Molecular Mechanisms by Which Imeglimin Improves Glucose Homeostasis

Yaribeygi, Habib; Maleki, Mina; Sathyapalan, Thozhukat; Jamialahmadi, Tannaz; Sahebkar, Amirhossein

doi:10.1155/2020/8768954

Cited by 23 publications

(24 citation statements)

References 26 publications

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“…As described in this review, the mode of action of Imeglimin is unique and distinct compared with other major classes of therapeutic agents. It involves dual effects, both to enhance insulin action and to reverse pancreatic β‐cell dysfunction 5 . The mode of action of Imeglimin is generally well aligned with our current understanding of the pathophysiology of T2D.…”

Section: Introductionmentioning

confidence: 84%

“…It involves dual effects, both to enhance insulin action and to reverse pancreatic β-cell dysfunction. 5 The mode of action of Imeglimin is generally well aligned with our current understanding of the pathophysiology of T2D. A genetic predisposition plus key environmental factors, principally overnutrition and reduced energy expenditure, are drivers of disease.…”

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confidence: 88%

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Mechanism of action of Imeglimin: A novel therapeutic agent for type 2 diabetes

Hallakou‐Bozec

Vial

Kergoat

et al. 2020

Diabetes Obesity Metabolism

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Imeglimin is an investigational first‐in‐class novel oral agent for the treatment of type 2 diabetes (T2D). Several pivotal phase III trials have been completed with evidence of statistically significant glucose lowering and a generally favourable safety and tolerability profile, including the lack of severe hypoglycaemia. Imeglimin's mechanism of action involves dual effects: (a) amplification of glucose‐stimulated insulin secretion (GSIS) and preservation of β‐cell mass; and (b) enhanced insulin action, including the potential for inhibition of hepatic glucose output and improvement in insulin signalling in both liver and skeletal muscle. At a cellular and molecular level, Imeglimin's underlying mechanism may involve correction of mitochondrial dysfunction, a common underlying element of T2D pathogenesis. It has been observed to rebalance respiratory chain activity (partial inhibition of Complex I and correction of deficient Complex III activity), resulting in reduced reactive oxygen species formation (decreasing oxidative stress) and prevention of mitochondrial permeability transition pore opening (implicated in preventing cell death). In islets derived from diseased rodents with T2D, Imeglimin also enhances glucose‐stimulated ATP generation and induces the synthesis of nicotinamide adenine dinucleotide (NAD+) via the ‘salvage pathway’. In addition to playing a key role as a mitochondrial co‐factor, NAD+ metabolites may contribute to the increase in GSIS (via enhanced Ca++ mobilization). Imeglimin has also been shown to preserve β‐cell mass in rodents with T2D. Overall, Imeglimin appears to target a key root cause of T2D: defective cellular energy metabolism. This potential mode of action is unique and has been shown to differ from that of other major therapeutic classes, including biguanides, sulphonylureas and glucagon‐like peptide‐1 receptor agonists.

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Section: Introductionmentioning

confidence: 84%

mentioning

confidence: 88%

Mechanism of action of Imeglimin: A novel therapeutic agent for type 2 diabetes

Hallakou‐Bozec

Vial

Kergoat

et al. 2020

Diabetes Obesity Metabolism

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“… 153 A recent study reported that imeglemin can improve insulin sensitivity through several molecular pathways including insulin signalling transduction via activating Akt phosphorylation. 154 …”

Section: Future Treatment Optionsmentioning

confidence: 99%

A review of therapeutic options for managing the metabolic aspects of polycystic ovary syndrome

