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. 2011 Oct;255(19-20):2258-2269.
doi: 10.1016/j.ccr.2011.06.015.

Anti-diabetic Effects of a Series of Vanadium Dipicolinate Complexes in Rats With Streptozotocin-Induced Diabetes

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Anti-diabetic Effects of a Series of Vanadium Dipicolinate Complexes in Rats With Streptozotocin-Induced Diabetes

Gail R Willsky et al. Coord Chem Rev. .
Free PMC article

Abstract

The effects of oral treatment of rats with streptozotocin-induced diabetes with a range of vanadium dipicolinate complexes (Vdipic) and derivatives are reviewed. Structure-reactivity relationships are explored aiming to correlate properties such as stability, to their insulin-enhancing effects. Three types of modifications are investigated; first, substitutions on the aromatic ring, second, coordination of a hydroxylamido group to the vanadium, and third, changes in the oxidation state of the vanadium ion. These studies allowed us to address the importance of coordination chemistry, and redox chemistry, as modes of action. Dipicolinate was originally chosen as a ligand because the dipicolinatooxovanadium(V) complex (V5dipic), is a potent inhibitor of phosphatases. The effect of vanadium oxidation state (3, 4 or 5), on the insulin-enhancing properties was studied in both the Vdipic and VdipicCl series. Effects on blood glucose, body weight, serum lipids, alkaline phosphatase and aspartate transaminase were selectively monitored. Statistically distinct differences in activity were found, however, the trends observed were not the same in the Vdipic and VdipicCl series. Interperitoneal administration of the Vdipic series was used to compare the effect of administration mode. Correlations were observed for blood vanadium and plasma glucose levels after V5dipic treatment, but not after treatment with corresponding V4dipic and V3dipic complexes. Modifications of the aromatic ring structure with chloride, amine or hydroxyl groups had limited effects. Global gene expression was measured using Affymetrix oligonucleotide chips. All diabetic animals treated with hydroxyl substituted V5dipic (V5dipicOH) and some diabetic rats treated with vanadyl sulfate had normalized hyperlipidemia yet uncontrolled hyperglycemia and showed abnormal gene expression patterns. In contrast to the normal gene expression profiles previously reported for some diabetic rats treated with vanadyl sulfate, where both hyperlipidemia and hyperglycemia were normalized. Modification of the metal, changing the coordination chemistry to form a hydroxylamine ternary complex, had the most influence on the anti-diabetic action. Vanadium absorption into serum was determined by atomic absorption spectroscopy for selected vanadium complexes. Only diabetic rats treated with the ternary V5dipicOH hydroxylamine complex showed statistically significant increases in accumulation of vanadium into serum compared to diabetic rats treated with vanadyl sulfate. The chemistry and physical properties of the Vdipic complexes correlated with their anti-diabetic properties. Here, we propose that compound stability and ability to interact with cellular redox reactions are key components for the insulin-enhancing activity of vanadium compounds. Specifically, we found that the most overall effective anti-diabetic Vdipic compounds were obtained when the compound administered had an increased coordination number in the vanadium complex.

Figures

Fig 1
Fig 1
Structures of compounds used.
Fig 2
Fig 2
Effect of oral chronic administration of V5dipic and dipic ligands on BG in rats with STZ-induced diabetes. Normal untreated (N, ●); Diabetic untreated (D, ■); N treated with VS(○), D treated with VS (□); D treated with dipic(△), D treated with dipicOH(◊), D treated with V5dipic(▲) Data redrawn from [18, 19, 32]. Data analyzed by one way ANOVA with multiple means testing. *** represents p < .001 vs diabetic rats.
Fig 3
Fig 3
Effect of oral chronic administration of V3dipic, V4dipic, or V5dipic on BG in rats with STZ-induced diabetes. Normal untreated (N, ●); Diabetic untreated (D, ■); D treated with V3dipic (◊); D treated with V4dipic(*); D treated with V5dipic(▲). The data for 14 days of treatment were previously published [19] and have been extended to 28 days. Data analyzed by one way ANOVA with multiple means testing *** represents p < .001 vs diabetic rats.
Fig 4
Fig 4
Effect of acute interperitoneal administration of V3dipic, V4dipic, or V5dipic on plasma glucose in rats with STZ-induced diabetes. A) Plasma glucose levels. Diabetic rats treated with saline (■), BMOV (□), V3dipic (◊), V4dipic (△), V5dipic (▲). B) Blood Total V levels as determined by atomic absorption spectrometry. BMOV (□), V3dipic (◊), V4dipic (△), V5dipic (▲). Data redrawn from previous publication [32]. Data analyzed by one way ANOVA with multiple means testing. ** represents p < .01 vs diabetic rats.
Fig 5
Fig 5
Effect of oral chronic administration of V3dipicCl, V4dipicCl, V5dipicCl, V5dipicNH2, BMOV, VS, and Vanadate on BG levels in normal rats and rats with STZ-induced diabetes. Data analyzed by one way ANOVA with multiple means testing. Symbols for treatment group indicated in Figure. Data redrawn from previous publications [21, 22]
Fig 6
Fig 6
Effect of oral chronic administration of hydroxylamine coordinated to V5dipic and V5dipicOH on BG levels in rats with STZ-induced diabetes. Data obtained as described in previous publications [18, 19, 32]. N (●), D (■), V5dipic (▲), V5dipic(MeHA) (|), V5dipicOH (◆), V5dipicOH(HA)(X). Data analyzed by one way ANOVA with multiple means testing. *** represents p < 0.001 vs diabetic rats.
Fig 7
Fig 7
Effect of oral chronic administration of VS on rats with STZ-induced diabetes. Parts of this figure has been previously published [71]. N (●), D (■), D-VS(R) responding with lowered BG and lowered Lipids (▲), D-VS not responding (NR) with lowered BG and but showing lowered Lipids (△), D-VS all responses of animals treated with VS (□).Data analyzed by one way ANOVA with multiple means testing. *** represents p < 0 .001 vs diabetic rats.
Fig 8
Fig 8
Heatmap for the 62 probe sets selected as being both altered by diabetes and corrected by oral administration of VS. The expression of each individual gene is compared with that of the median of the N group, represented by black in the group of arrays for the N rats. The intensity of the color indicates the variability of the expression of that probe set in the group. Data from N and D untreated and treated with VS (where the treated rats showed lowered diabetic hyperlipidemia and hyperglycemia (D-VS BG low L low) have previously been published [71]. New data for D animals treated with VS in which only lipids were lowered (D-VS BG high, L low) and D animals treated with the liganded V5dipicOH (D-Lig BG high, L low).
Fig 9
Fig 9
The 51V NMR spectra of [VO(dipic)(MeHNO)(H2O) recorded as the pH was varied from 2-8 (A-G). Each spectrum was recorded from a separate sample with an initial concentration of 2 mm complex. Monomeric vanadate and the predominant hydroxylamido:V species are labeled as V1 and *, respectively. Figure reproduced from Smee et al [20] with permission.
Fig 10
Fig 10
Percentage of intact V5dipicX as a function of pH. 51V-NMR data obtained from previously published work by Smee et al. [20, 23]. X= H (○); OH (◆); NH2 (□); NO2 (●); Cl (*)

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