Vanadium in diabetes: 100 years from Phase 0 to Phase I.

A little over one hundred years ago, a vanadium-containing compound was assessed clinically for use in treatment of human diabetic patients. The results were somewhat ambiguous, but nonetheless, intriguing. In 2000, the first Phase I clinical trial of a designed vanadium-based pharmaceutical agent (bis(ethylmaltolato)oxovanadium(IV), BEOV), was completed by Medeval Ltd., Manchester, UK. Results here, too, were promising, but not without some difficult remaining questions. In this review, we look back at the many questions asked and answered regarding vanadium's glucose-enhancing potential, its biodistribution and biomolecular transformation, and its mechanism(s) of action, and consider some of the newest developments in the field, including novel delivery methods for vanadium in diabetes treatment.

[1]  G. Willsky,et al.  Aqueous chemistry of the vanadium(III) (V(III)) and the V(III)-dipicolinate systems and a comparison of the effect of three oxidation states of vanadium compounds on diabetic hyperglycemia in rats. , 2005, Inorganic chemistry.

[2]  G. Dubyak,et al.  The insulin-mimetic effects of vanadate in isolated rat adipocytes. Dissociation from effects of vanadate as a (Na+-K+)ATPase inhibitor. , 1980, The Journal of biological chemistry.

[3]  Multifunctional actions of vanadium compounds on insulin signaling pathways: Evidence for preferential enhancement of metabolic versus mitogenic effects , 1998 .

[4]  J. Libman,et al.  Hydrophobic carriers of vanadyl ions augment the insulinomimetic actions of vanadyl ions in rat adipocytes. , 1992, Biochemistry.

[5]  A. Pansini,et al.  Effects of vanadium on glucose metabolism in vitro. , 1979, Life sciences.

[6]  H. Sakurai,et al.  New antidiabetic vanadyl–pyridone complexes: effect of equivalent transformation of coordinating atom in the ligand , 2003 .

[7]  R. Pederson,et al.  Long-term effectiveness of oral vanadyl sulphate in streptozotocin-diabetic rats , 1993, Diabetologia.

[8]  H. Degani,et al.  Vanadium in Biological Systems , 1990, Springer Netherlands.

[9]  J. Henquin,et al.  Comparison of the effects of various vanadium salts on glucose homeostasis in streptozotocin-diabetic rats. , 1994, European journal of pharmacology.

[10]  S. Brichard,et al.  Long term improvement of glucose homeostasis by vanadate treatment in diabetic rats. , 1988, Endocrinology.

[11]  A. Benchimol,et al.  Vanadium, Excretion, toxicity, lipid effect in man. , 1963, The American journal of clinical nutrition.

[12]  T. Wiegmann,et al.  Intestinal absorption and secretion of radioactive vanadium (48VO3-) in rats and effect of Al(OH)3. , 1982, Journal of toxicology and environmental health.

[13]  H. Sakurai,et al.  Insulin-like effect of vanadyl ion on streptozotocin-induced diabetic rats. , 1990, The Journal of endocrinology.

[14]  A. Keramidas,et al.  Vanadium chemistry and biochemistry of relevance for use of vanadium compounds as antidiabetic agents , 1995, Molecular and Cellular Biochemistry.

[15]  C. Carrano,et al.  Binding of vanadate to human serum transferrin. , 1984, Journal of inorganic biochemistry.

[16]  R. Bartrons,et al.  Insulin-like effects of vanadate on glucokinase activity and fructose 2,6-bisphosphate levels in the liver of diabetic rats. , 1988, The Journal of biological chemistry.

[17]  D. W. Ribbons,et al.  Acetylacetone-cleaving enzyme Dke1: a novel C-C-bond-cleaving enzyme from Acinetobacter johnsonii. , 2003, The Biochemical journal.

[18]  A. V. Xavier Frontiers in Bioinorganic chemistry , 1986 .

[19]  R. Hye,et al.  Animal models of diabetes mellitus: physiology and pathology. , 1983, The Journal of surgical research.

[20]  H. Sakurai,et al.  Structure-dependent metallokinetics of antidiabetic vanadyl-picolinate complexes in rats: studies on solution structure, insulinomimetic activity, and metallokinetics. , 2002, Journal of inorganic biochemistry.

