Abstract
The number of patients with type 2 diabetes mellitus (T2DM) is increasing rapidly worldwide. Glucose transporter 4 (GLUT4) is one of the main proteins that transport blood glucose into the cells and is a target in the treatment of T2DM. In this study, we investigated the mechanism of action of dandelion chloroform extract (DCE) on glucose uptake in L6 cells. The glucose consumption of L6 cell culture supernatant was measured by a glucose uptake assay kit, and the dynamic changes of intracellular GLUT4 and calcium (Ca2+) levels were monitored by laser scanning confocal microscopy in L6 cell lines stably expressing IRAP-mOrange. The GLUT4 fusion with the plasma membrane (PM) was traced via myc-GLUT4-mOrange. GLUT4 expression and AMP-activated protein kinase (AMPK), protein kinase B (PKB/Akt), protein kinase C (PKC), and phosphorylation levels were determined by performing western blotting. GLUT4 mRNA expression was detected by real-time PCR. DCE up-regulated GLUT4 expression, promoted GLUT4 translocation and fusion to the membrane eventually leading to glucose uptake, and induced AMPK phosphorylation in L6 cells. The AMPK inhibitory compound C significantly inhibited DCE-induced GLUT4 expression and translocation while no inhibitory effect was observed by the phosphatidylinositol 3-kinase (PI3K) inhibitor Wortmannin and PKC inhibitor Gö6983. These data suggested that DCE promoted GLUT4 expression and transport to the membrane through the AMPK signaling pathway, thereby stimulating GLUT4 fusion with PM to enhance glucose uptake in L6 cells. DCE-induced GLUT4 translocation was also found to be Ca2+-independent. Together, these findings indicate that DCE could be a new hypoglycemic agent for the treatment of T2DM.
Highlights
Type 2 diabetes mellitus (T2DM) is known as non-insulindependent diabetes mellitus and accounts for 90%–95% of all cases of diabetes [1]
Because of the known strong colocalization of Insulinresponsive aminopeptidase (IRAP) and Glucose transporter 4 (GLUT4) [15, 22], these data imply that dandelion chloroform extract (DCE) promotes GLUT4 translocation to the plasma membrane (PM)
We found that 30 μg/mL of DCE significantly increased IRAP expression on the cell membrane (Figure 2(b)), indicating that DCE promoted GLUT4 translocation to the PM
Summary
Type 2 diabetes mellitus (T2DM) is known as non-insulindependent diabetes mellitus and accounts for 90%–95% of all cases of diabetes [1]. Abnormal glucose and lipid metabolism is the main feature of T2DM. In the early stages of disease, pancreatic β-cells retain the ability to secrete insulin but the patient develops insulin resistance, resulting in the compensatory secretion of more insulin from pancreatic β-cells to maintain normal blood glucose levels. When β-cells lose this compensatory ability, blood glucose levels rise, causing T2DM [2]. Available medications for the treatment of diabetes are divided into four categories: insulin, insulin secretagogues, insulin sensitizers, and prandial glucose regulators. Many of these drugs have serious adverse effects in patients with poor tolerance. Medicinal plants are increasingly being used in modern clinical medicine and have been administered as alternative treatments for T2DM, with reported superior curative effects and few side effects [3]
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