Abstract
Aloperine (ALO), a quinolizidine alkaloid isolated from Sophora alopecuroides L. used in the traditional Uygur medicine, induced a significant increase in cellular glucose uptake of L6 cells, suggesting it has the potential to relieve hyperglycemia. Therefore, we investigated the effects of ALO on type 2 diabetes mellitus (T2DM) through in vitro and in vivo studies. The translocation of glucose transporter 4 (GLUT4) and changes in intracellular Ca2+ levels were real-time monitored in L6 cells using a laser scanning confocal microscope and related protein kinase inhibitors were used to explore the mechanism of action of ALO. Furthermore, high fat diet combined with low-dose streptozotocin (STZ) was used to induce T2DM in rats, and ALO was given to the stomach of T2DM rats for 4 weeks. In vitro results showed that ALO-induced enhancement of GLUT4 expression and translocation were mediated by G protein-PLC-PKC and PI3K/Akt pathways and ALO-enhanced intracellular Ca2+ was involved in activating PKC via G protein-PLC-IP3R-Ca2+ pathway, resulting in promoted GLUT4 plasma membrane fusion and subsequent glucose uptake. ALO treatment effectively ameliorated hyperglycemia, glucose intolerance, insulin resistance and dyslipidemia, alleviated hepatic steatosis, protected pancreatic islet function and activated GLUT4 expression in insulin target tissues of T2DM rats. These findings demonstrated that ALO deserves attention as a potential hypoglycemic agent.
Highlights
Diabetes mellitus is an endocrinal and metabolic disease, caused by the inability of pancreas to produce required insulin and/or an inability of the body to effectively respond to insulin (Lauritano and Ianora, 2016)
To elucidate whether the enhanced glucose uptake was due to ALO enhanced trafficking to the PM and Glucose transporter 4 (GLUT4) expression, we measured the intensity of Insulin-regulated aminopeptidase (IRAP)-mOrange fluorescence and the expression of GLUT4 in L6 cells
In the present study, following the addition of ALO, glucose uptake in L6 cells was promoted in a dosedependent manner (Figure 1B). and a significant increase in IRAP-mOrange fluorescence was observed at the PM (Figures 1C,D), the GLUT4 protein level in the cell as wells as on the plasma membrane exhibited significant upward trends (Figures 1E–F)
Summary
Diabetes mellitus is an endocrinal and metabolic disease, caused by the inability of pancreas to produce required insulin and/or an inability of the body to effectively respond to insulin (Lauritano and Ianora, 2016). Insulin resistance is the typical characteristic of T2DM, a condition in which the targeted cells fail to respond to the hormone insulin stimulation (Kadowaki, 2000). Dysfunction of glucose transporters, glycogen synthesis, and glycogen oxidation can result in insulin resistance in the muscle tissue. GLUT4 is the main protein that transports blood glucose into the cells of muscle and fat tissue, which has been thought as a therapeutic target for pharmacological intervention strategies to control diabetic hyperglycemia (Carvalho et al, 2005; Morgan et al, 2011)
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