[21]  Y. Shechter,et al.  Insulin-like stimulation of glucose oxidation in rat adipocytes by vanadyl (IV) ions , 1980, Nature.

[22]  C. Kahn,et al.  Metabolic effects of sodium metavanadate in humans with insulin-dependent and noninsulin-dependent diabetes mellitus in vivo and in vitro studies. , 1995, The Journal of clinical endocrinology and metabolism.

[23]  M. Gresser,et al.  Mechanism of Inhibition of Protein-tyrosine Phosphatases by Vanadate and Pervanadate* , 1997, The Journal of Biological Chemistry.

[24]  S. Brichard,et al.  Effects of vanadium complexes with organic ligands on glucose metabolism: a comparison study in diabetic rats , 1999, British journal of pharmacology.

[25]  Y. Adachi,et al.  Bis(allixinato)oxovanadium(IV) complex is a potent antidiabetic agent: studies on structure-activity relationship for a series of hydroxypyrone-vanadium complexes. , 2006, Journal of medicinal chemistry.

[26]  J. Domingo,et al.  Tiron administration minimizes the toxicity of vanadate but not its insulin mimetic properties in diabetic rats. , 1992, Life sciences.

[27]  G. Elberg,et al.  Antilipolytic Actions of Vanadate and Insulin in Rat Adipocytes Mediated by Distinctly Different Mechanisms. , 1997, Endocrinology.

[28]  D. Lyster,et al.  Kinetic analysis and comparison of uptake, distribution, and excretion of 48V-labeled compounds in rats. , 1998, Journal of applied physiology.

[29]  F. Bernheim,et al.  THE ACTION OF VANADIUM ON THE OXIDATION OF PHOSPHOLIPIDS BY CERTAIN TISSUES , 1939 .

[30]  M. Battell,et al.  Vanadium compounds as insulin mimics. , 1999, Metal ions in biological systems.

[31]  C. Orvig,et al.  Metal complexes of maltol and close analogues in medicinal inorganic chemistry. , 2006, Chemical Society reviews.

[32]  J. McNeill,et al.  Bis(maltolato)oxovanadium(IV) is a potent insulin mimic. , 1992, Journal of medicinal chemistry.

[33]  J. McNeill,et al.  Insulin-enhancing vanadium(III) complexes. , 2001, Inorganic chemistry.

[34]  I. Fábián,et al.  Kinetics of ligand substitution reactions in the oxovanadium(IV) /maltol system , 2002 .

[35]  J. Somerville,et al.  Effect of vanadium on serum cholesterol. , 1962, American heart journal.

[36]  D. Maysinger,et al.  From Vanadis to Atropos: vanadium compounds as pharmacological tools in cell death signalling. , 1998, Trends in pharmacological sciences.

[37]  M. T. Pope,et al.  Isopoly-vanadates, -niobates, and -tantalates , 1968 .

[38]  R. Giridhar,et al.  Effect of bis[curcumino]oxovanadium complex on non-diabetic and streptozotocin-induced diabetic rats. , 2005, Journal of Trace Elements in Medicine and Biology.

[39]  M. Symons,et al.  Structure and Reactivity of the Oxyanions of Transition Metals. , 1963 .

[40]  Susie M. Miller,et al.  Chemistry and insulin-mimetic properties of bis(acetylacetonate)oxovanadium(IV) and derivatives. , 2000, Inorganic chemistry.

[41]  B. C. McCabe,et al.  Metabolism of added orthovanadate to vanadyl and high-molecular-weight vanadates by Saccharomyces cerevisiae. , 1984, The Journal of biological chemistry.

[42]  F. Marumo,et al.  Abnormal accumulation of vanadium in patients on chronic hemodialysis therapy. , 1990, Nephron.

[43]  M. Khamaisi,et al.  Treatment of diabetes with vanadium salts: general overview and amelioration of nutritionally induced diabetes in the Psammomys obesus gerbil , 2001, Diabetes/metabolism research and reviews.

