Repurposing Metformin for Cardiovascular Disease

Bai

et al. 2020

BMC Cardiovasc Disord

Background: Previous studies demonstrated impaired lipid metabolism and augmented aerobic glycolysis in AF. The authors aimed to investigate whether the use of metformin, an AMPK activator, could reverse this metabolic remodeling in chronic AF and to explore the underlying mechanisms. Methods: We conducted chronic AF animal models with 18 beagle dogs and divided them into SR (pacemaker implanted without pacing), AF (pacemaker implanted with sustained pacing at a frequency of 400 beats/min for 6 weeks), and metformin+AF group (daily oral administration of metformin was initiated 1 week before surgery and continued throughout the study period). After electrophysiological measurements, the left atrial appendage tissue samples were taken from the beating heart for further analysis. Protein expression, histological analysis, and biochemical measurements were conducted.Results: The AF groups showed decreased expression of FAT/CD36, CPT-1, VLCAD, increased concentration of free fatty acid and triglyceride, and increased lipid deposition. The activation of AMPK/PGC-1α/PPARα pathway was decreased. The key factors of the Warburg effect, including HIF-1α, GLUT-1, PDK1, HK, and LDH, increased in AF group compared to SR group. The expression of PDH decreased significantly, accompanied by increased atrial lactate production. The extent of fibrosis increased significantly in the left atrial appendage of AF group. dERP, ∑WOV, and AF inducibility increased while ERP decreased in AF group compared to SR group. The use of metformin attenuated all these changes effectively.Conclusions: Metformin improves lipid metabolism and reverses the Warburg effect in chronic AF via AMPK activation. It attenuates atrial electrical and structural remodeling.

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Metformin improves lipid metabolism and reverses the Warburg effect in a canine model of chronic atrial fibrillation

Bai

et al. 2020

BMC Cardiovasc Disord

Metformin [Working Title]

“…Cardiovascular diseases (CVD) are the leading cause of death and disability in the world. Metformin might have sustained beneficial role on reducing CVD risk and mortality [105,106]. The cardioprotective effects include reduction of weight gain and hyperinsulinemia, improvement of endothelial function and fibrinolysis, and reduction of low-grade inflammation, oxidative stress, and glycation.…”

Section: Cardiovascular Diseasesmentioning

confidence: 99%

“…Several clinical trials for metformin on participants with or without T1D diabetes have been completed [106]. Trials Metformin in Insulin Resistant Left Ventricular Dysfunction (TAYSIDE, NCT00473876) and Reducing with Metformin Vascular Adverse Lesions of Type 1 Diabetes (REMOVAL, NCT01483560) have promising data.…”

Section: Cardiovascular Diseasesmentioning

confidence: 99%

“…In an 8-week period of metformin treatment for nondiabetic participants with cardiac syndrome X, metformin improved endothelium-dependent microvascular response, maximal ST-segment depression, Duke score, and chest pain incidence, which suggested that metformin may improve vascular function and decrease myocardial ischemia [118]. However, several studies reported that metformin was not found to be effective in their participants [106].…”

Section: Cardiovascular Diseasesmentioning

confidence: 99%

See 1 more Smart Citation

New Insight into Metformin Mechanism of Action and Clinical Application

Yan¹,

Kover²,

Moore³

2020

Metformin is the first-line medication for Type 2 diabetes (T2D) treatment, and it is the only US FDA approved oral antidiabetic medication for pediatric patients with T2D 10 years and older. Metformin is also used to treat polycystic ovary syndrome (PCOS), another condition with underlying insulin resistance. The clinical applications of metformin are continuing to expand into other fields including cancer, aging, cardiovascular diseases, and neurodegenerative diseases. Metformin modulates multiple biological pathways. Its novel properties and effects continue to evolve; however, its molecular mechanism of action remains incompletely understood. In this chapter, we focus on the recent translational research and clinical data on the molecular action of metformin and the evidence linking the effects of metformin on insulin resistance, prediabetes, diabetes, aging, cancer, PCOS, cardiovascular diseases, and neurodegenerative diseases. Metformin 2 Mechanisms of actionThe potential mechanisms of metformin action involve several pathways. The AMPK-pathway plays an important role in metformin actions [2, 3]. Metformin inhibits the mitochondrial respiratory chain (complex I), which increases the AMP to ATP ratio, leading to the phosphorylation of AMP-activated protein kinase (AMPK) at Thr-172. We have demonstrated that metformin treatment increases protein level of phosphorylated AMPK in high-glucose-treated endothelial cells [4]. The phosphorylated AMPK subsequently phosphorylates multiple downstream effectors to regulate cellular metabolism and energy homeostasis [5]. These downstream effectors include thioredoxin interacting protein (TXNIP) and TBC1D1, a RAB-GTPase activating protein and a member of the tre-2/BUB2/cdc1 domain family. Phosphorylated TXNIP and TBC1D1 increase the plasma membrane localization of glucose transporter 1 (GLUT1) and GLUT4, respectively [6, 7], and regulate glycogen synthases (GYS1 and GYS2) to prevent the storage of glycogen [8]. Some actions of metformin have been found to be AMPK-independent [9].In diabetic mice, metformin has an effect on gut microbiota by inducing a profound shift in the gut microbial community profile, resulting in an increase in the Akkermansia spp. population [10] and cAMP-induced agmatine production [11], which may decrease absorption of glucose from the gastrointestinal tract and increase lipid metabolism respectively. In addition, metformin decreases insulin-induced suppression of fatty acid oxidation and lowers lipid content of hepatic cells [12].New Insight into Metformin Mechanism of Action and Clinical Application DOI: http://dx.doi.org/10.5772/intechopen.91148 association with insulin resistance. Metformin decreases the level of circulating branched-chain amino acids and reduces insulin resistance in a high-fat diet mouse model [22]. Metformin treatment lowers plasma ADMA which is associated with improved glycemic control in patients with T2D [23].Recent studies indicate that phosphatidylinositol-3-kinase/protein kinase B protein (PI3K/PKB, also known as ...

Journal Cellular Physiology

Metformin protects against vascular calcification through the selective degradation of Runx2 by the p62 autophagy receptor

Phadwal

Koo

Jones

et al. 2022

Vascular calcification is associated with aging, type 2 diabetes, and atherosclerosis, and increases the risk of cardiovascular morbidity and mortality. It is an active, highly regulated process that resembles physiological bone formation. It has previously been established that pharmacological doses of metformin alleviate arterial calcification through adenosine monophosphate-activated protein kinase (AMPK)-activated autophagy, however the