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Hypertension. 2001;38:701-704
doi: 10.1161/hy09t1.095392
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(Hypertension. 2001;38:701.)
© 2001 American Heart Association, Inc.

Obesity- and Diabetes-Related Hypertension

Insulin-Mimetic Action of Vanadate

Role of Intracellular Magnesium

Mario Barbagallo; Ligia J. Dominguez; Lawrence M. Resnick

Institute of Internal Medicine and Geriatrics, University of Palermo (M.B., L.J.D.), Italy; and Hypertension Center, Cornell University Medical School (L.M.R.), New York, NY.

Correspondence to: Mario Barbagallo, MD, Professor of Medicine, Head of Geriatric Medicine, University of Palermo, Via F. Scaduto 6/c, Palermo, Italy. E-mail: mabar{at}unipa.it

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 (Mgi) 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 Mgi, we utilized 31P-nuclear magnetic resonance spectroscopy to measure Mgi in erythrocytes from normal (NL, n=10) and hypertensive (HTN, n=12) subjects, before and after incubation with insulin and with different doses of sodium vanadate. In NL, vanadate elevated Mgi levels, with maximum efficacy at 50 7mgr;mol/L (186±6 to 222±6 7mgr;mol/L, P>0.01), as did physiologically maximal doses of insulin, 200 7mgr;U/mL (185±6 to 222±8 7mgr;mol/L, P<0.01). In HTN, only vanadate, but not insulin, increased Mgi (insulin: 173±7 to 180±9 7mgr;mol/L, P=NS; vanadate: 170±7 to 208±10 7mgr;mol/L, P<0.01). Mgi responses to insulin (r=0.637, P<0.001), but not to vanadate (r=0.15, P=NS), were closely and directly related to basal Mgi levels. We conclude that (1) both vanadate and insulin stimulate erythrocyte Mgi levels; (2) cellular Mgi responses to insulin, but not to vanadate, depend on basal Mgi content—the lower the basal Mgi, the less the Mgi response to insulin. As such, (3) Mgi responses to vanadate were equivalent among HTN and NL, whereas HTN cells exhibited blunted Mgi responses to insulin, and (4) the ability of vanadate to improve insulin sensitivity clinically may be mediated, at least in part, by its ability to increase Mgi levels, which in turn, helps to determine cellular insulin action.


Key Words: magnesium • vanadate • insulin • nuclear magnetic resonance spectroscopy

The 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 (Mgi), is a characteristic feature of insulin resistance in essential hypertension and type 2 diabetes mellitus, but it is not clear to what extent lower Mgi levels contribute to insulin resistance, result from it, or both. Abnormalities of Mgi and cytosolic free calcium (Cai) 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.3–6 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 Mgi deficiency and cellular Cai accumulation.5–7 We have previously demonstrated a direct relation of Mgi levels to glucose disposal, to insulinemic responses following glucose loading, and to insulin-induced stimulation of Mgi.5–8 Conversely, because the ability of insulin-like growth factor I (IGF-I) to improve insulin sensitivity may depend on its stimulation of Mgi,9 we wondered whether the ability of vanadate to improve insulin action was also linked to cellular magnesium metabolism.

We therefore utilized 31P-nuclear magnetic resonance (NMR) spectroscopic techniques to assess Mgi responses to vanadate compared with insulin in erythrocytes from normotensive and essential hypertensive individuals.

Subjects and Methods

Twenty milliliters of venous blood were drawn from unmedicated normotensive (n=10, male/female=5/5) and hypertensive (n=12, male/female=7/5) 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 >150/90 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 before the study, as well as renal or hepatic failure, excluded the subject from consideration.

Cells from both normotensive and hypertensive subjects were incubated in the presence of varying doses of vanadate (1 to 1000 7mgr;mol/L) in a water bath maintained at 37°C, and Mgi concentrations were measured serially over a period of 180 minutes. The vanadate dose inducing a maximal Mgi response (50 7mgr;mol/L) was then compared with a physiologically maximal dose of insulin (200 mU/mL)7 in separate experiments. Vanadate or insulin was directly added to the packed cells after centrifugation, immediately before the NMR measurement (see below). In another series of experiments (n=8), vanadate (50 7mgr;mol/L) was added to the hypertensive cells after 60 minutes incubation with insulin (200 mU/mL). Insulin and vanadate actions on Mgi were also tested, in cells from normotensive individuals, in the presence of a tyrosine kinase inhibitor (genistein, 100 7mgr;mol/L), and of a protein kinase inhibitor (staurosporin, 1 7mgr;mol/L).

