Anti-diabetic effects of vanadium(III, IV, V)–chlorodipicolinate complexes in streptozotocin-induced diabetic rats

Abstract

Vanadium(III, IV, V)-chlorodipicolinate (dipic-Cl) complexes, including H[VIII(dipic-Cl)2] · 5H2O (V3dipic-Cl), VIVO(dipic-Cl)(H2O)2 (V4dipic-Cl) and K[VVO2(dipic-Cl)] (V5dipic-Cl), were prepared with the indicated oxidation states. Our aim was to evaluate the anti-diabetic effects of V3dipic-Cl, V4dipic-Cl and V5dipic-Cl in streptozotocin-induced diabetic rats. Vanadium complexes were orally administered to diabetic rats at concentrations of 0.1-0.3 mg/ml in the drinking water. We found that vanadium-chlorodipicolinate (V-dipic-Cl) complexes at the concentration of 0.1 mg/ml did not exhibit blood glucose-lowering effects when administered to diabetic rats for 20 days. However, the levels of fasting blood glucose in diabetic rats were decreased after treatment with 0.3 mg/ml of V4dipic-Cl and V5dipic-Cl complexes for the following 20 days. Although administration of both V4dipic-Cl and V5dipic-Cl significantly lowered diabetic hyperglycemia, the vanadium intake from administration of V4dipic-Cl is nearly 1.5-fold greater compared to that of V5dipic-Cl. Treatment with the H2dipic-Cl ligand and all three V-dipic-Cl complexes significantly lowered serum cholesterol, while administration of the V5dipic-Cl complex lowered serum cholesterol significantly more than administration of the ligand alone. Treatment with ligand alone did not have an effect on serum triglyceride, while administration of the V4dipic-Cl and V5dipic-Cl significantly lowered the elevated serum triglyceride associated with diabetes. Oral administration of the ligand and all V-dipic-Cl complexes did significantly lower diabetes elevated serum alkaline phosphatase. Treatment with H2dipic-Cl ligand and V4dipic-Cl and V5dipicCl significantly lowered diabetes elevated aspartate amino transferase. These results indicate that the health of the treated animals did not seem to be further compromised compared to that of diabetic animals. In addition, oral administration of H2dipic-Cl, V3dipic-Cl, V4dipic-Cl and V5dipic-Cl did not alter diabetic serum creatinine and blood urea nitrogen levels, suggesting no significant side effects of vanadium treatment on renal functions at the dose of 0.3 mg/ml in diabetic rats. The results presented here suggest that the anti-diabetic effects of treatment with V-dipic-Cl complexes were likely associated in part with the oxidation state of vanadium.

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

“…In particular, their potential insulin mimetic capacity has been extensively investigated [10][11][12][13][14][15][16]. It has been shown that VCs can be used to mitigate insufficient insulin response in DM thus presenting insulin-mimetic properties in vitro and [17][18][19][20] in vivo [21][22][23][24], and two of them were tested in clinical trials [25]. To date, the main limitation for the clinical use of VCs in the treatment of diabetes has been their potential toxicity [26].…”

“…A large number of vanadium (IV and V) complexes have been synthesized, structurally characterized [28][29][30][31] and their biological activity tested using adequate cellular models by measuring glucose uptake levels [32,33], inhibition of free fatty acid release [33,34] and in vivo studies with diabetic rat models to test their capacity to reverse diabetic features [23,24,35,36]. Among the many vanadium compounds reported in the literature, emphasis is given to the bis(matolato)oxidovanadium(IV) (BMOV) [11,14,37] and the similar one bis(ethylmaltolato) oxidovanadium(IV) (BEOV) [25], the only vanadium compounds tested in clinical trials to date, but other compounds like bis(1,2-dimethyl-3-hydroxy-4-pyridinonato)oxidovanadium(IV), [VO(dmpp) 2 ] [31,33,[36][37][38][39][40][41], bis(picolinato)oxidovanadium(IV) [VO(pic) 2 ] [24,42,43] and bis(allixinato)oxidovanadium(IV) [18,44,45] have also attracted much interest due to the positive results which have been obtained through in vitro and in vivo studies.…”

“…Among the many vanadium compounds reported in the literature, emphasis is given to the bis(matolato)oxidovanadium(IV) (BMOV) [11,14,37] and the similar one bis(ethylmaltolato) oxidovanadium(IV) (BEOV) [25], the only vanadium compounds tested in clinical trials to date, but other compounds like bis(1,2-dimethyl-3-hydroxy-4-pyridinonato)oxidovanadium(IV), [VO(dmpp) 2 ] [31,33,[36][37][38][39][40][41], bis(picolinato)oxidovanadium(IV) [VO(pic) 2 ] [24,42,43] and bis(allixinato)oxidovanadium(IV) [18,44,45] have also attracted much interest due to the positive results which have been obtained through in vitro and in vivo studies.…”

VO(dmpp)2 normalizes pre-diabetic parameters as assessed by in vivo magnetic resonance imaging and spectroscopy

“…At the moment several vanadium compounds (VCs) such as bis(maltolato) oxovanadium(IV) (BMOV) and bis(ethylmaltolato) oxovanadium(IV) (BEOV) [5][6][7], (dipicolinato)oxovanadium(IV) [8,9], bis(picolinato)oxovanadium(IV) [10], bis(allixinato) oxovanadium(IV) [11][12][13], and bis(1,2-dimethyl-3-hydroxy-4-pyridinonato) oxovanadium(IV) (VO(dmpp) 2 ) [14][15][16] have shown a promising antidiabetic activity. Actually, BEOV passed phases I and II in human trials [6].…”

Study of the antidiabetic capacity of the VO(dmpp)2 complex

“…The oxidation state of the VC seems to be also an important feature for its therapeutic effectiveness and research has been carried out in this field [12]. However, an accurate ex vivo/in vivo determination of the oxidation state of the V species which actually are responsible for the antidiabetic properties remains unclarified.…”