Is the Hypoglycemic Action of Vanadium Compounds Related to the Suppression of Feeding?

Vanadium compounds exhibit effective hypoglycemic activity in both type I and type II diabetes mellitus. However, there was one argument that the hypoglycemic action of vanadium compounds could be attributable to the suppression of feeding—one common toxic aspect of vanadium compounds. To clarify this question, we investigated in this work the effect of a vanadyl complex, BSOV (bis((5-hydroxy-4-oxo-4H-pyran-2-yl)methyl-2-hydroxy-benzoatato) oxovanadium (IV)), on diabetic obese (db/db) mice at a low dose (0.05 mmol/kg/day) when BSOV did not inhibit feeding. The experimental results showed that this dose of BSOV effectively normalized the blood glucose level in diabetic mice without affecting the body weight growth. Western blotting assays on the white adipose tissue of db/db mice further indicated that BSOV treatment significantly improved expression of peroxisome proliferator-activated receptor γ (PPARγ) and activated AMP-activated protein kinase (AMPK). In addition, vanadium treatment caused a significant suppression of phosphorylation of c-Jun N-terminal protein kinase (JNK), which plays a key role in insulin-resistance in type II diabetes. This is the first evidence that the mechanism of insulin enhancement action involves interaction of vanadium compounds with JNK. Overall, the present work indicated that vanadium compounds exhibit antidiabetic effects irrelevant to food intake suppression but by modulating the signal transductions of diabetes and other metabolic disorders.     

The influence of a new vanadium compound, bis(2,2'-bipyridine)oxovanadium(IV) sulphate on liver golgi complexes from control and streptozotocin-diabetic rats.

Among the previously studied organic vanadium derivatives showing an anti-diabetic action, we investigated a new complex, bis(2,2'-bipyridine)oxovanadium(IV) sulphate. We tested its ability to normalise parameters previously described for streptozotocin (STZ)-diabetes, such as lower yields of Golgi-rich membrane fraction isolation, decreased activity of Golgi membrane marker enzyme - galactosyltransferase (GalT) - and altered morphology of rat liver Golgi complexes. Oral application as a drinking solution of 1.8 mmol bis(2,2'-bipyridine)oxovanadium(IV) (dissolved in 0.09 M NaCl) caused a similar dispersion of GalT activities in both vanadium treated groups, control and diabetic. Very low activities of the enzyme (characteristic for untreated diabetes) we found only in approximately 35 % of the STZ-diabetic rats treated with the new vanadium compound. The morphology of liver Golgi complexes in diabetic rats treated with bis(2,2'-bipyridine)oxovanadium(IV) sulphate was improved, which manifested itself in the reappearance of vacuoles with VLDL and coated and uncoated secretory vesicles. In view of biochemical and morphological parameters of normalised diabetic rat liver Golgi apparatus, the new vanadium complex was more effective than bis(oxalato)oxovanadium(IV) or bis(kojato)oxovanadium(IV), but in our experimental model, the best anti-diabetic, orally applied drug was the bis(maltolato)oxovanadium(IV) previously investigated.     

Bis(maltolato)oxovanadium(IV) (BMOV) Attenuates Apoptosis in High Glucose-Treated Cardiac Cells and Diabetic Rat Hearts by Regulating the Unfolded Protein Responses (UPRs)

Endoplasmic reticulum stress (ERS)-induced unfolded protein response (UPR) and the subsequent cell deaths are essential steps in the pathogenesis of diabetic cardiomyopathy (DCM), a main cause of diabetics’ morbidity and mortalities. The bis(maltolato)oxovanadium(IV) (BMOV), a potent oral vanadium complex with anti-diabetic properties and insulin-mimicking effects, was shown to improve cardiac dysfunctions in diabetic models. Here, we examined the effects of BMOV on UPR pathway protein expression and apoptotic cell deaths in both high glucose-treated cardiac H9C2 cells and in the hearts of diabetic rats. We show that in both the high glucose-treated cardiac cells and in the hearts of streptozotocin (STZ) diabetic rats, there was an overall activation of the UPR signaling, including both apoptotic (e.g., the cascades of PERK/EIf2α/ATF4/CHOP and of IRE1/caspase 12/caspase 3) and pro-survival (GRP78 and XBP1) signaling. A high amount of apoptotic cell deaths was also detected in both diabetic conditions. The administration of BMOV suppressed both the apoptotic and pro-survival UPR signaling and significantly attenuated apoptotic cell deaths in both conditions. The overall suppression of UPR signaling by BMOV suggests that the drug protects diabetic cardiomyopathy by counteracting reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress. Our findings lend support to promote the use of BMOV in the treatment of diabetic heart diseases.     