Abdalla

Deshmukh

Atkin

et al. 2020

Therapeutic Advances in Endocrinology

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Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. Metabolic sequelae associated with PCOS range from insulin resistance to type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Insulin resistance plays a significant role in the pathophysiology of PCOS and it is a reliable marker for cardiometabolic risk. Although insulin sensitising agents such as metformin have been traditionally used for managing metabolic aspects of PCOS, their efficacy is low in terms of weight reduction and cardiovascular risk reduction compared with newer agents such as incretin mimetics and SGLT2 inhibitors. With current pharmaceutical advances, potential therapeutic options have increased, giving patients and clinicians more choices. Incretin mimetics are a promising therapy with a unique metabolic target that could be used widely in the management of PCOS. Likewise, bariatric procedures have become less invasive and result in effective weight loss and the reversal of metabolic morbidities in some patients. Therefore, surgical treatment targeting weight loss becomes increasingly common in the management of obese women with PCOS. Newer emerging therapies, including twincretins, triple GLP-1 agonists, glucagon receptor antagonists and imeglemin, are promising therapeutic options for treating T2DM. Given the similarity of metabolic and pathological features between PCOS and T2DM and the variety of therapeutic options, there is the potential to widen our strategy for treating metabolic disorders in PCOS in parallel with current therapeutic advances. The review was conducted in line with the recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome 2018.

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“… 84 , 85 Its unique mechanism of action (MOA) ( Figure 3 ) not only increases glucose-dependant insulin secretion but also reduces IR. 86 , 87 It acts by inhibiting the process of oxidative phosphorylation in the mitochondria of aerobic cells which in turn leads to favourable metabolic effects. 86 Imeglimin counteracts a variety of metabolic disruptions at play in T2DM.…”

Section: Gliminsmentioning

confidence: 99%

“… 86 , 87 It acts by inhibiting the process of oxidative phosphorylation in the mitochondria of aerobic cells which in turn leads to favourable metabolic effects. 86 Imeglimin counteracts a variety of metabolic disruptions at play in T2DM. It accelerates the phosphorylation of Akt (protein kinase B) leading to enhanced insulin signalling 88 and has also been linked to the induction of insulin sensitivity in the β-cells.…”

Section: Gliminsmentioning

confidence: 99%

Therapeutics for type-2 diabetes mellitus: a glance at the recent inclusions and novel agents under development for use in clinical practice

Shah

Abdalla

Deshmukh

et al. 2021

Therapeutic Advances in Endocrinology

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Diabetes mellitus (DM) is a chronic, progressive, and multifaceted illness resulting in significant physical and psychological detriment to patients. As of 2019, 463 million people are estimated to be living with DM worldwide, out of which 90% have type-2 diabetes mellitus (T2DM). Over the years, significant progress has been made in identifying the risk factors for developing T2DM, understanding its pathophysiology and uncovering various metabolic pathways implicated in the disease process. This has culminated in the implementation of robust prevention programmes and the development of effective pharmacological agents, which have had a favourable impact on the management of T2DM in recent times. Despite these advances, the incidence and prevalence of T2DM continue to rise. Continuing research in improving efficacy, potency, delivery and reducing the adverse effect profile of currently available formulations is required to keep pace with this growing health challenge. Moreover, new metabolic pathways need to be targeted to produce novel pharmacotherapy to restore glucose homeostasis and address metabolic sequelae in patients with T2DM. We searched PubMed, MEDLINE, and Google Scholar databases for recently included agents and novel medication under development for treatment of T2DM. We discuss the pathophysiology of T2DM and review how the emerging anti-diabetic agents target the metabolic pathways involved. We also look at some of the limiting factors to developing new medication and the introduction of unique methods, including facilitating drug delivery to bypass some of these obstacles. However, despite the advances in the therapeutic options for the treatment of T2DM in recent years, the industry still lacks a curative agent.

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Molecular Mechanisms by Which Imeglimin Improves Glucose Homeostasis

Cited by 23 publications

References 26 publications

Mechanism of action of Imeglimin: A novel therapeutic agent for type 2 diabetes

Mechanism of action of Imeglimin: A novel therapeutic agent for type 2 diabetes

A review of therapeutic options for managing the metabolic aspects of polycystic ovary syndrome

Therapeutics for type-2 diabetes mellitus: a glance at the recent inclusions and novel agents under development for use in clinical practice

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