[44]  H. Kishida,et al.  Curcuminoids and sesquiterpenoids in turmeric (Curcuma longa L.) suppress an increase in blood glucose level in type 2 diabetic KK-Ay mice. , 2005, Journal of agricultural and food chemistry.

[45]  H. Shamoon,et al.  Oral Vanadyl Sulfate Improves Insulin Sensitivity in NIDDM but Not in Obese Nondiabetic Subjects , 1996, Diabetes.

[46]  J. McNeill,et al.  Effect of vanadate on elevated blood glucose and depressed cardiac performance of diabetic rats. , 1985, Science.

[47]  B. R. Nechay Mechanisms of action of vanadium. , 1984, Annual review of pharmacology and toxicology.

[48]  J. McNeill,et al.  Toxicological aspects of vanadyl sulphate on diabetic rats: effects on vanadium levels and pancreatic B-cell morphology. , 1990, Pharmacology & toxicology.

[49]  H. Sakurai,et al.  Enteric‐coating capsulation of insulinomimetic vanadyl sulfate enhances bioavailability of vanadyl species in rats , 2002, The Journal of pharmacy and pharmacology.

[50]  I. G. Fantus,et al.  Peroxide(s) of vanadium: a novel and potent insulin-mimetic agent which activates the insulin receptor kinase. , 1987, Biochemical and biophysical research communications.

[51]  I. G. Fantus,et al.  Pervanadate [peroxide(s) of vanadate] mimics insulin action in rat adipocytes via activation of the insulin receptor tyrosine kinase. , 1989, Biochemistry.

[52]  J. Gordon Use of vanadate as protein-phosphotyrosine phosphatase inhibitor. , 1991, Methods in enzymology.

[53]  D. Crans,et al.  The chemistry and biochemistry of vanadium and the biological activities exerted by vanadium compounds. , 2004, Chemical reviews.

[54]  M. Bendayan,et al.  Effect of vanadate administration on blood glucose and insulin levels as well as on the exocrine pancreatic function in streptozotocin-diabetic rats , 1989, Diabetologia.

[55]  C. Orvig,et al.  Reduction of [VO2(ma)2]- and [VO2(ema)2]- by ascorbic acid and glutathione: kinetic studies of pro-drugs for the enhancement of insulin action. , 2002, Inorganic Chemistry.

[56]  G. L. Curran Effect of certain transition group elements on hepatic synthesis of cholesterol in the rat. , 1954, The Journal of biological chemistry.

[57]  D. Crans (4-Hydroxypyridine-2,6-dicarboxylato)oxovanadate(V)—a new insulin-like compound: chemistry, effects on myoblast and yeast cell growth and effects on hyperglycemia in rats with STZ-induced diabetes , 2003 .

[58]  J. McNeill,et al.  Complementary inhibition of synoviocyte, smooth muscle cell or mouse lymphoma cell proliferation by a vanadyl curcumin complex compared to curcumin alone. , 2004, Journal of inorganic biochemistry.

[59]  M. Brady,et al.  The vanadyl (VO2+) chelate bis(acetylacetonato)oxovanadium(IV) potentiates tyrosine phosphorylation of the insulin receptor , 2005, JBIC Journal of Biological Inorganic Chemistry.

[60]  L. Cantley,et al.  The fate of cytoplasmic vanadium. Implications on (NA,K)-ATPase inhibition. , 1979, The Journal of biological chemistry.

[61]  A. Shisheva,et al.  Quercetin selectively inhibits insulin receptor function in vitro and the bioresponses of insulin and insulinomimetic agents in rat adipocytes. , 1992, Biochemistry.

[62]  B. Joe,et al.  Biological Properties of Curcumin-Cellular and Molecular Mechanisms of Action , 2004, Critical reviews in food science and nutrition.

[63]  A. Aviv,et al.  Balance and tissue distribution of vanadium after short-term ingestion of vanadate. , 1982, The Journal of nutrition.

[64]  W. R. Harris,et al.  Behavior of vanadate and vanadyl ion in canine blood. , 1984, Journal of inorganic biochemistry.

[65]  S. Brichard,et al.  The role of vanadium in the management of diabetes. , 1995, Trends in pharmacological sciences.