Streptozotocin-induced alterations in rat liver Golgi complexes are ameliorated by BMOV [Bis(maltolato)oxovanadium(IV)] activity.

Twenty years ago, we detected the interdependence between structure and function of rat liver Golgi complexes that are characteristic for streptozotocin diabetes, which served us in further investigations as a useful indicator of the effectiveness of drugs we were testing. This work presented results obtained in eight groups of rats (four control and four diabetic) that were administered orally either bis(maltolato)oxovanadium(IV) [BMOV] or maltol alone. The activities of the rat liver Golgi marker enzyme, galactosyltransferase [GalT], as well as the morphology of Golgi complexes were studied in situ using an electron microscope; parallel estimations of vanadium concentration and phospholipid percentage were made in Golgi-rich preparations isolated from the liver. Our main findings were normalization in diabetic animals orally treated with 1.8 mmol BMOV in 0.09 mol NaCl solutions over seven days, which demonstrated an accompanying increase in phosphatidic acid (PA) percentage (p < 0.05) compared to controls. In the diabetic groups, Pearson's test showed a positive double correlation between GalT activity, vanadium concentration, and PA percentage in Golgi-rich membrane preparations from the liver. Additionally, a negative correlation was found between vanadium concentration and phosphatidylcholine percentage in the fractions.     

Differences in plasma homocysteine levels between Zucker fatty and Zucker diabetic fatty rats following 3 weeks oral administration of organic vanadium compounds

PURPOSE: Recently, our laboratory group has reported that rats with Type 1 diabetes have decreased plasma homocysteine and cysteine levels compared to non-diabetic controls and that organic vanadium treatment increased plasma homocysteine concentrations to non-diabetic concentrations. However, to date, no studies have been done investigating the effects of organic vanadium compounds on plasma homocysteine and its metabolites in Type 2 diabetic animal model. These studies examined the effect of organic vanadium compounds [bis(maltolato)oxovanadium(IV) and bis(ethylmaltolato)oxovanadium(IV); BMOV and BEOV] administered orally on plasma concentrations of homocysteine and its metabolites (cysteine and cysteinylglycine) in lean, Zucker fatty (ZF) and Zucker diabetic fatty (ZDF) rats. ZF rats are a model of pre-diabetic Type 2 diabetes characterized by hyperinsulinemia and normoglycemia. The ZDF rat is a model of Type 2 diabetes characterized by relative hypoinsulinemia and hyperglycemia. METHODS: Zucker lean and ZF rats received BMOV in the drinking water at a dose of 0.19 +/- 0.02 mmol/kg/day. Lean and ZDF rats received BEOV by oral gavage daily at dose of 0.1 mmol/kg. The treatment period for both studies was 21 days. At termination, animals were fasted overnight (approximately 16 h) and blood samples were collected by cardiac puncture for determination of plasma glucose, insulin and homocysteine levels. Plasma homocysteine and its metabolites levels were determined using high-pressure liquid chromatography. Plasma glucose was determined using a Glucose Analyzer 2. Plasma insulin levels were determined by radioimmunoassay. Plasma triglycerides were determined by an enzymatic assay methodology. RESULTS: ZF (n = 4) and ZDF (n = 10) rats had significantly lower plasma homocysteine as compared to their respective lean groups (ZF 0.78 +/- 0.1 micromol/L vs. Zucker lean 2.19 +/- 0.7 micromol/L; ZDF 1.71 +/- 0.2 micromol/L vs. Zucker lean 3.02 +/- 0.3 micromol/L; p < 0.05). BMOV treatment in ZF rats restored plasma homocysteine levels to those observed in lean untreated rats (ZF treated: 2.04 +/- 0.2 micromol/L; lean 2.19 +/- 0.7 micromol/L). There was a modest effect of BMOV treatment on plasma glucose levels in ZF rats. BEOV treatment significantly decreased the elevated plasma glucose levels in the ZDF rats (lean 7.9 +/- 0.1 mmol/L; lean + vanadium 7.7 +/- 0.2 mmol/L; ZDF 29.9 +/- 0.4 mmol/L; ZDF + vanadium 17.4 +/- 0.3 mmol/L, p < 0.05). Organic vanadium treatment reduced cysteine levels in both ZF and ZDF rats. No differences in total plasma cysteinylglycine concentrations were observed. CONCLUSION: Plasma homocysteine levels are significantly reduced in a pre-diabetic model of Type 2 diabetes, which was restored to lean levels upon vanadium treatment; however, this restoration of plasma homocysteine levels was not seen in ZDF Type 2 diabetic rats following vanadium treatment. In the latter case vanadium treatment may not have totally overcome the insulin resistance seen in these animals.     

