Super-resolution microscopy reveals the insulin-resistance-regulated reorganization of GLUT4 on plasma membranes

Gao, Lan; Chen, Junling; Gao, Jing; Xiong, Wenyong

doi:10.1242/jcs.192450

Cited by 33 publications

(59 citation statements)

References 43 publications

(44 reference statements)

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“…As previous studies have shown, an increase in glucose uptake is caused by a change in the distribution of glucose transporters from intracellular storage vesicles to the plasma membrane in fat and skeletal muscle cells (Vincent et al, 2005; Pessin and Saltiel, 2000; Leto and Saltiel, 2012). Glucose transporter 4 (GLUT4) is the main transporter of glucose in muscle and fat cells and functions to control cellular glucose metabolism and whole-body energy homeostasis, which are both strongly linked to type 2 diabetes (Kubota et al, 2011; Huang et al, 2016; Gao et al, 2017). The selective downregulation of GLUT4 in adipose and muscle tissues can cause insulin resistance which increases the risk of developing diabetes (Abel et al, 2001; Leney and Tavare, 2009).…”

Section: Introductionmentioning

confidence: 99%

Neferine Promotes GLUT4 Expression and Fusion With the Plasma Membrane to Induce Glucose Uptake in L6 Cells

et al. 2019

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Glucose transporter 4 (GLUT4) is involved in regulating glucose uptake in striated muscle, liver, and adipose tissue. Neferine is a dibenzyl isoquinoline alkaloid derived from dietary lotus seeds and has multiple pharmacological effects. Therefore, this study investigated neferine’s role in glucose translocation to cell surface, glucose uptake, and GLUT4 expression. In our study, neferine upregulated GLUT4 expression, induced GLUT4 plasma membrane fusion, increased intracellular Ca2+, promoted glucose uptake, and alleviated insulin resistance in L6 cells. Furthermore, neferine significantly activated phosphorylation of AMP-activated protein kinase (AMPK) and protein kinase C (PKC). AMPK and PKC inhibitors blocked neferine-induced GLUT4 expression and increased intracellular Ca2+. While neferine-induced GLUT4 expression and intracellular Ca2+ were inhibited by G protein and PLC inhibitors, only intracellular Ca2+ was inhibited by inositol trisphosphate receptor (IP3R) inhibitors. Thus, neferine promoted GLUT4 expression via the G protein-PLC-PKC and AMPK pathways, inducing GLUT4 plasma membrane fusion and subsequent glucose uptake and increasing intracellular Ca2+ through the G protein-PLC-IP3-IP3R pathway. Treatment with 0 mM extracellular Ca2+ + Ca2+ chelator did not inhibit neferine-induced GLUT4 expression but blocked neferine-induced GLUT4 plasma membrane fusion and glucose uptake, suggesting the latter two are Ca2+-dependent. Therefore, we conclude that neferine is a potential treatment for type 2 diabetes.

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Section: Introductionmentioning

confidence: 99%

Neferine Promotes GLUT4 Expression and Fusion With the Plasma Membrane to Induce Glucose Uptake in L6 Cells

et al. 2019

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“…Abundant evidence has proved that spatial recruitment and clustering of proteins and lipids into lipid rafts is a remarkable feature in a variety of signaling and transferring processes (22,23), for instance insulin receptors, integrin, and T cell antigen receptors (22,24). Even the members of GLUT family (GLUT4 and GLUT1) have been found to associate with DRMs (4,25). However, due to the use of detergents for extracting lipid rafts in these experiments that broke the natural condition of cell membranes, the validity and accuracy of the colocalization between…”

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confidence: 99%

Mechanistic insights into GLUT1 activation and clustering revealed by super-resolution imaging

