title: 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.
abstract: BACKGROUND
  The effect of in vivo treatment with ursolic acid (UA) on glycemia in hyperglycemic rats and its mechanism of action on muscle were studied.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  UA is a potential anti-diabetic agent with pharmacological properties for insulin resistance and diabetes therapy.
authors.affiliation: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Allisson Jhonatan Gomes
authors.initials: AJ
authors.lastname: Castro
authors.affiliation: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Marisa Jádna Silva
authors.initials: MJ
authors.lastname: Frederico
authors.affiliation: Universidade Federal da Fronteira Sul, Campus Universitário Laranjeiras do Sul, Laranjeiras do Sul, PR, Brazil.
authors.forename: Luisa Helena
authors.initials: LH
authors.lastname: Cazarolli
authors.affiliation: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Camila Pires
authors.initials: CP
authors.lastname: Mendes
authors.affiliation: Departamento de Química, Centro de Ciências Físicas e Matemáticas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Lizandra Czermainski
authors.initials: LC
authors.lastname: Bretanha
authors.affiliation: Departamento de Biologia Celular, Embriologia e Genética, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Éder Carlos
authors.initials: ÉC
authors.lastname: Schmidt
authors.affiliation: Departamento de Biologia Celular, Embriologia e Genética, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Zenilda Laurita
authors.initials: ZL
authors.lastname: Bouzon
authors.affiliation: Departamento de Anatomia, Universidade Estadual do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Veronica Aiceles
authors.initials: VA
authors.lastname: de Medeiros Pinto
authors.affiliation: Departamento de Anatomia, Universidade Estadual do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Cristiane
authors.initials: C
authors.lastname: da Fonte Ramos
authors.affiliation: Departamento de Química, Centro de Ciências Físicas e Matemáticas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Moacir Geraldo
authors.initials: MG
authors.lastname: Pizzolatti
authors.affiliation: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil. Electronic address: mena.barreto@ufsc.br.
authors.forename: Fátima Regina Mena Barreto
authors.initials: FR
authors.lastname: Silva
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002118:Calcium / Q000097:blood / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D015151:Immunoblotting; D007328:Insulin / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D007770:L-Lactate Dehydrogenase / Q000097:blood / Q000378:metabolism; D008297:Male; D046529:Microscopy, Electron, Transmission; D015394:Molecular Structure; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*; D000097245:Ursolic Acid
chemical_list: D001786:Blood Glucose; D002118:Calcium; D005947:Glucose; D051275:Glucose Transporter Type 4; D006003:Glycogen; D007004:Hypoglycemic Agents; D007328:Insulin; D007770:L-Lactate Dehydrogenase; D011494:Protein Kinases; D014315:Triterpenes; D000097245:Ursolic Acid; C495694:Slc2a4 protein, rat
keywords: Calcium; GLUT4; Hyperglycemia; Insulin; Secretagogue; Triterpene