title: In vitro effects of bis(1,2-dimethyl-3-hydroxy-4-pyridinonato)oxidovanadium(IV), or VO(dmpp)2, on insulin secretion in pancreatic islets of type 2 diabetic Goto-Kakizaki rats.
abstract: Vanadium compounds have been explored as therapy of diabetes, and most studies have focussed on insulin mimetic effects, i.e. reducing hyperglycemia by improving glucose sensitivity and thus glucose uptake in sensitive tissues. We have recently shown that bis(1,2-dimethyl-3-hydroxy-4-pyridinonato)oxidovanadium(IV), VO(dmpp)2, has promising effects when compared to another vanadium compound, bis(maltolato)oxidovanadium(IV), BMOV, and insulin itself, in isolated adipocytes and in vivo in Goto-Kakizaki (GK) rats, an animal model of hereditary type 2 diabetes (T2D).We now have investigated in GK rats whether VO(dmpp)2 also modulates another important defect in T2D, impaired insulin secretion. VO(dmpp)2, but not BMOV, stimulated insulin secretion from isolated GK rat pancreatic islets at high, 16.7mM, but not at low–normal, 3.3 mM, glucose concentration. Mechanistic studies demonstrate that the insulin releasing effect of VO(dmpp)2 is due to its interaction with several steps in the stimulus-secretion coupling for glucose, including islet glucose metabolism and K-ATP channels, L-type Ca2+ channels, modulation by protein kinases A and C, as well as the exocytotic machinery. In conclusion, VO(dmpp)2 exhibits properties of interest for treatment of the insulin secretory defect in T2D, in addition to its well-described insulin mimetic activity.
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Solna D2:04, SE-171 76 Stockholm, Sweden.
authors.forename: Julien
authors.initials: J
authors.lastname: Pelletier
authors.affiliation: Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, Portugal.
authors.forename: Neuza
authors.initials: N
authors.lastname: Domingues
authors.affiliation: Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, Portugal; Coimbra Chemistry Centre, Rua Larga, University of Coimbra, 3004-535 Coimbra, Portugal.
authors.forename: M Margarida C A
authors.initials: MM
authors.lastname: Castro
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Solna D2:04, SE-171 76 Stockholm, Sweden. Electronic address: claes-goran.ostenson@ki.se.
authors.forename: Claes-Göran
authors.initials: CG
authors.lastname: Östenson
mesh_terms: D000818:Animals; D056831:Coordination Complexes / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004353:Drug Evaluation, Preclinical; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D046509:Tissue Culture Techniques
chemical_list: D056831:Coordination Complexes; D007004:Hypoglycemic Agents; D007328:Insulin; C000592623:bis(1,2-dimethyl-3-hydroxy-4-pyridinonato)oxidovanadium(IV)
keywords: Goto-Kakizaki rats; Insulin secretion; Pancreatic islets; Type 2 diabetes; VO(dmpp)(2)