Preparation and characterization of vanadyl complexes with bidentate maltol-type ligands; in vivo comparisons of anti-diabetic therapeutic potential

A series of 2-alkyl-3-hydroxy-4-pyrone oxovanadium(IV) compounds has been synthesized, characterized, and tested for bioactivity as potential insulin-enhancing agents. The vanadyl complexes, bis(maltolato)oxovanadium(IV), BMOV, bis(ethylmaltolato)oxovanadium(IV), BEOV, and bis(isopropylmaltolato)oxovanadium(IV), BIOV, were compared against vanadyl sulfate for glucose-lowering ability, when administered i.p. to STZ-diabetic rats, at a one-time dose of 0.1 mmol kg(-1)body weight. Blood levels of vanadium were determined at regular intervals, to 72 h, following i.p. injection. All complexes tested exceeded vanadyl sulfate in glucose-lowering ability; this effect was not correlated, however, with blood vanadium levels. Analysis of the pharmacokinetics of the disappearance of [ethyl-1-(14)C]BEOV after an oral gavage dose (50 mg kg(-1), 0.144 mmol kg(-1), in a 10 mL kg(-1) volume of 1% CMC solution) indicated clearly that metal ion-ligand dissociation took place relatively soon after oral ingestion of the complex. Half-lives of fast phase uptake and slow phase disappearance for (14)C and V were calculated from a two-compartment model for whole blood, plasma, liver, kidney, bone, small intestine, and lung, ranging from 17 min ( t(1/2)alpha for (14)C, liver) to 30 days ( t(1/2)beta for V, bone). Curves of disappearance of plasma and whole blood (14)C and V diverged dramatically within the first hour after administration of the vanadium complex.     

Comparison of anti-hyperglycemic effect amongst vanadium, molybdenum and other metal maltol complexes

A wide variety of vanadium-containing complexes have been tested, both in vivo and in vitro, as possible therapeutic agents for the oral treatment of type 2 diabetes mellitus. None so far has surpassed bis(maltolato)oxovanadium(IV) (BMOV) for glucose- and lipid-lowering in an orally available formulation. Ligand choice is clearly an important factor in pharmacological efficacy of vanadium compounds as insulin enhancing agents. In this study, we kept the ligand and dose the same, varying instead the metal ion bound to the maltolato ligand in a series of binary complexes of neutral charge. A requirement for vanadyl ion as the metal ion of choice was apparent; no other metal ion tested served as a suitable substitute. Amongst [MoO(2)](2+), Co(II), Cu(II), Cr(III), and Zn(II), only [MoO(2)](2+) and Co(II) showed any hypoglycemic activity at the ED(50) dose for bis(maltolato)oxovanadium(IV), 0.6 mmolkg(-1) by oral gavage in streptozotocin (STZ)-diabetic rats within 72 h of administration of compound.     

Effect of chronic treatment with Bis(maltolato)oxovanadium (IV) in rat model of non-insulin-dependent-diabetes

Effect of chronic treatment with Bis(maltolato)oxovanadium (IV) (BMOV) was studied in streptozotocin (STZ)-induced neonatal non-insulin-dependent-diabetic (NIDDM) rats. Intraperitoneal injection of STZ (90 mg kg(-1)) in Wistar rat pups (day 2 old) produced mild hyperglycemia, impaired glucose tolerance and insulin resistance at the age of 3 months. Treatment with BMOV (0.23 mM kg(-1)) in drinking water for 6 weeks produced a significant decrease in elevated serum glucose levels without any significant change in serum insulin levels in diabetic rats. BMOV treatment significantly decreased integrated area under the glucose curve without any significant change in integrated area under the insulin curve indicating improved glucose tolerance. Treatment also significantly increased K(ITT) value of diabetic rats indicating increased insulin sensitivity. BMOV treatment significantly reduced hypercholesterolemia in diabetic rats. Treatment also significantly decreased serum triglyceride levels in both diabetic and non-diabetic rats. The data suggest that chronic BMOV treatment improves glucose and lipid homeostasis. These effects appear to be due to the insulin sensitizing action of vanadium.     