[66]  J. Li,et al.  Vanadium salts as insulin substitutes: mechanisms of action, a scientific and therapeutic tool in diabetes mellitus research. , 1996, Critical reviews in biochemistry and molecular biology.

[67]  H. Sakurai,et al.  Metallokinetic analysis of disposition of vanadyl complexes as insulin-mimetics in rats using BCM-ESR method. , 2000, Journal of inorganic biochemistry.

[68]  H. Sakurai,et al.  Long-term acting and orally active vanadyl-methylpicolinate complex with hypoglycemic activity in streptozotocin-induced diabetic rats , 1997 .

[69]  M. Battell,et al.  Influence of chelation and oxidation state on vanadium bioavailability, and their effects on tissue concentrations of zinc, copper, and iron , 2002, Biological Trace Element Research.

[70]  C. Orvig,et al.  Boon and Bane of Metal Ions in Medicine , 2003, Science.

[71]  A. Taraszewska,et al.  Histological and ultrastructural changes in the rat brain following systemic administration of picolinic acid. , 1995, Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie.

[72]  L. Josephson,et al.  Isolation of a potent (Na-K)ATPase inhibitor from striated muscle. , 1977, Biochemistry.

[73]  Tilton Be,et al.  Metabolism of trace amounts of vanadium 48 in rat organs and liver subcellular particles. , 1966 .

[74]  H. Sakurai,et al.  Speciation of insulin-mimetic VO(IV)-containing drugs in blood serum. , 2000, Journal of inorganic biochemistry.

[75]  A. Keramidas,et al.  Synthesis, Structure, and Biological Activity of a New Insulinomimetic Peroxovanadium Compound: Bisperoxovanadium Imidazole Monoanion , 1997 .

[76]  H. Sakurai,et al.  A new orally active insulin-mimetic vanadyl complex: bis(pyrrolidine-N-carbodithioato)oxovanadium (IV). , 1994, Journal of medicinal chemistry.

[77]  G. Elberg,et al.  Insulin-like actions of vanadate are mediated in an insulin-receptor-independent manner via non-receptor protein tyrosine kinases and protein phosphotyrosine phosphatases , 1995, Molecular and Cellular Biochemistry.

[78]  T. Kiss,et al.  Aqueous Chemistry of Ammonium (Dipicolinato)oxovanadate(V): The First Organic Vanadium(V) Insulin-Mimetic Compound , 2000 .

[79]  L. Nanninga,et al.  Vanadyl (IV) and vanadate (V) binding to selected endogenous phosphate, carboxyl, and amino ligands; calculations of cellular vanadium species distribution. , 1986, Archives of biochemistry and biophysics.

[80]  S. Brichard,et al.  Long term improvement of glucose homeostasis by vanadate in obese hyperinsulinemic fa/fa rats. , 1989, Endocrinology.

[81]  I. Glynn,et al.  Commercial ATP containing traces of vanadate alters the response of (Na+ + K+)ATPase to external potassium , 1978, Nature.

[82]  H. Shamoon,et al.  Oral vanadyl sulfate improves hepatic and peripheral insulin sensitivity in patients with non-insulin-dependent diabetes mellitus. , 1995, The Journal of clinical investigation.

[83]  J. Meyerovitch,et al.  Oral administration of vanadate normalizes blood glucose levels in streptozotocin-treated rats. Characterization and mode of action. , 1987, The Journal of biological chemistry.

[84]  D. H. Templeton,et al.  Crystal Structure of Vanadyl Bisacetylacetonate. Geometry of Vanadium in Fivefold Coordination , 1960 .

[85]  C. Geraldes,et al.  Uptake and metabolic effects of insulin mimetic oxovanadium compounds in human erythrocytes. , 2005, Journal of inorganic biochemistry.

[86]  R. Pederson,et al.  Long-Term Effects of Vanadyl Treatment on Streptozocin-Induced Diabetes in Rats , 1989, Diabetes.

[87]  I. Glynn,et al.  Vanadate inhibits (Na+ + K+)ATPase by blocking a conformational change of the unphosphorylated form , 1979, Nature.

