Katherine H. Thompson

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) (VOL(2)) 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.

Coordination chemistry of vanadium in metallopharmaceutical candidate compounds

Abstract The discovery of vanadiums insulin-like behaviour in vitro, and later of the orally available glucose- and lipid-lowering capability of these same compounds in vivo, has stimulated renewed interest in vanadium coordination chemistry. Besides the anti-diabetic effects for which it is now so well known, vanadium also exhibits a number of other therapeutic effects including anti-tumour and anti-inflammatory activities. In this review, emphasis will be on the most recent developments in the coordination chemistry of vanadium(III), (IV) and (V), as related to development of these compounds for pharmaceutical use. How best to measure bioactivity and the pharmaceutical relevance of accompanying increased oxidative stress will also be considered.

Design of targeting ligands in medicinal inorganic chemistry.

This tutorial review will highlight recent advances in medicinal inorganic chemistry pertaining to the use of multifunctional ligands for enhanced effect. Ligands that adequately bind metal ions and also include specific targeting features are gaining in popularity due to their ability to enhance the efficacy of less complicated metal-based agents. Moving beyond the traditional view of ligands modifying reactivity, stabilizing specific oxidation states, and contributing to substitution inertness, we will discuss recent work involving metal complexes with multifunctional ligands that target specific tissues, membrane receptors, or endogenous molecules, including enzymes.

Metal complexes in medicinal chemistry: new vistas and challenges in drug design

An overview is presented of selected metal-based pharmaceuticals, either diagnostic or therapeutic, with emphasis on specific attributes and in vivo interactions of these compounds relevant to their use in medicinal applications. Both the advantages and the challenges of this approach are outlined, with possibilities for future developments accentuated.

Design of vanadium compounds as insulin enhancing agents

Vanadium compounds, in vitro, stimulate glucose uptake and inhibit lipid breakdown, in a manner remarkably reminiscent of insulin’s effects. In vivo, vanadium enhances insulin’s plasma glucose and lipid-lowering properties, leading to normalization of diabetic symptoms in the presence of only minimal endogenous insulin. The coordination chemistry of vanadium has great versatility for adjustment of pharmacological characteristics. Vanadium compounds are generally also very redox active, which is both advantageous and detrimental for optimizing biochemical function. In this perspective, we review and comment on how these properties have been revealed, what questions have arisen along the way, and where future investigations may be headed. While this is not a comprehensive overview of all available compounds touted as ‘insulin enhancing agents’, it will focus on those which are distinctive in some way, or which are representative of the larger library of vanadium compounds, including all currently known relevant oxidation states of vanadium.

Tissue antioxidant status in streptozotocin-induced diabetes in rats : effects of dietary manganese deficiency

Interactions between manganese (Mn) deficiency and streptozotocin (STZ)-diabetes with respect to tissue antioxidant status were investigated in male, Sprague-Dawley rats. All rats were fed either a Mn-deficient (1 ppm) or a Mn-sufficient (45 ppm) diet for 8 wk. Diabetes was then induced by tail-vein injection of STZ (60 mg/kg body weight), after which the rats were kept for an additional 4 or 8 wk. The control groups comprised rats not injected with STZ and fed either Mn-deficient or Mn-sufficient diets for a total of 12 wk.The Mn-deficient diet decreased the activities of manganese superoxide dismutase (MnSOD) in kidney and heart, and of copperzinc superoxide dismutase (CuZnSOD) in kidney, in the non-diabetic animals. In the diabetic rats, the Mn-deficient diet induced more pronounced decreases in activities of these same enzymes, and also increased liver MnSOD activity. Plasma and hepatic vitamin E levels increased progressively with the duration of diabetes, independent of dietary Mn intake. Lipid peroxidation, as measured by H2O2-induced production of thiobarbituric acid reactive substances in erythrocytes, also increased, concomitant with decreased liver and kidney glutathione (GSH) levels. These findings demonstrate for the first time an interactive effective between Mn deficiency and STZ-diabetes, resulting in amplification of tissue antioxidant changes seen with either Mn deficiency or STZ-diabetes alone. This effect of Mn deprivation in experimental diabetes suggests a physiological role for Mn as an antioxidant nutrient.

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.

Essential trace elements of potential importance in nutritional management of diabetes mellitus

Both type I and type II diabetes mellitus are associated with alterations in tissue concentrations of several essential trace elements. Some of these changes are associated with an impairment of glucose homeostasis, which is corrected after supplementation with the appropriate micronutrient. This review focuses on well controlled human and animal studies with particular attention to those suggesting improvements in carbohydrate metabolism after supplementation with the particular micronutrient.

Effects of manganese and vitamin E deficiencies on antioxidant enzymes in streptozotocin-diabetic rats

Abstract Vitamin E and manganese deficiencies have been shown independently to affect the capacity to scavenge endogenously produced reactive oxygen species (ROS) in streptozotocin (STZ)-diabetic, Sprague-Dawley rats. Whether combined vitamin E and manganese deficiencies would additively affect oxidative stress was assessed in this study. Plasma and hepatic vitamin E were severely depleted in vitamin E-deficient rats, and susceptibility to lipid peroxidation in kidney, heart, liver, and pancreas tissues was increased, independent of manganese. Activities of key antioxidant enzymes, including superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase in heart, liver, kidney, and pancreas were altered by manganese and vitamin E deficiencies, although no additive effects were observed. Hemoglobin glycosylation was elevated in vitamin E-deficient, diabetic rats, an effect that further underscores the increased oxidative stress in vitamin E deficiency states.

Vanadium-Containing Insulin Biomimetic Drugs

Vanadium-containing metallocomplexes are being widely investigated as potential insulin-enhancing or replacement pharmaceutical agents. Experimental evidence of inorganic vanadium’s insulin-mimetic effects, with the immensely appealing feature of oral bioavailability, has prompted design and development of novel organic ligands. Desirable features include low molecular weight, neutral charge, thermodynamic and hydrolytic stability, and a balance between aqueous solubility and lipophilicity. From the initial development of bis(maltolato)oxovanadium(IV), containing the ligand, maltol, which is an approved food additive, to more recent development of metallocomplexes such as imidazoleoxobisperoxovanadate(V), which seek to mimic the active site of vanado-enzymes, such as bromperoxidase, researchers have examined a variety of compounds as solutions to the problems of improved absorption, coupled with minimal toxicity. Also detailed are 5-, 6-, and 7-coordinated compounds, with V-N, V-O, V-S, and temporary complexation, as well as the peroxovanadates currently in development as insulin-mimetic agents.