31P-NMR Analysis of Mgi
Erythrocyte Mgi was measured according to a previously described method.3 Briefly, heparinized blood was centrifuged at 2000 rpm for 10 minutes, and the plasma was discarded. The remaining packed erythrocyte fraction was decanted into a 12-mm NMR tube, and after addition of vanadate or insulin, 31P-NMR spectra were recorded at 81 MHz at 37°C with a GE 300-MHz NMR spectrometer in the Fourier transform mode with wide-band proton noise decoupling. Mgi levels were determined according to the formula Mgi=Kd(MgATP)x[{Phi}-1-1], where {Phi}, the free, unbound fraction of ATP, is calculated from the chemical shift differences of the {alpha}- and ß-phosphoryl resonances of ATP in the 31P-NMR spectrum, and Kd(MgATP)=38 7mgr;mol/L at 37°C.

Statistical Analyses
The statistical significance of differences in Mgi responses to each hormone treatment versus basal (no treatment) was estimated by ANOVA, using appropriate post-hoc t test for multiple comparisons. The relations between measured variables were assessed by linear regression analysis and Pearson correlation coefficients. Statistical tests were performed with the CRUNCH software package on an IBM-compatible PC. All data are presented as mean±SEM.

Results

Basal Mgi levels were lower in erythrocytes from essential hypertensives compared with normotensive subjects (186±6 versus 171±7 7mgr;mol/L, P<0.05). In dose-response experiments, vanadate elevated Mgi in erythrocytes from normotensive and hypertensive subjects at a threshold dose of 15 7mgr;mol/L, and a maximal effect was observed at 50 7mgr;mol/L (Figure 1). In the time course experiments, the effect of vanadate was observed at 30 minutes and peaked at 60 minutes of incubation both in normotensive subjects and in hypertensive subjects (P<0.05 at each time versus basal) (Figure 2).



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  		Figure 1. Dose-response curve of the effect of vanadate (1 to 1000 nmol/L) on erythrocyte 31P-NMR–determined Mgi levels in normotensive individuals. Each point represents the mean±SEM of 10 subjects.*P<0.05, **P<0.01 vs basal Mgi levels.



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  		Figure 2. Time-course of vanadate (50 nmol/L) effects on Mgi levels in normotensive (A) and essential hypertensive (B) subjects. C, {Delta}Mgi at each time point, showing no different effect of vanadate in normotensive and hypertensive subjects *P<0.05.

In contrast, insulin’s effect to stimulate Mgi levels was present in cells from normotensive subjects but not in cells from hypertensive subjects (Figure 3). Vanadate (50 7mgr;mol/L) also significantly increased Mgi in insulin-treated cells from hypertensive subjects, in whom insulin alone (200 mU/mL) did not alter Mgi levels (basal Mgi: 176±8 7mgr;mol/L; Mgi after addition of insulin: 182±9 7mgr;mol/L, P=NS; Mgi after sequential addition of vanadate: 203±8 7mgr;mol/L, P<0.05). In cells from normal subjects, staurosporin or genistein inhibited the insulin-induced Mgi increase (from 179.8±1.3 to 180.9±1.6 7mgr;mol/L, P=NS, n=6) but did not alter the ability of vanadate to stimulate Mgi (from 177.0±1.5 to 210.0±3.9 7mgr;mol/L, P<0.001, n=6).



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  		Figure 3. Time-course of insulin (200 mU/mL) effects on Mgi levels in normotensive (A) and essential hypertensive (B) subjects. C, {Delta} Mgi at each time point, showing a blunted effect of insulin in hypertensive subjects *P<0.05 vs basal Mgi levels.

The different Mgi responses to vanadate versus insulin in hypertensive versus normotensive cells were true both for maximal absolute Mgi levels attained and for the change in Mgi from baseline values. For all subjects, regardless of diagnostic clinical blood pressure category, the cellular Mgi responsiveness to insulin was closely linked to basal Mgi (r=0.637, P<0.01): the lower the basal Mgi level, the more blunted the cell Mgi response (Figure 4A). This was not true for vanadate, for which stimulation of Mgi occurred independently of basal Mgi levels in normotensive and hypertensive subjects (r=0.15, P=NS) (Figure 4B).



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  		Figure 4. Effects of basal Mgi on insulin-induced (A) and vanadate-induced (B) changes in 31P-NMR–determined Mgi. Insulin-stimulated Mgi was significantly correlated with basal Mgi, whereas the response to vanadate was independent of basal Mgi.

Discussion

Magnesium, the second most abundant intracellular cation, is involved in a number of important biochemical reactions, including all ATP transfer reactions. Possibly because of its relevance to all protein kinases, magnesium appears to mediate hormonal as well as other biochemical aspects of cellular glucose utilization.10 The Mgi deficiency that has been demonstrated in insulin-resistant states such as hypertension and type 2 diabetes may thus contribute to suppressed glucose metabolism and insulin action.6,7,11

The insulin-mimetic action of vanadate on glucose homeostasis and peripheral tissues has been well established both in vitro and in vivo.1,2,12–16 In animal models of diabetes, vanadate treatment decreases hyperglycemia and insulin levels and improves tolerance to oral glucose.15 In humans, vanadate increases nonoxidative glucose disposal, as measured by indirect calorimetry, and decreases insulin requirements in diabetic patients, suggesting that it may have a potential role as adjunctive therapy in patients with diabetes mellitus.12