Metallokinetic characteristics of antidiabetic bis(allixinato)oxovanadium(IV)-related complexes in the blood of rat

The antidiabetic effect of vanadium is a widely accepted phenomenon; some oxovanadium(IV) complexes have been found to normalize high blood glucose levels in both type 1 and type 2 diabetic animals. In light of the future clinical use of these complexes, the relationship among their chemical structures, physicochemical properties, metallokinetics, and antidiabetic activities must be closely investigated. Recently, we found that among bis(3-hydroxypyronato)oxovanadium(IV) [VO(3hp)₂] related complexes, bis(allixinato)oxovanadium(IV) [VO(alx)₂] exhibits a relatively strong hypoglycemic effect in diabetic animals. Next, we examined its metallokinetics in the blood of rats that received five VO(3hp)₂-related complexes by the blood circulation monitoring–electron paramagnetic resonance method. The metallokinetic parameters were obtained from the blood clearance curves based on a two-compartment model; most parameters, such as area under the concentration curve and mean residence time, correlated significantly with the in vitro insulinomimetic activity in terms of 1/IC₅₀ (IC₅₀ is the 50% inhibitory concentration of the complex required for the release of free fatty acids in adipocytes) and the lipophilicity of the complex (log P _com). The oxovanadium(IV) concentration was significantly higher and the species resided longer in the blood of rats that received VO(alx)₂ than in the blood of rats that received VO(3hp)₂ or bis(kojato)oxovanadium(IV); VO(alx)₂ also exhibited higher log P _com and 1/IC₅₀ values. On the basis of these results, we propose that the introduction of lipophilic groups at the C2 and C6 positions of the 3hp ligand is an effective method to enhance the hypoglycemic effect of the complexes, as supported by the observed in vivo exposure and residence in the blood.     

Improvement of diabetes, obesity and hypertension in type 2 diabetic KKAy mice by bis(allixinato)oxovanadium(IV) complex

Previously, we found that bis(allixinato)oxovanadium(IV) (VO(alx)(2)) exhibits a potent hypoglycemic activity in type 1-like diabetic mice. Since the enhancement of insulin sensitivity is involved in one of the mechanisms by which vanadium exerts its anti-diabetic effects, VO(alx)(2) was further tested in type 2 diabetes with low insulin sensitivity. The effect of oral administration of VO(alx)(2) was examined in obesity-linked type 2 diabetic KKA(y) mice. Treatment of VO(alx)(2) for 4 weeks normalized hyperglycemia, glucose intolerance, hyperinsulinemia, hypercholesterolemia and hypertension in KKA(y) mice; however, it had no effect on hypoadiponectinemia. VO(alx)(2) also improved hyperleptinemia, following attenuation of obesity in KKA(y) mice. This is the first example in which a vanadium compound improved leptin resistance in type 2 diabetes by oral administration. On the basis of these results, VO(alx)(2) is proposed to enhance not only insulin sensitivity but also leptin sensitivity, which in turn improves diabetes, obesity and hypertension in an obesity-linked type 2 diabetic animal.     

Hypoglycemic Effect of Macrocyclic Binuclear Oxovanadium (IV) Complex on Streptozotocin-Induced Diabetic Rats

Though vanadium complexes mimic the action of insulin, owing to their toxicity, research is still in progress for a new vanadium complex with maximum efficacy at low concentration and without any side effects. A novel macrocyclic binuclear oxovanadium complex was synthesized, its composition and structure were confirmed by spectral studies and its efficacy was studied in streptozotocin-induced diabetic rats over a period of 30 days. The oral administration of the complex normalizes the blood glucose level in the diabetic rats and also maintains normoglycemia after a glucose load. The biochemical studies revealed that the complex is not toxic to the system. The nontoxic nature of this complex may be due to the presence of the vanadyl ions in an intact form. The study highlights the nontoxic and hypoglycemic effects of the new macrocyclic binuclear oxovanadium complex.     

