1.
Sources and Structure
1.1
Sources
Vanadium is what is known as an 'ultratrace' mineral in human nutrition.[1] It is not one of the classical 24 vitamins and minerals, although it is needed for certain reactions in the body, such as formation of a pervanadate requierd for phosphorylation of some protein receptors.[2] Typically between 6-20mcg of vanadium are consumed daily, mostly via peppers and seafood.[2]
Vanadium has a history of usage in diabetes treatment, where oral administration of sodium vanadate preceded the discovery of insulin in 1921.[3]
2.
Pharmacology
2.2
Enzymatic Interactions
Vanadium, as vanadate in vivo inhibits the P-type phosphorylated ATPases[6][7] and protein tyrosine phosphatases (PTPs).[8] The dose to inhibit ATPases, however, is clinically significant only in toxic levels. Inhibition of PTP increases various tyrosine phosphorylation processes (as the phosphatases were inhibitory enzymes in phosphorylation).
Various effects come from PTP inhibition, such as inhibition of System A Amino Acid uptake into cells which transports neutral AA[5] It can increase glucose uptake and GLUT4 mobilization via a phosphoinositol-3-kinase (PI3K) independent pathway (unlike insulin).[9] The mechanism of action for vanadium acting as an insulin mimetic is increased general phosphorylation acting upon insulin receptor tyrosine kinase (of which get phosphorylated under the influence of insulin, as well as PTP inhibition).
3.
Interactions with Glucose Metabolism
3.1
Mechanisms
Vanadium containing compounds are known to inhibited protein tyrosine phosphatases (PTPs)[10][11] as vanadium containing compounds tend to form a trigonal bipyramidal structure that can either act as a competitive inhibitor of phosphoryl transfer (which is the case for sodium orthovanadate) or an oxidizer of the cysteine residue of the PTP loop (peroxovanadate complexes).[12] Similar to other PTP inhibiting compound (PTP1B inhibitors include berberine and ursolic acid) vanadium can prolong signalling through the insulin receptor via preventing the negative regulation of IRS-1 degradation, which is induced downstream of insulin receptor signalling (via mTOR[13] signalling to S6K1[14]) and works via PTPs to suppress[15] and stimulate the degradation[16][17] of IRS-1 as a form of negative feedback.
1mmol/L sodium orthovanadate appears to enhance signalling (L6 myocyte) by around 25% and is associated with inhibiting the decline in PI3K/IRS-1 complex activity, but has been noted to not inhibit the loss in mass of IRS-1.[18]
Insulin eventually suppresses its own signalling via stimulating PTP enzymes (including PTP1B) which degrade IRS-1, the degration of IRS-1 then curtails further insulin signalling. Vanadium, like other PTP inhibitors, can prolong the signalling of insulin by preventing the degradation of IRS-1
3.2
Interventions
One study that had separate groups of persons with Type II Diabetes and Healthy but obese controls noted that 100mg of Vanadium for 3 weeks was able to suppress glucose output from the liver in both groups, but only the diabetic group experienced an increase in insulin sensitivity while healthy controls had no significant changes in blood glucose parameters.[19]
One human study (n=14) with 40-50yr old persons with Impaired Glucose Tolerance given 50mg twice daily (100mg daily) for a period of one month (30 days) noted that, in response to a euglycemic-hyperinsulinemic clamp, that vanadium treatment failed to improve insulin sensitivity and led to a small but significant increase in triglycerides.[20]
In persons without Type II Diabetes, the effects of Vanadium supplementation appear to be lesser to the point of ineffective
A study in type II diabetics (n=6) noted that after vanadium administration at 100mg daily during weeks 3-5 of a 7 week study (with placebo given for the beginning and final two study) noted that testing after 3 weeks of Vanadium administration was associated with increased glucose uptake and insulin sensitivity which was still noted 2 weeks after cessation of vanadium; these improvements were accompanied by a decrease in HbA1c from 9.6+/-0.6% to 8.8+/-0.6%.[21] Using Vanadium (as sulfate) at 150mg for 6 weeks was associated with a 20% reduction in fasting blood glucose and a decrease of HbA1c from 8.1+/-0.4 to 7.6+/-0.4%.[22] Although this study noted a reduction in endogenous glucose production by 20% in diabetics, the correlation of this reduction to the reduction in fasting blood glucose was r=0.6.[22]
However, the quality of these studies has been brought into question. This systemic review aimed to assess all double blind placebo-controlled studies on Vanadium and preliminary ended their search when they found none.[23] Studies that existed, and those cited above, tend to have no placebo group and are limited to small samples sizes; their significant results have much less statistical power than other compounds.
Although it shows some benefit, the studies that suggest this benefit are low powered and Vanadium has less good evidence for its usage despite the amount of human interventions
4.
Cardiovascular Health
4.1
Cholesterol and Triglycerides
100mg daily for 30 days in persons with impaired glucose tolerance failed to modify LDL-C, HDL-C, or total cholesterol while it led to a slight increase in triglycerides from 1.4+/-0.6mmol/L to 1.7+/-0.5mmol/L.[20]
5.
