Imeglimin, a novel glimin oral antidiabetic, exhibits a good efficacy and safety profile in type 2 diabetic patients

Pīrāgs, Valdis; Lebovitz, Harold E.; Fouqueray, Pascale

doi:10.1111/j.1463-1326.2012.01611.x

Cited by 89 publications

(100 citation statements)

References 18 publications

(18 reference statements)

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“…These results are consistent with preclinical studies, where imeglimin increased glucose‐stimulated insulin secretion during a similar hyperglycaemic clamp method in diabetic N0STZ rats . Recent studies in humans also show evidence for enhanced insulin secretion during an oral glucose tolerance or a mixed‐meal test after 4 or 8 weeks of imeglimin treatment . Although an indirect effect on insulin secretion secondary to an improved glycaemia cannot be completely excluded, there is clear evidence for a direct effect of imeglimin on β‐cell function.…”

Section: Discussionsupporting

confidence: 93%

Imeglimin increases glucose‐dependent insulin secretion and improves β‐cell function in patients with type 2 diabetes

Pacini¹,

Mari²,

Fouqueray

et al. 2015

Diabetes Obesity Metabolism

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Section: Discussionsupporting

confidence: 93%

Imeglimin increases glucose‐dependent insulin secretion and improves β‐cell function in patients with type 2 diabetes

Pacini¹,

Mari²,

Fouqueray

et al. 2015

Diabetes Obesity Metabolism

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“…Management of type 2 diabetes emphasizes glycaemic control in terms of HbA 1c (lowering fasting and post-prandial blood glucose concentrations); there is an ongoing need for new agents which have sustained efficacy and excellent safety. Early studies showed that imeglimin is as effective as metformin in regulating glycaemic control [1]. This paper strengthens these findings by investigating other effects of imeglimin, including peripheral skeletal glucose uptake and insulin secretion.…”

Section: Discussionsupporting

confidence: 53%

“…The aim of developing imeglimin was to provide a safe and well-tolerated drug with unique pharmacological properties that can effectively treat the underlying metabolic defects in patients with type 2 diabetes mellitus. Indeed, imeglimin has already achieved its clinical proof of concept in an extensive Phase I/II programme [1]. In addition, because imeglimin appears to have a different mechanism of action to other oral anti-diabetic compounds, it may be suitable for safe and effective combination with other drugs routinely used for treating type 2 diabetes and its common co-morbidities.…”

Section: Introductionmentioning

confidence: 99%

Imeglimin - A New Oral Anti-Diabetic that Targets the Three Key Defects of type 2 Diabetes

Fouqueray¹,

Leverve²,

Fontaine³

et al. 2011

J Diabetes Metab

111

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Study background: The objective of this collated research paper is to highlight the anti-diabetic effects and mode of action of imeglimin, the first in a new tetrahydrotriazine-containing class of oral anti-diabetic agents: the glimins. Imeglimin acts on both insulin resistant organs (liver and muscle) and pancreatic β-cells (insulin secretion in response to glucose and protection against apoptosis). Methods:The aim of the investigations reported here is to present data on the mode of action of imeglimin and its anti-diabetic effects, demonstrating that it represents a promising treatment for type 2 diabetes by acting on the three key pathological defects of the disease, namely excessive hepatic glucose production, impaired peripheral glucose uptake by skeletal muscle, and insufficient insulin secretion.Results: Imeglimin significantly lowered fasting plasma glucose concentrations in a dose-dependent manner in STZ rats. HbA1c was significantly reduced (P<0.01) by imeglimin (6.2%) compared with controls (9.83%). At a 150 mg·kg -1 dose, imeglimin significantly improved glucose tolerance compared with controls (AUC 0-3h 2,402 vs 3,449 mmol·L·h -1 respectively). With regards to its mode of action, imeglimin significantly decreased the rate of hepatic gluconeogenesis, stimulated muscle glucose uptake, induced a potentiation of glucose-dependent insulin secretion, and decreased β-cell apoptosis. Conclusion:Our investigations found that imeglimin uniquely targets the three key defects of type 2 diabetes. It could provide more durable, sustained glycemic control than currently achieved with oral anti-diabetics and has the potential to be used at any stage in the disease continuum. Imeglimin's potential for combination with other oral antidiabetics is also under investigation.

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“…Imeglimin is the first in a new tetrahydrotriazine-containing class of oral glucose-lowering agents-the glimins-and is currently in phase 2b clinical development (U.S./European Union EudraCT 2012-004045-33). Several clinical trials have shown imeglimin to be well tolerated and exhibit benefits on HbA 1c as monotherapy and add-on therapy (3)(4)(5). Imeglimin acts on the liver, muscle, and the pancreas (6), three key organs involved in the pathophysiology of type 2 diabetes through suspected mechanisms targeting the mitochondria and reduced oxidative stress.…”

mentioning

confidence: 99%

Imeglimin Normalizes Glucose Tolerance and Insulin Sensitivity and Improves Mitochondrial Function in Liver of a High-Fat, High-Sucrose Diet Mice Model

et al. 2014

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Imeglimin is the first in a new class of oral glucose-lowering agents currently in phase 2b development. Although imeglimin improves insulin sensitivity in humans, the molecular mechanisms are unknown. This study used a model of 16-week high-fat, high-sucrose diet (HFHSD) mice to characterize its antidiabetic effects. Six-week imeglimin treatment significantly decreased glycemia, restored normal glucose tolerance, and improved insulin sensitivity without modifying organs, body weights, and food intake. This was associated with an increase in insulin-stimulated protein kinase B phosphorylation in the liver and muscle. In liver mitochondria, imeglimin redirects substrate flows in favor of complex II, as illustrated by increased respiration with succinate and by the restoration of respiration with glutamate/malate back to control levels. In addition, imeglimin inhibits complex I and restores complex III activities, suggesting an increase in fatty acid oxidation, which is supported by an increase in hepatic 3-hydroxyacetyl-CoA dehydrogenase activity and acylcarnitine profile and the reduction of liver steatosis. Imeglimin also reduces reactive oxygen species production and increases mitochondrial DNA. Finally, imeglimin effects on mitochondrial phospholipid composition could participate in the benefit of imeglimin on mitochondrial function. In conclusion, imeglimin normalizes glucose tolerance and insulin sensitivity by preserving mitochondrial function from oxidative stress and favoring lipid oxidation in liver of HFHSD mice.

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Imeglimin, a novel glimin oral antidiabetic, exhibits a good efficacy and safety profile in type 2 diabetic patients

Cited by 89 publications

References 18 publications

Imeglimin increases glucose‐dependent insulin secretion and improves β‐cell function in patients with type 2 diabetes

Imeglimin increases glucose‐dependent insulin secretion and improves β‐cell function in patients with type 2 diabetes

Imeglimin - A New Oral Anti-Diabetic that Targets the Three Key Defects of type 2 Diabetes

Imeglimin Normalizes Glucose Tolerance and Insulin Sensitivity and Improves Mitochondrial Function in Liver of a High-Fat, High-Sucrose Diet Mice Model

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