Influence of chelation and oxidation state on vanadium bioavailability,and their effects on tissue concentrations of zinc,copper, and iron

Today, vanadium compounds are frequently included in nutritional supplements and are also being developed for therapeutic use in diabetes mellitus. Previously, tissue uptake of vanadium from bis(maltolato)oxovanadium(IV) (BMOV) was shown to be increased compared to its uptake from vanadyl sulfate (VS). Our primary objective was to test the hypothesis that complexation increases vanadium uptake and that this effect is independent of oxidation state. A secondary objective was to compare the effects of vanadium complexation and oxidation state on tissue iron, copper, and zinc. Wistar rats were fed either ammonium metavanadate (AMV), VS, or BMOV (1.2 mM each in the drinking water). Tissue uptake of V following 12 wk of BMOV or AMV was higher than that from VS (p<0.05). BMOV led to decreased tissue Zn and increased bone Fe content. The same three compounds were compared in a cellular model of absorption (Caco-2 cells). Vanadium uptake from VS was higher than that from BMOV or AMV at 10 min, but from BMOV (250 μM only, 60 min), uptake was far greater than from AMV or VS. These results show that neither complexation nor oxidation state alone are adequate predictors of relative absorption, tissue accumulation, or trace element interactions.     

Increased potency of vanadium using organic ligands

Thein vivo glucose lowering effect of orally administered inorganic vanadium compounds in diabetes was first reported in our laboratory in 1985. While both vanadate and vanadyl forms of vanadium are orally active, they are still not well absorbed. We have synthesized several organic vanadium compounds and one compound, bis(maltolato)oxovanadium(IV) or BMOV, has been extensively investigated. BMOV proved effective in lowering plasma glucose and lipids in STZ-diabetic rats when administered in drinking water over a 25 week period. The maintenance dose (0.18 mmol/kg/day) was approximately 50% of that required for vanadyl sulfate (VS). Secondary complications of diabetes were prevented by BMOV and no marked toxicity was noted. Oral gavage of STZ-diabetic rats with BMOV also reduced blood glucose levels. The ED₅₀ for BMOV was 0.5 mmol/kg, while for VS the estimated ED₅₀ was 0.9 mmol/kg. BMOV was also effective by the intraperitoneal route in STZ-diabetic rats. The ED₅₀ was 0.08 mmol/kg compared to 0.22 mmol/kg for VS. Some animals treated p.o. or i.p. remained euglycemic for up to 14 weeks. An i.v. infusion of BMOV of 0.05 mmol/kg over a 30 min period reduced plasma glucose levels by 50% while VS was not effective.     

In vivo effects of vanadium on GLUT4 translocation in cardiac tissue of STZ-diabetic rats

The effect of vanadium treatment on insulin-stimulated glucose transporter type 4 (GLUT4) translocation was studied in cardiac tissue of streptozotocin (STZ)-induced diabetic rats by determining the subcellular distribution of GLUT4. Four groups of rats were examined: control and diabetic, with or without bis(maltolato)oxovanadium(IV) (BMOV, an organic form of vanadium) treatment for 8 weeks. The effect of vanadium on insulin-induced GLUT4 translocation was studied at 5 min as the early insulin response and at 15 min after insulin injection as the maximal insulin response.At 5 min after insulin injection, plasma membrane GLUT4 level in the diabetic-treated group was not different from the control groups and was significantly higher than that of the insulin-stimulated diabetic group, indicating an enhancement of insulin response on GLUT4 translocation brought about by vanadium treatment. In contrast to that at 5 min after insulin injection, no significant difference in the plasma membrane GLUT4 level was observed between the diabetic and the diabetic-treated groups at 15 min after insulin injection. GLUT4 mobilization from the intracellular pool in response to insulin was also investigated at 15 min after insulin injection. Basal intracellular GLUT4 content was significantly higher in the diabetic-treated group when compared to the diabetic group under the same condition. However, the increased basal intracellular GLUT4 in the diabetic-treated group did not result in more insulin-mediated GLUT4 translocation at 15 min after insulin injection. In conclusion, the finding that plasma membrane GLUT4 in the diabetic-treated group is significantly higher than that of the diabetic group at 5 min but not at 15 min post-insulin injection indicates that vanadium treatment enhances insulin-mediated GLUT4 translocation in cardiac tissue by enhancing its early response.     