Nutrient-Nutrient Interactions
5.1
mTOR inhibition
One study using rapamycin (inhibitor of mTOR; used in this study to inhibit IRS-1 degradation which is a negative regulator of insulin signalling) noted that rapamycin and sodium orthovanadate (1mmol/L) were synergistic in increasing glucose uptake into an L6 myocyte in the presence of insulin from 26.42+/-3.73% (seen in vanadium alone) to 97.83+/-8.54% (combination; rapamycin alone caused 39.9+/-3.39% uptake).[18] This was due to inhibiting degradation of IRS-1 and prolonging signalling through the insulin receptor, which promoted PI3K induced glucose uptake, and was probably since vanadium could inhibit the degradation of PI3K/IRS-1 association (rapamycin ineffective) while rapamycin preventing the actual degradation of protein content of IRS-1 (vanadium ineffective).[18]
References
- ^Nielsen FHThe importance of diet composition in ultratrace element researchJ Nutr.(1985 Oct)
- ^Nielsen FHNutritional requirements for boron, silicon, vanadium, nickel, and arsenic: current knowledge and speculationFASEB J.(1991 Sep)
- ^Sakurai HA new concept: the use of vanadium complexes in the treatment of diabetes mellitusChem Rec.(2002)
- ^Kadota S, Fantus IG, Deragon G, Guyda HJ, Hersh B, Posner BIPeroxide(s) of vanadium: a novel and potent insulin-mimetic agent which activates the insulin receptor kinaseBiochem Biophys Res Commun.(1987 Aug 31)
- ^http://ajpcell.physiology.org/content/272/1/C156.abstract
- ^Cantley LC Jr, Josephson L, Warner R, Yanagisawa M, Lechene C, Guidotti GVanadate is a potent (Na,K)-ATPase inhibitor found in ATP derived from muscleJ Biol Chem.(1977 Nov 10)
- ^Nechay BR, Saunders JPInhibition by vanadium of sodium and potassium dependent adenosinetriphosphatase derived from animal and human tissuesJ Environ Pathol Toxicol.(1978 Nov-Dec)
- ^Swarup G, Cohen S, Garbers DLInhibition of membrane phosphotyrosyl-protein phosphatase activity by vanadateBiochem Biophys Res Commun.(1982 Aug)
- ^Tsiani E, Bogdanovic E, Sorisky A, Nagy L, Fantus IGTyrosine phosphatase inhibitors, vanadate and pervanadate, stimulate glucose transport and GLUT translocation in muscle cells by a mechanism independent of phosphatidylinositol 3-kinase and protein kinase CDiabetes.(1998 Nov)
- ^Jackson TK, Salhanick AI, Sparks JD, Sparks CE, Bolognino M, Amatruda JMInsulin-mimetic effects of vanadate in primary cultures of rat hepatocytesDiabetes.(1988 Sep)
- ^Heffetz D, Bushkin I, Dror R, Zick YThe insulinomimetic agents H2O2 and vanadate stimulate protein tyrosine phosphorylation in intact cellsJ Biol Chem.(1990 Feb 15)
- ^Solow BT, Harada S, Goldstein BJ, Smith JA, White MF, Jarett LDifferential modulation of the tyrosine phosphorylation state of the insulin receptor by IRS (insulin receptor subunit) proteinsMol Endocrinol.(1999 Oct)
- ^Takano A, Usui I, Haruta T, Kawahara J, Uno T, Iwata M, Kobayashi MMammalian target of rapamycin pathway regulates insulin signaling via subcellular redistribution of insulin receptor substrate 1 and integrates nutritional signals and metabolic signals of insulinMol Cell Biol.(2001 Aug)
- ^Haruta T, Uno T, Kawahara J, Takano A, Egawa K, Sharma PM, Olefsky JM, Kobayashi MA rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1Mol Endocrinol.(2000 Jun)
- ^Aguirre V, Werner ED, Giraud J, Lee YH, Shoelson SE, White MFPhosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin actionJ Biol Chem.(2002 Jan 11)
- ^Rice KM, Turnbow MA, Garner CWInsulin stimulates the degradation of IRS-1 in 3T3-L1 adipocytesBiochem Biophys Res Commun.(1993 Feb 15)
- ^Pederson TM, Kramer DL, Rondinone CMSerine/threonine phosphorylation of IRS-1 triggers its degradation: possible regulation by tyrosine phosphorylationDiabetes.(2001 Jan)
- ^O'Connor JC, Freund GGVanadate and rapamycin synergistically enhance insulin-stimulated glucose uptakeMetabolism.(2003 Jun)
- ^Halberstam M, Cohen N, Shlimovich P, Rossetti L, Shamoon HOral vanadyl sulfate improves insulin sensitivity in NIDDM but not in obese nondiabetic subjectsDiabetes.(1996 May)
- ^Jacques-Camarena O, González-Ortiz M, Martínez-Abundis E, López-Madrueño JF, Medina-Santillán REffect of vanadium on insulin sensitivity in patients with impaired glucose toleranceAnn Nutr Metab.(2008)
- ^Cohen N, Halberstam M, Shlimovich P, Chang CJ, Shamoon H, Rossetti LOral vanadyl sulfate improves hepatic and peripheral insulin sensitivity in patients with non-insulin-dependent diabetes mellitusJ Clin Invest.(1995 Jun)
- ^Vanadyl Sulfate Improves Hepatic and Muscle Insulin Sensitivity in Type 2 Diabetes
- ^Smith DM, Pickering RM, Lewith GTA systematic review of vanadium oral supplements for glycaemic control in type 2 diabetes mellitusQJM.(2008 May)