Metformin in cardiovascular diabetology: a focused review of its impact on endothelial function

Abstract

As a first-line treatment for diabetes, the insulin-sensitizing biguanide, metformin, regulates glucose levels and positively affects cardiovascular function in patients with diabetes and cardiovascular complications. Endothelial dysfunction (ED) represents the primary pathological change of multiple vascular diseases, because it causes decreased arterial plasticity, increased vascular resistance, reduced tissue perfusion and atherosclerosis. Caused by “biochemical injury”, ED is also an independent predictor of cardiovascular events. Accumulating evidence shows that metformin improves ED through liver kinase B1 (LKB1)/5'-adenosine monophosphat-activated protein kinase (AMPK) and AMPK-independent targets, including nuclear factor-kappa B (NF-κB), phosphatidylinositol 3 kinase-protein kinase B (PI3K-Akt), endothelial nitric oxide synthase (eNOS), sirtuin 1 (SIRT1), forkhead box O1 (FOXO1), krüppel-like factor 4 (KLF4) and krüppel-like factor 2 (KLF2). Evaluating the effects of metformin on endothelial cell functions would facilitate our understanding of the therapeutic potential of metformin in cardiovascular diabetology (including diabetes and its cardiovascular complications). This article reviews the physiological and pathological functions of endothelial cells and the intact endothelium, reviews the latest research of metformin in the treatment of diabetes and related cardiovascular complications, and focuses on the mechanism of action of metformin in regulating endothelial cell functions.

The Effects of Separate and Combined Treatment of Male Rats with Type 2 Diabetes with Metformin and Orthosteric and Allosteric Agonists of Luteinizing Hormone Receptor on Steroidogenesis and Spermatogenesis

“…MF, which is widely used for T2DM treatment, not only improves metabolic status and insulin sensitivity, but also restores functions of the cardiovascular, urinary, nervous and other systems impaired in diabetic conditions [ 17 , 83 , 84 , 85 , 86 , 87 , 88 ]. MF also has a positive effect on the reproductive system and fertility.…”

Role of Epicardial Adipose Tissue in Cardiovascular Diseases: A Review

“…The exact mechanism by which metformin interacts with EAT is not clear, but it appears to shift the metabolism into fat oxidation and upregulate the thermogenesis [193,194]. It has recently been shown to be effective against endothelial dysfunction [195]. Chen et al reported that metformin reduced the secretion of the proinflammatory cytokine, activin A, from epicardial fat [196].…”

“…Statins anti-inflammatory [160,[162][163][164][165] modulation of EAT [164] ↓ EAT metabolic activity [163] PCSK-9 inhibitors unknown Metformin anti-inflammatory [186,187,[196][197][198]200] ↑ fat oxidation and thermogenesis [193,194] ↓ endothelial dysfunction [195] activation of adenosine monophosphate-activated protein kinase [198,200] Thiazolidinediones anti-inflammatory [190,191,[204][205][206] SGLT2 inhibitors anti-inflammatory [210,217] ↓ endothelial dysfunction [213] stimulation of visceral fat burn [215] ↑ EAT cells sensitivity to insulin [217] GLP-1 agonists ↑ pre-adipocyte differentiation [225] ↑ thermogenesis [226] ↑ adipocyte browning [226] DPP-4 inhibitors anti-inflammatory [231][232][233] downregulation of the receptor for advanced glycation end-products [234] ↑ cyclic adenosine monophosphate/protein kinase A signaling and IL-6 production [235] ↓ ROS generation and intercellular adhesion molecule-1 expression [236] Table 1. Cont.…”

Skeletal Muscle Microvascular Dysfunction in Obesity-Related Insulin Resistance: Pathophysiological Mechanisms and Therapeutic Perspectives

“…The regulation of microvascular function is controlled by the balance in the activation of the sympathetic and parasympathetic nervous system, as well as by local metabolic and myogenic autoregulatory mechanisms. The microvascular endothelium plays multifaceted biological functions, including serving as a semipermeable physiological barrier and component of innate immunity, as well as regulation of vascular tone, mechano-transduction, procoagulant/anticoagulant balance, endothelial repair, and angiogenesis, among other functions [29]. It produces both vasodilators/anti-thrombogenic factors and vasoconstrictors/prothrombotic factors.…”

“…Metformin is the first-line drug for treating patients with DM type 2 and is increasingly also used for clinical management of other insulin-resistant states such as prediabetes and polycystic ovarian disease [164] on account of known cardiovascular benefits and pleiotropic effects. A growing body of evidence suggests that metformin improves vascular endothelial dysfunction via AMPK dependent and independent mechanisms, including downregulation of NF-κB and upregulation of PI3K-Akt-eNOS, Sirt1, forkhead box O1 (FOXO1), and krüppel-like factors (KLF) 2 and 4 [29]. Compared to control, obese diabetic patients treated with metformin expressed lower levels of inflammatory markers such as hsCRP, TNF-α, and Toll-like receptors 2/4 [165].…”