A new halogenated antidiabetic vanadyl complex, bis(5-iodopicolinato)oxovanadium(IV): in vitro and in vivo insulinomimetic evaluations and metallokinetic analysis

A new vanadyl complex, bis(5-iodopicolinato)oxovanadium(IV), VO(IPA)2, with a VO(N2O2) coordination mode, was prepared by mixing 5-iodopicolinic acid and VOSO4 at pH 5, with the structure characterized by electronic absorption, IR, and EPR spectra. Introduction of the halogen atom on to the ligand enhanced the in vitro insulinomimetic activity (IC50 = 0.45 mM) compared with that of bis(picolinato)oxovanadium(IV) (IC50 = 0.59 mM). The hyperglycemia of streptozotocin-induced insulin-dependent diabetic rats was normalized when VO(IPA)2 was given by daily intraperitoneal injection. The normoglycemic effect continued for more than 14 days after the end of treatment. To understand the insulinomimetic action of VO(IPA)2, the organ distribution of vanadium and the blood disposition of vanadyl species were investigated. In diabetic rats treated with VO(IPA)2, vanadium was distributed in almost all tissues examined, especially in bone, indicating that the action of vanadium is not peripheral. Vanadyl concentrations in the blood of normal rats given VO(IPA)2 remain significantly higher and longer than those given other complexes because of its slower clearance rate. VO(IPA)2 binds with the membrane of erythrocytes, probably owing to its high hydrophobicity in addition to its binding with serum albumin. The longer residence of vanadyl species shows the higher normoglyceric effects of VO(IPA)2 among three complexes with the VO(N2O2) coordination mode. On the basis of these results, VO(IPA)2 is indicated to be a preferred agent to treat insulin-dependent diabetes mellitus in experimental animals.     

Model complexes for amavadine,a vanadium natural product

Amavadine is a vanadium natural product from the mushroom Amanita muscaria. Earlier reports have characterized the compound as a vanadyl (VO²⁺) complex with two N-hydroxy-αα-iminodipropionic acid ligands, but no hypothesis as to its function has yet been put forward. We report here the synthesis, isolation, and properties of bis(iminodiacetato)oxovanadium(IV) and bis(αα-iminodipropionato)oxovanadium(IV). The complex bis(ββ-iminodipropionato)oxovanadium(IV) has been prepared in solution. These complexes serve as models for Amavadine. The structures of the models are analogous to that of Amavadine, with two bidentate, singly charged ligands bonding through one oxygen and one nitrogen atom. The visible spectra suggest the possibility of 1:1 complexes in solution in addition to the 2:1 ligand to metal complexes. Preliminary electrochemical data suggest reversible V(IV) ? V(III) couples.     

Vanadium treatment of type 2 diabetes: A view to the future

3-Hydroxy-2-methyl-4-pyrone and 2-ethyl-3-hydroxy-4-pyrone (maltol and ethyl maltol, respectively) have proven especially suitable as ligands for vanadyl ions, in potential insulin enhancing agents for diabetes mellitus. Both bis(maltolato)oxovanadium(IV) (BMOV), and the ethylmaltol analog, bis(ethylmaltolato)oxovanadium(IV) (BEOV), have the desired intermediate stability for pro-drug use, and have undergone extensive pre-clinical testing for safety and efficacy. Pharmacokinetic evaluation indicates a pattern of biodistribution consistent with fairly rapid dissociation and uptake, binding to serum transferrin for systemic circulation and transport to tissues, with preferential uptake in bone. These bis-ligand oxovanadium(IV) (VOL₂) compounds have a clear advantage over inorganic vanadyl sulfate in terms of bioavailability and pharmaceutical efficacy. BEOV has now completed Phase I and has advanced to Phase II clinical trials. In the Phase I trial, a range of doses from 10 mg to 90 mg BEOV, given orally to non-diabetic volunteers, resulted in no adverse effects; all biochemical parameters remained within normal limits. In the Phase IIa trial, BEOV (AKP-020), 20 mg, daily for 28 days, per os, in seven type 2 diabetic subjects, was associated with reductions in fasting blood glucose and %HbA1c; improved responses to oral glucose tolerance testing, versus the observed worsening of diabetic symptoms in the two placebo controls.     