[88]  T. Luckey,et al.  Chemical toxicity of metals and metalloids , 1978 .

[89]  F. Hamel,et al.  Transdermally delivered peroxovanadium can lower blood glucose levels in diabetic rats. , 1999, International journal of pharmaceutics.

[90]  J. McNeill,et al.  Vanadium complexes with mixed O,S anionic ligands derived from maltol: synthesis, characterization, and biological studies. , 2005, Inorganic chemistry.

[91]  J. McNeill,et al.  Vanadyl-biguanide complexes as potential synergistic insulin mimics. , 1999, Journal of inorganic biochemistry.

[92]  H. Degani,et al.  Electron paramagnetic resonance studies and insulin-like effects of vanadium in rat adipocytes. , 1981, Biochemistry.

[93]  J. Li,et al.  L-Glutamic acid gamma-monohydroxamate. A potentiator of vanadium-evoked glucose metabolism in vitro and in vivo. , 1999, The Journal of biological chemistry.

[94]  H. Greene,et al.  More sensitive flameless atomic absorption analysis of vanadium in tissue and serum. , 1982, Clinical chemistry.

[95]  J. McNeill,et al.  Glucose-lowering effects of a new organic vanadium complex, bis(maltolato)oxovanadium(IV). , 1993, Canadian journal of physiology and pharmacology.

[96]  G. Elberg,et al.  Vanadate Activates Membranous Nonreceptor Protein Tyrosine Kinase in Rat Adipocytes , 1997, Diabetes.

[97]  R. DeFronzo,et al.  The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright © 2001 by The Endocrine Society COMMENT Vanadyl Sulfate Improves Hepatic and Muscle Insulin Sensitivity in Type 2 Diabetes* , 2022 .

[98]  D. Kivelson,et al.  ESR Studies and the Electronic Structure of Vanadyl Ion Complexes , 1964 .

[99]  J. McNeill,et al.  Sustained prevention of myocardial and metabolic abnormalities in diabetic rats following withdrawal from oral vanadyl treatment. , 1989, Metabolism: clinical and experimental.

[100]  J. McNeill,et al.  Comparison of the glucose-lowering properties of vanadyl sulfate and bis(maltolato)oxovanadium(IV) following acute and chronic administration. , 1995, Canadian journal of physiology and pharmacology.

[101]  L. Rossetti,et al.  Correction of chronic hyperglycemia with vanadate, but not with phlorizin, normalizes in vivo glycogen repletion and in vitro glycogen synthase activity in diabetic skeletal muscle. , 1989, The Journal of clinical investigation.

[102]  S. Pugazhenthi,et al.  Effects of high sucrose diet on insulin-like effects of vanadate in diabetic rats , 1993, Molecular and Cellular Biochemistry.

[103]  C H Best,et al.  Pancreatic Extracts in The Treatment of Diabetes Mellitus , 1956, Diabetes.

[104]  E. Newsholme,et al.  Effects of chronic administration of vanadate to the rat on the sensitivity of glycolysis and glycogen synthesis in skeletal muscle to insulin. , 1987, Biochemical pharmacology.

[105]  K. Schwarz,et al.  Growth Effects of Vanadium in the Rat , 1971, Science.

[106]  M. Abrams,et al.  Medicinal inorganic chemistry: introduction. , 1999, Chemical reviews.

[107]  E. Erdmann,et al.  Vanadate and its significance in biochemistry and pharmacology. , 1984, Biochemical pharmacology.

[108]  A. R. Byrne,et al.  Vanadium in foods and in human body fluids and tissues. , 1978, The Science of the total environment.

[109]  Y. Shechter,et al.  Organic vanadium chelators potentiate vanadium-evoked glucose metabolism in vitro and in vivo: establishing criteria for optimal chelators. , 2000, Molecular pharmacology.

[110]  J. Domingo,et al.  Acute toxicity of vanadium compounds in rats and mice. , 1984, Toxicology letters.

[111]  Qiang Zhang,et al.  Pharmacodynamics and pharmacokinetics of the insulin-mimetic agent vanadyl acetylacetonate in non-diabetic and diabetic rats. , 2005, Journal of inorganic biochemistry.

