, it would present a novel effective options, irrespective of the pathophysiology of T2D cases.

Comparative study was conducted for muscle strength for two groups in treatment of imeglimin vs control [7]. The applicants included T2D cases, in which I group (n=27) and C group (n=29). They were evaluated for 6 months for several markers. They included the following up the changes in fat mass, quadriceps muscle strength, lean body mass (LBM) and grip strength from week 0 to week 24. As a result, I group showed higher changes in the strength of quadriceps knee extension than group C as 13+/-19% vs 2.1+/-1.4% (p=0.022), respectively. There were no significant changes in grip strength. Then, imeglimin may have positive benefit for muscle strength in T2D without altering LBM. Further randomized controlled trials (RCT) will be required for validating these findings.

For imeglimin, anti-atherosclerotic effects were investigated using atherosclerosis mice model with treating streptozotocin (STZ) [8]. There were 3 groups of ApoE KO mice, where 1^st was non-DM group without STZ, 2^nd was ApoE KO mice with STZ plus carboxymethyl cellulose (CMC) as control, and 3^rd was ApoE KO mice with STZ plus imeglimin (twice daily). Three groups were studied for plaque formation histologically in aortic arch and expression degrees against several vascular factors. As a result, 3^rd groups presented beneficial effects on plaque formation in the aortic arch, that seemed to be independent of lipid and glycemic control. Proliferation and migration of vascular smooth muscle cells were found in 2^nd group, but it was remarkably decreased by imeglimin therapy (3^rd group). Furthermore, imeglimin has decreased inflammation, oxidative stress or inflammasome in ApoE Ko mice. Expression degrees of macrophage were remarkably decreased by imeglimin administration.

In pancreatic beta cells, impaired mitochondrial function may lead to impaired GSIS and also T2D, which can highlight clinical benefit of autophagic elimination for usual mitochondrial quality control (mQC) [9]. Chronic effect of imeglimin on mQC in diabetic beta-cell is not known for its detail yet. Consequently, imeglimin as OHA was compared for metformin that is similar anti-diabetic agent, and insulin. The method included clinical efficacy on clearance of dysfunctional mitochondria for mitophagy in beta cell of diabetic model mice db/db mice and mitophagy reporter (CMMR) mice. When treated by imeglimin and insulin, not by metformin, the experiment showed decreased ROS production, less numbers of dysfunctional mitochondria, and normal degree of mitophagic activity of db/db beta cells. Further, imeglimin and insulin showed the restoration of insulin secretion and decreased apoptosis of beta cell in db/db mice. From these, imeglimin reduced dysfunctional mitochondria by mitophagy of diabetic mice, which may bring preservation of beta cell function with better glycemic variability of T2D.

From basic medical information, mitochondria are organelles observed in the animal cells. Mitochondria always use aerobic respiration in order to generate ATP (adenosine triphosphate) [10]. Mitochondrial dysfunction would be an apparent pathological feasure of T2D. For treatment of T2D, imeglimin has been a novel OHA, which has unique action mechanism targeting mitochondrial bioenergetics. Imeglimin has been known to reduce ROS production, and to improve mitochondrial function with integrity, and to improve the function and structure of endoplasmic reticulum (ER). By these changes, it can enhance glucose-stimualted insulin secretion degree and can decrease the apoptosis of beta cells, which leads to the preservation of beta cell mass. Mitochondrial impairment has been closely related with endothelial dysfunction, that would be early events for atherosclerosis. Imeglimin can increase endothelial function for T2D cases through glycemic control-dependent and also independent systems. For experimental animals such as mice, imeglimin could improve renal and cardiac function through the improvement of ER and mitochondrial function associated with the improvement of endothelial function. Besides glucose-lowering efficacy, it can become an applicable therapeutic option for diabetic macroangiopathic and microangiopathic complications of T2D.

In summary, latest impressive topics about imeglimin (Twymeeg) have been introduced in this report. Imeglimin has been expected to show multi-potential beneficial clinical effects for not only T2D but also other arteriosclerotic diseases or neurodegenerative diseases. Further development of research will be expected for diabetic practice and OHAs.

Conflict of Interest: The authors declare no conflict of interest.

Funding: There was no funding received for this paper.

1. Simon-Szabo L, Lizak B, Sturm G, Somogyi A, Takacs I, Nemeth Z. Molecular Aspects in the Development of Type 2 Diabetes and Possible Preventive and Complementary Therapies. Int J Mol Sci. 2024; 25: 9113.
2. Sjoholm A. Glucokinase activators and imeglimin: new weaponry in the armamentarium against type 2 diabetes. BMJ Open Diabetes Res Care. 2024; 12: e004291.
3. Bando H, Okada M, Iwatsuki N, Ogawa T, Sakamoto K. Diabetic Elderly with Keeping Less Arteriosclerosis Treated by Imeglimin (Twymeeg). Asp Biomed Clin Case Rep. 2024; 7: 126-130.
4. Okada M, Bando H, Iwatsuki N, Ogawa T, Sakamoto K. Diabetic patient with arteriosclerosis and cholelithiasis treated by imeglimin (Twymeeg) and vildagliptin/metformin (EquMet). Int J EndocrinolDiabetes. 2023; 6: 154.
5. Shrestha SC, Gupta S. Imeglimin: The New Kid on the Block. Curr Diab Rep. 2024; 24: 13-18.
6. Nagamine J. [Pharmacological profile and clinical efficacy of imeglimin hydrochloride (TWYMEEG^®Tablets), the orally drug for type 2 diabetes mellitus with the first dual mode of action in the world]. Nihon Yakurigaku Zasshi. 2023; 158: 193-202.
7. Oyanagi T, Kawanabe S, Tsukiyama H, Nishine A, Nakamura Y, Nakagawa T, et al. The Effects of Imeglimin on Muscle Strength in Patients with Type 2 Diabetes: A Prospective Cohort Study. Diabetes Ther. 2024.
8. Sanada J, Kimura T, Shimoda M, Iwamoto Y, Iwamoto H, Dan K, et al. Protective effects of imeglimin on the development of atherosclerosis in ApoE KO mice treated with STZ. Cardiovasc Diabetol. 2024; 23: 105.
9. Aoyagi K, Nishiwaki C, Nakamichi Y, Yamashita SI, Kanki T, Ohara-Imaizumi M. Imeglimin mitigates the accumulation of dysfunctional mitochondria to restore insulin secretion and suppress apoptosis of pancreatic β-cells from db/db mice. Sci Rep. 2024; 14: 6178.
10. Yanai H, Adachi H, Hakoshima M, Katsuyama H. Glucose-Lowering Effects of Imeglimin and Its Possible Beneficial Effects on Diabetic Complications. Biology (Basel). 2023; 12: 726.