Amelioration of diabetic dyslipidemia by macrocyclic binuclear oxovanadium complex on streptozotocin induced diabetic rats

Diabetic dyslipidemia, the main causative factor for the progression of vascular complications in diabetes, is caused due to hyperglycemia and excess mobilisation of fatty acids. Recently we have reported on a novel macrocyclic binuclear oxovanadium (MBOV) complex synthesized by us with significant hypoglycemic efficacy and without any apparent toxicity on streptozotocin induced diabetic rats. In the present study, streptozotocin induced diabetic rats were treated with the vanadium complex (5 mg/kg body weight/day) for a period of 30 days and at the end of the treatment period the status of the lipid profile in the plasma, liver and kidney was evaluated. Also the fatty acid composition of liver and kidney were analysed by gas chromatography. The increased levels of lipid contents in plasma and tissues observed in diabetic rats were reverted back to near normal levels by the administration of the vanadium complex. Also the decreased levels of HDL cholesterol and increased levels of LDL cholesterol in plasma of diabetic rats were restored to near normal levels by the treatment with the vanadium complex. The altered fatty acid composition in liver and kidney were restored by the treatment. The results enhance the claim for the macrocyclic binuclear oxovanadium complex as a potent anti-diabetogenic drug.This revised version was published online in May 2005 with a corrected article title.     

Vanadyl-thiazolidinedione combination agents for diabetes therapy

A series of vanadium compounds, chelated by ligands containing a thiazolidinedione moiety as an additional insulin-enhancing component, were produced in this study to create potentially synergistic compounds. A set of four bifunctional ligand precursors were synthesized: (+/-)-5-[4-[(5-hydroxy-4-oxo-4H-pyran-2-ylmethyl)amino]benzyl]thiazolidine-2,4-dione (HL(1)), (+/-)-5-[4-[(5-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridin-2-ylmethyl)amino]benzyl]thiazolidine-2,4-dione (HL(2)), 5-[4-(5-hydroxy-4-oxo-4H-pyran-2-ylmethoxy)benzylidene]thiazolidine-2,4-dione (HL(3)), and (+/-)-5-[4-(5-hydroxy-4-oxo-4H-pyran-2-ylmethoxy)benzyl]thiazolidine-2,4-dione (HL(4)), each containing a metal chelating portion as well as a thiazolidinedione moiety. From this set of ligand precursors, air-stable VO(L(1))(2), VO(L(3))(2), and VO(L(4))(2) were prepared. The four ligand precursors and three complexes were tested for insulin-enhancing potential in STZ-diabetic rats and compared to rosiglitazone and BMOV, respectively. Both the ligand precursors HL(1) and HL(3) showed enhanced activity compared with that of rosiglitazone. The complex VO(L(3))(2) showed the most efficacious hypoglycemic effects in this study; however, neither additive nor synergistic effects were observed using this acute animal model.     

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

In this work we report biochemical ex vivo studies with a vanadium compound containing a pyridinone ligand, the bis(1,2-dimethyl-3-hydroxy-4-pyridinonate)oxovanadium (IV), V^IVO(dmpp)₂, which has shown to have promising antidiabetic activity. The experiments were carried out on primary adipocytes of 6-8 week old Wistar rats. Insulin-stimulated glucose uptake studies were performed using a radioactive assay by measuring the (U)-¹⁴C-glucose taken up by the isolated adipocytes for 30 min. Adipocytes were incubated with and without insulin and in the presence and absence of different concentrations of V^IVO(dmpp)₂ (100-500 μM) for 45 min. We observed that in a nontoxic concentration, as demonstrated by the Alamar Blue test, V^IVO(dmpp)₂ significantly increases glucose uptake, in the absence of insulin, by 5-folds higher than basal, and it has a significant inhibitory effect of 78% on free fatty acid release in isolated adipocytes from normal rats. We also demonstrated that it promotes the phosphorylation of Akt1, a key protein in the insulin signaling cascade. These results were compared with those obtained with another vanadium compound reported in the literature, with a similar structure, the bis(maltolato)oxovanadium (IV) (BMOV), which is now in clinical trials. Our ex vivo results clearly indicate that V^IVO(dmpp)₂ is a good candidate to be a promising drug for the treatment of diabetes and other metabolic disorders.