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

Abstract

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

Molecular Interplay between microRNA-34a and Sirtuin1 in Hyperglycemia-Mediated Impaired Angiogenesis in Endothelial Cells: Effects of Metformin

“…Preclinical in vivo studies and clinical data suggest that metformin possesses pleiotropic effects that protect the endothelium (Mather et al, 2001;Zhang et al, 2013;Arunachalam et al, 2014;Kinaan et al, 2015). However, the effect of metformin on miR-34a and its impact on endothelial function have not previously been studied.…”

Rutaecarpine ameliorates hyperlipidemia and hyperglycemia in fat-fed, streptozotocin-treated rats via regulating the IRS-1/PI3K/Akt and AMPK/ACC2 signaling pathways

“…In the WHO Model List of Essential Medicines of 2011, metformin is one of only two oral anti-diabetic drugs (the other one is glibenclamide) [9] . However, side effects, such as lactic acidosis and permanent nerve damage, limit its application in certain populations [10,11] . The insulin receptor signaling pathway is a major mechanism underlying the development of diabetes and MetS.…”

Targeting endothelial metaflammation to counteract diabesity cardiovascular risk: Current and perspective therapeutic options

“…Despite almost 6 decades of research, the cellular mechanisms that underlie the cardioprotective effects of metformin are not completely understood, but a number of clinical studies report an improved endothelial function associated to increased flow-mediated vasodilatation in patients treated with metformin (reviewed in [112]). On one side, the vascular protective actions of metformin are thought to be secondary to the antihyperglycemic effects of this drug, mediated via activation of adenosine 5′-monophosphate-activated protein kinase (AMPK) and subsequent inhibition of hepatic gluconeogenesis, fatty acid oxidation and insulin sensitizing action in striated muscle and adipose tissue [113]. On the other hand, data from both clinical and bench studies 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 indicate that metformin has a direct action on the endothelium that seem to involve a reduction in oxidative stress secondary to modulation of mitochondrial complex 1, and activation of signaling pathways controlled by the deacetylase Sirtuin 1 (SIRT-1) [114].…”