title: Betulinic acid and 1,25(OH)₂ vitamin D₃ share intracellular signal transduction in glucose homeostasis in soleus muscle.
abstract: The effect of betulinic acid on glycemia and its mechanism of action compared with 1,25(OH)2 vitamin D3 in rat muscle were investigated. Betulinic acid improved glycemia, induced insulin secretion and increased the glycogen content and glucose uptake in muscle tissue. Additionally, the integrity of both PI3K and the cytoskeleton is necessary for the stimulatory action of betulinic acid in glucose uptake. The genomic effect was apparent, since cycloheximide and PD98059 nullified the stimulatory effect of betulinic acid on glucose uptake. Therefore, although this compound did not modify the DNA transcription, the protein translation was significantly improved. Also, betulinic acid increased the GLUT4 immunocontent and its translocation was corroborated by GLUT4 localization at the plasma membrane (after 180 min). On the other hand, the effect of 1,25(OH)2 vitamin D3 on glucose uptake is not mediated by PI3K and microtubule activity. In contrast, the nuclear activity of 1,25(OH)2 vitamin D3 is necessary to trigger glucose uptake. In addition, the increased DNA transcription and GLUT4 immunocontent provide evidence of a mechanism by which 1,25(OH)2 vitamin D3 contributes to glycemia. In conclusion, betulinic acid acts as an insulin secretagogue and insulinomimetic agent via PI3K, MAPK and mRNA translation and partially shares the genomic pathway with 1,25(OH)2 vitamin D3 to upregulate the GLUT4. In summary, betulinic acid regulates glycemia through classical insulin signaling by stimulating GLUT4 synthesis and translocation. In addition, it does not cause hypercalcemia, which is highly significant from the drug discovery perspective.
authors: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors: Allisson Jhonatan Gomes
authors: AJ
authors: Castro
authors: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors: Marisa Jádna Silva
authors: MJ
authors: Frederico
authors: Universidade Federal da Fronteira Sul, Campus Universitário Laranjeiras do Sul, Laranjeiras do Sul, PR, Brazil.
authors: Luisa Helena
authors: LH
authors: Cazarolli
authors: Departamento de Química, Centro de Ciências Físicas e Matemáticas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors: Lizandra Czermainski
authors: LC
authors: Bretanha
authors: Departamento de Química, Centro de Ciências Físicas e Matemáticas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors: Luciana de Carvalho
authors: Lde C
authors: Tavares
authors: Departamento de Análises Clínicas, Centro de Ciências da Saúde, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors: Ziliani da Silva
authors: Zda S
authors: Buss
authors: Departamento de Biologia Celular, Embriologia e Genética, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors: Márcio Ferreira
authors: MF
authors: Dutra
authors: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors: Ariane Zamoner Pacheco
authors: AZ
authors: de Souza
authors: Departamento de Química, Centro de Ciências Físicas e Matemáticas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors: Moacir Geraldo
authors: MG
authors: Pizzolatti
authors: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil. Electronic address: mena.barreto@ufsc.br.
authors: Fátima Regina Mena Barreto
authors: FR
authors: Silva
mesh_terms: D000818:Animals; D001692:Biological Transport; D001786:Blood Glucose / Q000378:metabolism; D002118:Calcium / Q000097:blood; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D006943:Hyperglycemia / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D053978:Pentacyclic Triterpenes; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D014315:Triterpenes / Q000494:pharmacology*; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology; D000094062:Betulinic Acid
chemical_list: D001786:Blood Glucose; D051275:Glucose Transporter Type 4; D007328:Insulin; D053978:Pentacyclic Triterpenes; C495693:Slc2a4 protein, mouse; D014315:Triterpenes; D014807:Vitamin D; C097949:1,25-dihydroxyvitamin D; D006003:Glycogen; D007770:L-Lactate Dehydrogenase; D005947:Glucose; D002118:Calcium; D000094062:Betulinic Acid
keywords: 1,25-D(3); GLUT4; Glycemia; Rosmarinus officinalis; Triterpenes