Metformin: An Old Drug for the Treatment of Diabetes but a New Drug for the Protection of the Endothelium

Medical Principles and Practice, Journal Year: 2015, Volume and Issue: 24(5), P. 401 - 415

Published: Jan. 1, 2015

The anti-diabetic and oral hypoglycaemic agent metformin, first used clinically in 1958, is today the choice or ‘gold standard' drug for treatment of type 2 diabetes polycystic ovary disease. Of particular importance diabetes, metformin affords protection against diabetes-induced vascular In addition, retrospective analyses suggest that with provides therapeutic benefits to patients several forms cancer. Despite almost 60 years clinical use, precise cellular mode(s) action remains controversial. A direct indirect role adenosine monophosphate (AMP)-activated protein kinase (AMPK), fuel gauge cell, has been inferred many studies, evidence activation AMPK may result from a mild inhibitory effect on mitochondrial complex 1, which turn would raise AMP activate AMPK. Discrepancies, however, between concentrations vitro studies versus levels caution should be applied before extending inferences derived cell-based seen patients. Conceivably, effects, some them, at least partially independent and/or respiration reflect either minor and, as yet, unidentified putative metabolite target protein(s)/signalling cascade. this review, we critically evaluate data have investigated pharmacokinetic properties basis hypoglycaemic, insulin-sensitising protective effects metformin.

Language: Английский

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Clinical Review of Antidiabetic Drugs: Implications for Type 2 Diabetes Mellitus Management

Frontiers in Endocrinology, Journal Year: 2017, Volume and Issue: 8

Published: Jan. 23, 2017

Type 2 diabetes mellitus (T2DM) is a global pandemic, as evident from the cartographic picture of by International Diabetes Federation (http://www.diabetesatlas.org/). (DM) chronic, progressive, incompletely understood metabolic condition chiefly characterized hyperglycemia. Either impaired insulin secretion, resistance to tissue actions or combination both are thought be commonest reasons contributing pathophysiology T2DM, spectrum disease originally arising and gradually progressing state complete loss secretory activity beta-cells pancreas. T2DM major contributor very large rise in rate non-communicable diseases affecting developed well developing nations. In this mini-review, we endeavor outline current management principles, including medications that currently used for pharmacologic management, lowering elevated blood glucose T2DM.

Language: Английский

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Metformin: From Mechanisms of Action to Therapies

Cell Metabolism, Journal Year: 2014, Volume and Issue: 20(6), P. 953 - 966

Published: Oct. 30, 2014

Language: Английский

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Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis

eLife, Journal Year: 2014, Volume and Issue: 3

Published: May 13, 2014

Recent epidemiological and laboratory-based studies suggest that the anti-diabetic drug metformin prevents cancer progression. How diminishes tumor growth is not fully understood. In this study, we report in human cells, inhibits mitochondrial complex I (NADH dehydrogenase) activity cellular respiration. Metformin inhibited proliferation presence of glucose, but induced cell death upon glucose deprivation, indicating cells rely exclusively on glycolysis for survival metformin. also reduced hypoxic activation hypoxia-inducible factor 1 (HIF-1). All these effects were reversed when metformin-resistant Saccharomyces cerevisiae NADH dehydrogenase NDI1 was overexpressed. vivo, administration to mice control those expressing NDI1. Thus, have demonstrated metformin's inhibitory progression are autonomous depend its ability inhibit I.

Language: Английский

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Epigenetic Mechanisms of Longevity and Aging

Cell, Journal Year: 2016, Volume and Issue: 166(4), P. 822 - 839

Published: Aug. 1, 2016

Language: Английский

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Role of smooth muscle cells in vascular calcification: implications in atherosclerosis and arterial stiffness

Cardiovascular Research, Journal Year: 2018, Volume and Issue: 114(4), P. 590 - 600

Published: Feb. 15, 2018

Vascular calcification is associated with a significant increase in all-cause mortality and atherosclerotic plaque rupture. Calcification has been determined to be an active process driven part by vascular smooth muscle cell (VSMC) transdifferentiation within the wall. Historically, VSMC phenotype switching viewed as binary, cells able adopt physiological contractile or alternate 'synthetic' response injury. More recent work, including lineage tracing however revealed that VSMCs are number of phenotypes, calcific (osteogenic, chondrocytic, osteoclastic), adipogenic, macrophagic phenotypes. Whilst mechanisms drive differentiation still being elucidated it becoming clear medial may differ several ways from intimal seen lesions, risk factors specific drivers for changes calcification. This article aims compare contrast role driving both atherosclerosis vessel media focusing on major calcification, aging, uraemia, mechanical stress, oxidative inflammation. The review also discusses novel findings have brought attention pro- anti-calcifying proteins, extracellular vesicles, mitochondrial dysfunction, uraemic milieu determinants

Language: Английский

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AMPK, insulin resistance, and the metabolic syndrome

Journal of Clinical Investigation, Journal Year: 2013, Volume and Issue: 123(7), P. 2764 - 2772

Published: June 30, 2013

Insulin resistance (IR) and hyperinsulinemia are hallmarks of the metabolic syndrome, as central adiposity, dyslipidemia, a predisposition to type 2 diabetes, atherosclerotic cardiovascular disease, hypertension, certain cancers. Regular exercise calorie restriction have long been known increase insulin sensitivity decrease prevalence these disorders. The subsequent identification AMP-activated protein kinase (AMPK) its activation by fuel deprivation led studies effects AMPK on both IR syndrome–related diseases. In this review, we evaluate body literature, with special emphasis hypothesis that dysregulation is pathogenic factor for disorders in humans target their prevention therapy.

Language: Английский

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Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin

Nature Medicine, Journal Year: 2013, Volume and Issue: 19(12), P. 1649 - 1654

Published: Nov. 3, 2013

Language: Английский

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Upregulated NLRP3 Inflammasome Activation in Patients With Type 2 Diabetes

Diabetes, Journal Year: 2012, Volume and Issue: 62(1), P. 194 - 204

Published: Oct. 20, 2012

Despite the recent attention focused on roles of nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome in pathogenesis type 2 diabetes, little is known about ex vivo profile activation diabetic patients. In this study, we investigated patterns NLRP3 monocyte-derived macrophages (MDMs) from drug-naïve patients with newly diagnosed diabetes. Type subjects had significantly increased mRNA protein expression NLRP3, apoptosis-associated speck-like containing a CARD (ASC), proinflammatory cytokines MDMs cultured autologous sera compared healthy controls. Upregulated interleukin (IL)-1β maturation, IL-18 secretion, caspase-1 cleavage were observed after stimulation various danger molecules (ATP, high-mobility group B1, free fatty acids, islet amyloid polypeptide, monosodium uric acid crystals). Mitochondrial reactive oxygen species required for IL-1β synthesis MDMs. Finally, months therapy antidiabetic drug metformin inhibited maturation diabetes through AMP-activated kinase (AMPK) activation. Taken together, these data suggest that elevated myeloid cells treatment contributes to modulation

Language: Английский

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Metformin Promotes Antitumor Immunity via Endoplasmic-Reticulum-Associated Degradation of PD-L1

Molecular Cell, Journal Year: 2018, Volume and Issue: 71(4), P. 606 - 620.e7

Published: Aug. 1, 2018

Language: Английский

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