New Insight into Metformin Mechanism of Action and Clinical Application

Abstract

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 ...

Metformin and Insulin Resistance: A Review of the Underlying Mechanisms behind Changes in GLUT4-Mediated Glucose Transport

“…Metformin is a widely prescribed insulin-sensitizing agent in current clinical use. Despite being most commonly associated with its ability to decrease plasma glucose levels, the knowledge about its novel properties and effects continues to evolve [31]. Its action modulates multiple biological pathways.…”

The effect of metformin on cognitive function: A systematic review and meta-analysis

“…Metformin has been found to have other beneficial properties in recent years, including the cardiovascular protective effect (Dore et al, 2018;Loi et al, 2019) and increasing insulin sensitivity have been identified for metformin in the past years as it is used for the treatment of polycystic ovary syndrome (PCOS) (Costello et al, 2019;Morley et al, 2017), prediabetes, gestational diabetes mellitus (GDM) and even for management overweight and obesity, currently (Castro-Martínez et al, 2014;Kitabchi et al, 2005). Metformin also reduces mortality due to diseases such as diabetes, cancer, and cardiovascular disease as a result of its anti-aging properties (Glossmann and Lutz, 2019;Soukas et al, 2019;Yan et al, 2020). Increasing lifespan in the animal models and humans (Anisimov et al, 2008(Anisimov et al, , 2011Glossmann and Lutz, 2019) is among other recognized properties of metformin.…”

Targeting Oxidative Phosphorylation-Proteasome Activity in Extracellular Detached Cells Promotes Anoikis and Inhibits Metastasis

“…Although, metformin promises as an anti-cancer agent [49,52], its mechanism of action in cancer of different origins is yet to be fully understood and whether it will be a potential therapy for metastasis-the leading cause of deaths in cancer [52,53]. Studies reported metformin had anticancer effect dependent or independent of AMPK activation [48,53]. AMPK activation was reported in various contexts to be involved in the modulation of stress and unfolded protein response (UPR) [54][55][56][57][58].…”

“…More so, metformin downregulated the expression of two highly expressed proteasome genes (PSMB2 and PSMD3) and abrogated antioxidant genes in ECM detached cells. Metformin modulates energy metabolism to induce its therapeutic effect in various disease conditions [53]. The observed reduction in ATP generated due to inhibition of complex I /OXPHOS fosters increased ROS generation and activation of AMPK in metformin-treated cells suggesting impaired mitochondrial metabolic function.…”