Yan

Zhou

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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The glucose transporter GLUT1, a plasma membrane protein that mediates glucose homeostasis in mammalian cells, is responsible for constitutive uptake of glucose into many tissues and organs. Many studies have focused on its vital physiological functions and close relationship with diseases. However, the molecular mechanisms of its activation and transport are not clear, and its detailed distribution pattern on cell membranes also remains unknown. To address these, we first investigated the distribution and assembly of GLUT1 at a nanometer resolution by super-resolution imaging. On HeLa cell membranes, the transporter formed clusters with an average diameter of ∼250 nm, the majority of which were regulated by lipid rafts, as well as being restricted in size by both the cytoskeleton and glycosylation. More importantly, we found that the activation of GLUT1 by azide or MβCD did not increase its membrane expression but induced the decrease of the large clusters. The results suggested that sporadic distribution of GLUT1 may facilitate the transport of glucose, implying a potential association between the distribution and activation. Collectively, our work characterized the clustering distribution of GLUT1 and linked its spatial structural organization to the functions, which would provide insights into the activation mechanism of the transporter.

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“…2009; Rossi et al 2012;Gao et al 2017) and has also been proposed for the brush-border NHE (presumably NHE3).…”

Section: Discussionmentioning

confidence: 95%

The Na⁺/H⁺ exchanger NHE1 localizes as clusters to cryptic lamellipodia and accelerates collective epithelial cell migration

Jensen

Pedersen

Morgen

et al. 2018

The Journal of Physiology

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Key points Exogenous Na+/H+ exchanger 1 (NHE1) expression stimulated the collective migration of epithelial cell sheets Stimulation with epidermal growth factor, a key morphogen, primarily increased migration of the front row of cells, whereas NHE1 increased that of submarginal cell rows, and the two stimuli were additive Accordingly, NHE1 localized not only to the leading edges of leader cells, but also in cryptic lamellipodia in submarginal cell rows NHE1 expression disrupted the morphology of epithelial cell sheets and three‐dimensional cysts Abstract Collective cell migration plays essential roles in embryonic development, in normal epithelial repair processes, and in many diseases including cancer. The Na+/H+ exchanger 1 (NHE1, SLC9A1) is an important regulator of motility in many cells and has been widely studied for its roles in cancer, although its possible role in collective migration of normal epithelial cells has remained unresolved. In the present study, we show that NHE1 expression in MDCK‐II kidney epithelial cells accelerated collective cell migration. NHE1 localized to the leading edges of leader cells, as well as to cryptic lamellipodia in submarginal cell rows. Epidermal growth factor, a kidney morphogen, increased displacement of the front row of collectively migrating cells and reduced the number of migration fingers. NHE1 expression increased the number of migration fingers and increased displacement of submarginal cell rows, resulting in additive effects of NHE1 and epidermal growth factor. Finally, NHE1 expression resulted in disorganized development of MDCK‐II cell cysts. Thus, NHE1 contributes to collective migration and epithelial morphogenesis, suggesting roles for the transporter in embryonic and early postnatal development.

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Super-resolution microscopy reveals the insulin-resistance-regulated reorganization of GLUT4 on plasma membranes

Cited by 33 publications

References 43 publications

Neferine Promotes GLUT4 Expression and Fusion With the Plasma Membrane to Induce Glucose Uptake in L6 Cells

Neferine Promotes GLUT4 Expression and Fusion With the Plasma Membrane to Induce Glucose Uptake in L6 Cells

Mechanistic insights into GLUT1 activation and clustering revealed by super-resolution imaging

The Na⁺/H⁺ exchanger NHE1 localizes as clusters to cryptic lamellipodia and accelerates collective epithelial cell migration

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Super-resolution microscopy reveals the insulin-resistance-regulated reorganization of GLUT4 on plasma membranes

Cited by 33 publications

References 43 publications

Neferine Promotes GLUT4 Expression and Fusion With the Plasma Membrane to Induce Glucose Uptake in L6 Cells

Neferine Promotes GLUT4 Expression and Fusion With the Plasma Membrane to Induce Glucose Uptake in L6 Cells

Mechanistic insights into GLUT1 activation and clustering revealed by super-resolution imaging

The Na+/H+ exchanger NHE1 localizes as clusters to cryptic lamellipodia and accelerates collective epithelial cell migration

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The Na⁺/H⁺ exchanger NHE1 localizes as clusters to cryptic lamellipodia and accelerates collective epithelial cell migration