title: Acylhydrazones contribute to serum glucose homeostasis through dual physiological targets.
abstract: In this study the in vivo and in vitro antidiabetic effects of four acylhydrazone derivatives were investigated in rats. The secretagogue action, oral glucose tolerance, insulinogenic index and mechanism of action of these acylhydrazones in relation to calcium uptake in pancreatic islets were studied. Also, the insulinomimetic effect on glycemia in diabetic rats was verified. Of the acylhydrazones studied, 1 and 4 were able to increase glucose tolerance in an acute time-course. A powerful secretagogue effect was exhibited by 1 and glibenclamide with an insulinogenic index around 3.9 and 1.3-fold higher than that of the hyperglycemic group, respectively. Moreover, an acute and dose-dependent effect of glibenclamide and 1 on calcium uptake in pancreatic islets was observed. The rapid stimulatory effect of 1 on calcium uptake seems to be mediated, at least in part, by ATP-dependent K+ channels (K+-ATP) since the stimulatory effect of 1 was similar to that observed for glibenclamide but was not potentiated by sulphonylurea. Furthermore, both extracellular and calcium from stocks mediate the signal transduction of stimulatory effect of 1 on calcium uptake which may contribute to insulin secretion. In addition, the insulinomimetic effect of 1 was evidenced through the level of serum glucose lowering in alloxan-induced diabetic rats. Also, 1 induced a significant increase in glycogen content in vivo and glucose uptake in soleus muscle in vitro. The results of this study indicate dual physiological targets for the acylhydrazone 1, i.e., pancreatic islets and skeletal muscle, as a result of insulin secretagogue and insulinomimetic action.
authors.affiliation: Universidade Federal de Santa Catarina, Departamento de Bioquímica, Centro de Ciências Biológicas, Campus Universitário, Bairro Trindade, Cx. Postal 5069, CEP: 88040-970, Florianópolis, SC, Brazil.
authors.forename: Marisa Jádna Silva
authors.initials: MJ
authors.lastname: Frederico
authors.forename: Allisson Jhonatan Gomes
authors.initials: AJ
authors.lastname: Castro
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mascarello
authors.forename: Camila Pires
authors.initials: CP
authors.lastname: Mendes
authors.forename: Virgínia Dermachi
authors.initials: VD
authors.lastname: Kappel
authors.forename: Taisa Regina
authors.initials: TR
authors.lastname: Stumpf
authors.forename: Paulo Cesar
authors.initials: PC
authors.lastname: Leal
authors.forename: Ricardo José
authors.initials: RJ
authors.lastname: Nunes
authors.forename: Rosendo Augusto
authors.initials: RA
authors.lastname: Yunes
authors.forename: Fátima Regina Mena Barreto
authors.initials: FR
authors.lastname: Silva
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000201:enzymology; D004797:Enzyme-Linked Immunosorbent Assay; D005951:Glucose Tolerance Test; D006706:Homeostasis / Q000187:drug effects*; D006835:Hydrazones / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar
chemical_list: D001786:Blood Glucose; D006835:Hydrazones; D007328:Insulin; D007770:L-Lactate Dehydrogenase