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

Abstract

Metformin is the most commonly used treatment to increase insulin sensitivity in insulin-resistant (IR) conditions such as diabetes, prediabetes, polycystic ovary syndrome, and obesity. There is a well-documented correlation between glucose transporter 4 (GLUT4) expression and the level of IR. Therefore, the observed increase in peripheral glucose utilization after metformin treatment most likely comes from the induction of GLUT4 expression and its increased translocation to the plasma membrane. However, the mechanisms behind this effect and the critical metformin targets are still largely undefined. The present review explores the evidence for the crucial role of changes in the expression and activation of insulin signaling pathway mediators, AMPK, several GLUT4 translocation mediators, and the effect of posttranscriptional modifications based on previously published preclinical and clinical models of metformin’s mode of action in animal and human studies. Our aim is to provide a comprehensive review of the studies in this field in order to shed some light on the complex interactions between metformin action, GLUT4 expression, GLUT4 translocation, and the observed increase in peripheral insulin sensitivity.

Jiangtang Sanhao formula ameliorates skeletal muscle insulin resistance via regulating GLUT4 translocation in diabetic mice

“…Several studies have confirmed the IR in skeletal muscle is the initial defect in T2DM that may appear decades before β-cell dysfunction and significant hyperglycemia development ( DeFronzo and Tripathy, 2009 ; Merz and Thurmond, 2020 ). Accumulating evidence suggests that glucose transporter 4 (GLUT4) is the rate-limiting step of glucose uptake in skeletal muscle cells, and the impaired GLUT4 translocation is the principal defect of IR in skeletal muscle ( Richter and Hargreaves, 2013 ; Sanvee et al, 2019 ; Herman et al, 2022 ). Several classic pathways have been found to be involved in the translocation mechanism of GLUT4, such as phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, and so on.…”

Assessment of Novel Oligopeptides from Rapeseed Napin (Brassica napus) in Protecting HepG2 Cells from Insulin Resistance and Oxidative Stress

“…In this study, a 2 mM dose of napin-derived oligopeptides was used primarily to elucidate the possible mechanisms of their protective effects against IR and oxidative stress in the IR-HepG2 cells. Recent studies reported that glucose consumption has been tightly related to GLUT4 on the plasma membrane, and glucose fails to freely enter cells through the lipid bilayer structure of the plasma membrane without GLUT4. , Therefore, it is necessary to investigate whether oligopeptides significantly increase GLUT4 expression and translocation in vitro or in vivo.…”

“…Recent studies reported that glucose consumption has been tightly related to GLUT4 on the plasma membrane, and glucose fails to freely enter cells through the lipid bilayer structure of the plasma membrane without GLUT4. 45,46 Therefore, it is necessary to investigate whether oligopeptides significantly increase GLUT4 expression and translocation in vitro or in vivo.…”

G6PD Deficiency Is Crucial for Insulin Signaling Activation in Skeletal Muscle

“…GLUT1 was not changed after G6PD knock-down or over-expression (Figure 2e,f). GLUT4 is an insulin sensitive glucose transporter, and it transports from being intracellular to the cell surface under insulin stimulation [19][20][21]. The positive effect of G6PD deficiency on GLUT4 expression indicates its potential role in insulin signaling.…”