[112]  J. McNeill,et al.  Vanadyl-thiazolidinedione combination agents for diabetes therapy. , 2003, Bioconjugate chemistry.

[113]  I. H. Tipton,et al.  ABNORMAL TRACE METALS IN MAN--VANADIUM. , 1963, Journal of chronic diseases.

[114]  J. K. Grady,et al.  Characterization of the binding, kinetics, and redox stability of vanadium(IV) and vanadium(V) protein complexes in serum , 1986 .

[115]  J. McNeill,et al.  Studies of vanadyl sulfate as a glucose-lowering agent in STZ-diabetic rats. , 1993, Biochemical and biophysical research communications.

[116]  R. Warner,et al.  Vanadate is a potent (Na,K)-ATPase inhibitor found in ATP derived from muscle. , 1977, The Journal of biological chemistry.

[117]  Edmond Lam,et al.  New insights into the interactions of serum proteins with bis(maltolato)oxovanadium(IV): transport and biotransformation of insulin-enhancing vanadium pharmaceuticals. , 2005, Journal of the American Chemical Society.

[118]  J. Selbin The Chemistry of Oxovanadium(IV) , 1965 .

[119]  C. Orvig,et al.  Vanadium compounds in the treatment of diabetes. , 2004, Metal ions in biological systems.

[120]  L. Cantley,et al.  Vanadate inhibits the red cell (Na+, K+) ATPase from the cytoplasmic side , 1978, Nature.

[121]  C. Bailey,et al.  New antidiabetic drugs , 1990 .

[122]  N. Chasteen,et al.  An electron paramagnetic resonance study of vanadyl(IV)-serum albumin complexes , 1976 .

[123]  H. Sakurai,et al.  Specific binding of vanadyl ion (VO2+) with thiolate of the cysteine-34 residue in serum albumin, demonstrated by CD spectroscopy and kinetic property , 2003 .

[124]  H. Sakurai,et al.  Chemical speciation of insulinomimetic VO(IV) complexes of pyridine-N-oxide derivatives: binary and ternary systems. , 2003, Journal of inorganic biochemistry.

[125]  Iontophoretic delivery of an insulin-mimetic peroxovanadium compound , 1997 .

[126]  A. Prasad Clinical, biochemical, and nutritional aspects of trace elements , 1982 .

[127]  J. K. Grady,et al.  Vanadium complexes of transferrin and ferritin in the rat. , 1986, Biochimica et biophysica acta.

[128]  F. G. Herring,et al.  Reaction chemistry of BMOV, bis(maltolato)oxovanadium(IV), a potent insulin mimetic agent , 1995 .

[129]  T. Clausen,et al.  The relationship between the transport of glucose and cations across cell membranes in isolated tissues. XI. The effect of vanadate on 45Ca-efflux and sugar transport in adipose tissue and skeletal muscle. , 1981, Biochimica et biophysica acta.

[130]  I. Glynn,et al.  A modifier of (Na+ + K+) ATPase in commercial ATP , 1977, Nature.

[131]  C. L. Sanders,et al.  Clearance and distribution of intratracheally instilled vanadium compounds in the rat. , 1982, Toxicology letters.

[132]  E. B. Paniago,et al.  Potentiometric, spectrophotometric and density functional study of the interaction of N-hydroxyacetamide with oxovanadium(IV): the influence of ligand to the V(IV)/V(V) oxi-reduction reaction. , 2003, Journal of inorganic biochemistry.

[133]  G. F. Fuhrmann,et al.  Effects of vanadate on intracellular reduction equivalents in mouse liver and the fate of vanadium in plasma, erythrocytes and liver. , 1984, Toxicology.

[134]  J. McNeill,et al.  One-year treatment of streptozotocin-induced diabetic rats with vanadyl sulphate. , 1994, Pharmacology & toxicology.

[135]  S. Brichard,et al.  Marked Improvement of Glucose Homeostasis in Diabetic ob/ob Mice Given Oral Vanadate , 1990, Diabetes.

[136]  D. Azarnoff,et al.  Effect of cholesterol synthesis inhibition in normocholesteremic young men. , 1959, The Journal of clinical investigation.