Our approach here was to compare the ionic effects of insulin with those of vanadate, the effect of which on Mgi levels has not previously been studied. We observed that (1) insulin at physiologically maximal concentrations significantly elevates Mgi levels in cells from normotensive subjects, but not in cells from hypertensive subjects; (2) for all subjects, independently of their designation as normotensive or hypertensive, Mgi responsiveness to insulin was closely and directly related to basal Mgi levels—the lower the basal Mgi, the less responsive was the cell to insulin; (3) vanadate also stimulates Mgi levels in erythrocytes; and (4) this vanadate effect differs somewhat from that of insulin itself, because (a) vanadate was equally effective in stimulating Mgi levels in cells from normotensive and hypertensive subjects, in a manner not dependent on basal Mgi levels, and (b) incubation of insulin-treated hypertensive cells with vanadate significantly stimulated Mgi.

The NMR techniques we used here possess certain advantages, including greater precision and reproducibility, and preserving conditions that closely represent the in situ extracellular environment. However, our data obtained in red blood cells need to be confirmed in other tissues, such as vascular smooth muscle.

Although other ionic actions of vanadate in erythrocytes have previously been demonstrated, vanadate increasing Cai,17,18 the direct effect of vanadate on cellular magnesium metabolism observed here has not been previously reported. That these effects are independent of insulin is suggested by (1) the dissociation of Mgi responses to insulin vis-á-vis vanadate stimulation. In fact, for insulin, but not for vanadate, cellular responsiveness depended on basal Mgi levels and (2) the ability of vanadate to improve insulin-induced stimulation of Mgi.

Although our present experiments cannot fully elucidate the causal mechanism(s) involved, the Mgi effects of vanadate vis-á-vis insulin suggest different mechanisms (and/or sites of action) of Mgi stimulation by vanadate and insulin. Our present results are in agreement with data in the literature that show vanadate does not alter basal and insulin-stimulated receptor kinase activities,19 suggesting that the corrective effect of vanadate on magnesium and glucose metabolism may be distal to insulin receptor kinase activity, which is a magnesium-dependent enzyme.13,19 Interestingly, the phosphatases that are inhibited by vanadate are all magnesium independent. We suggest, therefore, that the magnesium dependency of insulin-dependent kinases may account for the blunting of insulin action in magnesium-depleted cells (Figures 3 and Figure 4A) and may also explain the dissociation of vanadate action from cellular magnesium content (Figure 4B). This is also supported by the experiments with the kinase inhibitors genistein and staurosporin, which inhibited the magnesium-stimulating actiSon of insulin but not of vanadate. Thus, the ability of vanadate to itself elevate Mgi in normotensive and hypertensive subjects may be clinically significant and may account at least in part for its ability to improve insulin sensitivity.6,11 By increasing Mgi, vanadate would offset the decreased Mg-dependent, insulin-stimulated phosphorylation of signaling peptides present in insulin resistance and thereby improve glucose transport.

Other reported effects of vanadate also need to be considered. In vitro incubation with vanadate at concentrations ranging from 20 to 80 7mgr;mol/L may increase smooth muscle contractility,20–26 and acute administration of vanadium compounds is known to elevate blood pressure.27–28 In support of these findings, in vitro incubation with vanadate was shown to increase Cai in rat aortic smooth muscle cells with an EC50 value of {approx}42 7mgr;mol/L,29 and vanadate may increase tension in rat aortic strips.24 However, vanadate (in 40 to 80 7mgr;mol/L range) may also promote endothelium-dependent vasodilation,30 may reduce systolic blood pressure in spontaneously hypertensive rats31 and may also ameliorate the exaggerated vasoconstriction in aortic tissue from the hyperinsulinemic/insulin-resistant obese Zucker rat.32 McNeill and coworkers31,33,34 have shown that long-term vanadium treatment of insulin-resistant/diabetic rats led to reduction in BP, perhaps related to normalization of metabolic alterations in the insulin-resistant and diabetic state by vanadium compounds. The changes in erythrocyte Mgi levels may be intimately linked to changes in erythrocyte Cai levels.35 In addition to alterations in Cai levels via activation of PLC-{gamma} and as a result of protein tyrosine phosphatase inhibition, via increased tyrosine kinase activity, vanadate at concentration ranges used in this study (50 7mgr;mol/L) could also affect sodium-pump activity.36 Finally, vanadate may promote hemolysis at high concentrations, and this may account for the low Mgi values seen at high vanadate concentrations (Figure 1).37

Altogether, the present study supports the overall hypothesis that the intracellular ionic milieu is at least 1 determinant of cellular responsiveness to insulin, and that vanadate alters Mgi homeostasis. Future studies are needed to elucidate in greater mechanistic detail how vanadate action on cellular magnesium metabolism contributes to its insulin-mimetic and/or vascular actions.

Received March 28, 2001; accepted June 28, 2001.

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