The mechanism of action of ursolic acid as insulin secretagogue and insulinomimetic is mediated by cross-talk between calcium and kinases to regulate glucose balance.

Allisson Jhonatan Gomes Castro, Marisa Jádna Silva Frederico, Luisa Helena Cazarolli, Camila Pires Mendes, Lizandra Czermainski Bretanha, Éder Carlos Schmidt, Zenilda Laurita Bouzon, Veronica Aiceles de Medeiros Pinto, Cristiane da Fonte Ramos, Moacir Geraldo Pizzolatti, Fátima Regina Mena Barreto Silva

Index: Biochim. Biophys. Acta 1850(1) , 51-61, (2015)

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Abstract

The effect of in vivo treatment with ursolic acid (UA) on glycemia in hyperglycemic rats and its mechanism of action on muscle were studied.The UA effects on glycemia, glycogen, LDH, calcium and on insulin levels were evaluated after glucose tolerance curve. The β-cells were evaluated through the transmission electron microscopy. UA mechanism of action was studied on muscles through the glucose uptake with/without specific insulin signaling inhibitors. The nuclear effect of UA and the GLUT4 expression on muscle were studied using thymidine, GLUT4 immunocontent, immunofluorescence and RT-PCR.UA presented a potent antihyperglycemic effect, increased insulin vesicle translocation, insulin secretion and augmented glycogen content. Also, UA stimulates the glucose uptake through the involvement of the classical insulin signaling related to the GLUT4 translocation to the plasma membrane as well as the GLUT4 synthesis. These were characterized by increasing the GLUT4 mRNA expression, the activation of DNA transcription, the expression of GLUT4 and its presence at plasma membrane. Also, the modulation of calcium, phospholipase C, protein kinase C and PKCaM II is mandatory for the full stimulatory effect of UA on glucose uptake. UA did not change the serum LDH and serum calcium balance.The antihyperglycemic role of UA is mediated through insulin secretion and insulinomimetic effect on glucose uptake, synthesis and translocation of GLUT4 by a mechanism of cross-talk between calcium and protein kinases.UA is a potential anti-diabetic agent with pharmacological properties for insulin resistance and diabetes therapy.Copyright © 2014 Elsevier B.V. All rights reserved.