Insulin-Mimetic Action of Vanadate

Abstract

Abstract-The insulin-mimetic effect of vanadate is well established, and vanadate has been shown to improve insulin sensitivity in diabetic rats and humans. Although the exact mechanism(s) remain undefined, we have previously demonstrated a direct relation of intracellular free magnesium (Mg i ) levels to glucose disposal, to insulinemic responses following glucose loading, and to insulin-induced ionic effects. To investigate whether the insulin-mimetic effects of vanadate could similarly be mediated by Mg i , we utilized 31 P-nuclear magnetic resonance spectroscopy to measure Mg i in erythrocytes from normal (NL, nϭ10) and hypertensive (HTN, nϭ12) Key Words: magnesium Ⅲ vanadate Ⅲ insulin Ⅲ nuclear magnetic resonance spectroscopy T he phosphatase inhibitor vanadate is a compound that has insulin-mimetic properties both in vitro and in vivo, and it has been proposed in the treatment of diabetes mellitus. 1 As such, vanadate lowers plasma glucose levels, increases peripheral glucose uptake, and improves insulin sensitivity. 1,2 Depletion of another mineral ion, intracellular free magnesium (Mg i ), is a characteristic feature of insulin resistance in essential hypertension and type 2 diabetes mellitus, but it is not clear to what extent lower Mg i levels contribute to insulin resistance, result from it, or both. Abnormalities of Mg i and cytosolic free calcium (Ca i ) have been closely related to the level of blood pressure, the extent of cardiac hypertrophy, and the degree of insulin resistance present in these clinical states. [3][4][5][6] Our group has proposed that the insulin resistance of hypertension and type 2 diabetes mellitus results, at least in part, from an ionic defect characterized by cellular Mg i deficiency and cellular Ca i accumulation. [5][6][7] We have previously demonstrated a direct relation of Mg i levels to glucose disposal, to insulinemic responses following glucose loading, and to insulin-induced stimulation of Mg i . [5][6][7][8] Conversely, because the ability of insulin-like growth factor I (IGF-I) to improve insulin sensitivity may depend on its stimulation of Mg i , 9 we wondered whether the ability of vanadate to improve insulin action was also linked to cellular magnesium metabolism.We therefore utilized 31 P-nuclear magnetic resonance (NMR) spectroscopic techniques to assess Mg i responses to vanadate compared with insulin in erythrocytes from normotensive and essential hypertensive individuals. Subjects and MethodsTwenty milliliters of venous blood were drawn from unmedicated normotensive (nϭ10, male/femaleϭ5/5) and hypertensive (nϭ12, male/femaleϭ7/5) subjects in the morning (9:00 AM to noon) after an overnight fast. Previous medications were withdrawn for at least 3 weeks; diuretics, for at least 3 months before study. Essential hypertension was diagnosed on the basis of at least 3 blood pressure readings Ͼ150/90 mm Hg in the absence of signs or symptoms of secondary forms of hypertension. A history of myocardial infarction, angina pectoris, or stroke in the last 6 months b...

Magnesium metabolism in type 2 diabetes mellitus, metabolic syndrome and insulin resistance

“…Mg deWciency, which may take the form of a chronic latent Mg deWcit rather than clinical hypomagnesemia, may have clinical importance because of the crucial role of Mg as a cofactor in many enzymatic reactions regulating glucose metabolism. A deWcient Mg status may not just be a secondary consequence of type 2 diabetes but may precedes and cause itself insulin resistance and altered glucose tolerance, and even type 2 diabetes [1,8,29]. We have suggested a role for Mg deWcit as a possible unifying mechanism of the of conditions associated to "insulin resistance", including type 2 diabetes mellitus, metabolic syndrome, essential hypertension [1,53,54] (Fig.…”

“…This glucose-mediated ionic eVects are independent of insulin action, since hyperglycemia induces ionic changes both in VSMC [26], and in red cells [23,24], where glucose transport is unaVected by insulin, and are clinically signiWcant since they occur at glucose concentrations achieved clinically (10 mM), in vivo in subjects with impaired glucose tolerance as well as frank diabetes mellitus. Since hyperglycemia per se signiWcantly contributes to insulin resistance in diabetes mellitus [27] and because reducing Mgi promotes vasoconstriction [28], it is possible to hypothesize a role of this glucose-induced Mg changes in the vasoconstriction present in chronic diabetic states [1,8,29]. The previously reported relations of fasting blood glucose and HbA1c levels (reXective of average glycemic levels over time in diabetic subjects) to cellular ion levels support the clinical signiWcance of these in vitro glucose induced changes [1,30,31], suggesting that circulating glucose concentrations, even within the "normal" range, may be a physiologic determinant of cytosolic Mg concentrations.…”

Does the Micronutrient Molybdenum Have a Role in Gestational Complications and Placental Health?

“…Phosphate and its metal analogues, including molybdate, can inhibit the activity of protein tyrosine phosphatase 1B, which is a prominent negative regulator of insulin and leptin signalling pathways, and may be a molybdoenzyme-independent mechanism of action for the anti-diabetic properties of molybdenum [124,125]. In humans, vanadium was also found to increase intracellular free magnesium levels in erythrocytes in vitro in a similar manner as physiological doses of insulin [126], which may provide an additional pathway through which the chemically similar molybdate anion could change the intracellular environment.…”

“…Furthermore, molybdate, given its unique redox chemistry and circulation in the blood and tissues, may act as a ROS scavenger itself, with molybdenum-based nanoparticles used as ROS scavengers in the literature, though this is speculative [21,22]. Moreover, the anion vanadate, which shares similar chemical geometry with molybdate, has been found to modulate intracellular free metal content [126]. It is possible that molybdate operates in a similar fashion to vanadate in modulating intracellular magnesium, which is a known antioxidant and anti-inflammatory agent.…”

Insulin-like action of novel metformin-containing vanadate as a new antidiabatic drug: Synthesis, characterization and crystal structure of [Metformin-H]2[V2O6] ]·H2O

“…The insulin-like action of vanadate is well known, and has been shown to improve insulin efficiency in diabetic rats and humans [8][9][10][11][12][13][14]. It has also been described that several vanadate oligomers impact enzymes, particularly the decavanadate species, [V 10 O 28 ] 6-, has been found to exhibit unique biological effect not only in vitro but also in vivo [15][16][17].…”