Therapeutic properties of VO(dmpp)2 as assessed by in vitro and in vivo studies in type 2 diabetic GK rats

Abstract

The bis(1,2-dimethyl-3-hydroxy-4-pyridinonato)oxidovanadium(IV), VO(dmpp) 2 , has shown anti-diabetic effects by in vitro studies in Wistar (W) rat adipocytes and in vivo in obese Zucker rats. The aim of this work is to confirm the therapeutic properties of VO(dmpp) 2 in non-obese type 2 diabetic Goto-Kakizaki (GK) rats. An in vivo study was carried out, treating W and GK rats during 21 days with a daily dose of VO(dmpp) 2 (44 μmol/kg). It was shown that VO(dmpp) 2 doesn't affect the normal increase of body weight of both W and GK rats, after 8 days of treatment ameliorates glycemia in GK rats (8.4 ± 0.3 vs 10.1 ± 0.2 mM in GK control, P b 0.001) but doesn't interfere with glucose levels in W rats and, after 21 days of treatment, improves the glucose intolerant profile of GK rats (13.1 ± 0.5 vs 20.6 ± 0.7 mM/min in GK control, P b 0.001), despite no increase of plasma insulin levels during glucose tolerance test. Additionally, it was demonstrated that VO(dmpp) 2 significantly enhances [3-3 H]-glucose uptake by W and GK rat adipocytes (non-toxic concentration of 100 μM: respectively 193 ± 20 and 254 ± 21%, P b 0.001, relative to the basal value) showing an efficacy similar to insulin 1.72 nM and better than the same concentration of BMOV (P b 0.01). Western blotting revealed that in W and GK rats VO(dmpp) 2 significantly promotes IRS2 (P b 0.05) and p-AKT expression (P b 0.001 and P b 0.05, respectively, relative to the respective controls) and in GK animals reduces the increase of PTP1β expression (P b 0.001, relative to GK control).

Thirty years through vanadium chemistry

“…This possibility was confirmed for e.g. BMOV [194] 22 and for V IV O(dhp) 2 24 [195]. As discussed in many publications, vanadium compounds activate numerous signaling pathways and transcription factors.…”

Vanadium: History, chemistry, interactions with α-amino acids and potential therapeutic applications

“…In 1985, inorganic salts such as NaVO 3 and VOSO 4 were considered again for the treatment of diabetes, but these inorganic salts presented several problems, such as, gastrointestinal distress and low absorption. For this reason, further studies with inorganic salts of vanadium were discarded and newer researches were made towards the complexation of V(IV)O with bidentate organic ligands such as maltolato [146][147][148], dmpp (1,2-dimethyl-3-hydroxy-4-pyridino nate) [149][150][151] and picolinate [148,152] with special attention for the later one, since picolinic acid is the intermediate metabolite of tryptophan and it is therefore less toxic to mammals organism promoting as well the absorption of various metals in the small intestine [153]. The chelating effect of the carrier ligand greatly influences the efficiency of the compound because determines the re-adsorption and improves the biodistribution, stability and tolerability of the metal ion in the organism [5,24,96].…”

“…The V IV O(dmpp) 2 (bis(1,2-dimethyl-3-hydroxy-4-pyridinonate)oxovanadium (IV)) complex has exhibited antidiabetic activity increasing glucose uptake in adipocytes promoting the phosphorylation of the Akt1, a key protein in insulin signaling [149]. A chronic in vivo treatment in with V IV O(dmpp) 2 decreases hyperglycemia and improves glucose tolerance [151]. Fig.…”

Vanadium(IV)-chlorodipicolinate inhibits 3T3-L1 preadipocyte adipogenesis by activating LKB1/AMPK signaling pathway

“…These include their ability to improve glucose homeostasis and insulin resistance in animal models of type 1 and type 2 diabetes mellitus [34][35][36][37][38][39][40][41]. It has been demonstrated that diaqua-(4-chloro-2,5-dipicolinato)oxidovanadium(IV) (VOdipicCl, [V IV O(dipic-Cl)(H 2 O) 2 ]) complex alleviated lipid abnormalities in streptozotocin(STZ)-induced diabetic rats [42][43][44].…”