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Altered Ionic Effects of Insulin in Hypertension: Role of Basal Ion Levels in Determining Cellular Responsiveness

Cardiovascular Center, Cornell University Medical Center (M.B., L.M.R.), New York, New York 10021; the Division of Endocrinology/Hypertension, Wayne State University Medical Center (M.B., O.B., M.B., L.M.R.), Detroit, Michigan 48201; and the Department of Physiology, Albert Einstein College of Medicine (R.K.G), Bronx, New York 10463

Address all correspondence and requests for reprints to: L. M. Resnick, M.D., Division of Endocrinology and Hypertension, Wayne State University Medical Center, University Health Center-4H, 4201 St. Antoine, Detroit, Michigan 48201.

	Abstract

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To investigate the ionic actions of insulin in hypertension, ¹⁹F- and ³¹P-nuclear magnetic resonance spectroscopy were used to measure cytosolic free calcium (Ca_i) and intracellular free magnesium (Mg_i) levels in red blood cells from normal (n = 9) and hypertensive (n = 9) subjects before and 30, 60, 120, and 180 min after in vitro incubation with insulin. In hypertensive patients, basal Ca_i levels were significantly higher (30.0 ± 2.2 vs. 19.8 ± 2.5 nmol/L; P < 0.05), and basal Mg_i levels were significantly lower (170 ± 10.9 vs. 209 ± 8 µmol/L; P < 0.05) than in normotensive subjects. In normal cells, insulin significantly elevated Ca_i to 39.8 ± 8.0, 50.1 ± 8.2, 69.3 ± 11.1, and 50.9 ± 13.4 nmol/L at 30, 60, 120, and 180 min and Mg_i to 238 ± 10 264 ± 14, 226 ± 11, and 216 ± 10 µmol/L at 30, 60, 120, and 180 min. In hypertensive subjects, the insulin-dependent Ca_i elevation was blunted, and Mg_i accumulation was completely suppressed. Continuous relationships were observed between basal values of each ion and insulin responses; the greater the Ca_i, the less the Ca_i rose (r = -0.574; P = 0.013), and the lower the Mg_i, the less Mg_i rose (r = 0.524; P = 0.025). Furthermore, a blunting of Mg_i responses to insulin could be reproduced in normal cells that were magnesium depleted by prior treatment either with A23187 in a calcium-free medium or with high glucose concentrations (15 mmol/L). Once again, insulin responsiveness followed basal Mg_i levels (r = 0.637; P < 0.001).

Together, these data demonstrate ionic aspects of insulin resistance in hypertension and suggest that Ca_i and Mg_i levels may regulate cellular responsiveness to insulin. This may help to explain the different vascular actions attributed to insulin in normal compared with insulin-resistant states such as hypertension.

	Introduction

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INSULIN resistance is often present in subjects with hypertension, obesity, and noninsulin-dependent diabetes mellitus (NIDDM); may be quantitatively related to peripheral vascular resistance and blood pressure (1, 2, 3); and is normally defined and measured in terms of altered indices of peripheral glucose utilization (4, 5). However, the mechanism(s) by which vascular consequences might ensue from this defect in glucose metabolism remains unclear, and we have sought to explain these relationships by investigating the potential role of altered steady state intracellular ion concentrations (6). We observed that in essential hypertensive (EH), obese, and/or diabetic subjects, the extent of cardiac hypertrophy, elevated blood pressure, and hyperinsulinemic responses to glucose loading are all closely related to altered steady state intracellular free magnesium (Mg_i), free calcium (Ca_i), and pH (7, 8, 9) levels.

Furthermore, insulin itself has primary direct cellular ionic actions, independent of glucose, to increase Ca_i and Mg_i in peripheral red blood cells, platelets, and vascular smooth muscle cells (10, 11, 12). As increasing Ca_i might promote vasoconstriction, whereas stimulating Mg_i would have an opposite vasodilatory effect, we wondered whether reports of insulin promoting vasoconstriction or vasodilation in different clinical circumstances (13) might result from an imbalance of insulin’s ionic actions. Therefore, in the present study we compared the direct in vitro effects of insulin on Ca_i and Mg_i in red blood cells obtained from normal and hypertensive subjects and in magnesium-depleted cells from normotensive (NT) subjects. Our results document ionic aspects of insulin resistance in hypertension and suggest, more generally, a role for Ca_i and Mg_i in determining cellular insulin responsiveness.

	Subjects and Methods

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After an overnight fast, 20 mL heparinized blood were drawn from NT, otherwise healthy, volunteers (n = 9; four men and five women; mean age, 40 ± 5 yr) and unmedicated, nondiabetic, EH subjects (n = 9; six men and three women; mean age, 46 ± 3 yr) between 0900–1200 h. EH was diagnosed on the basis of blood pressure greater than 150/90 mm Hg measured on three different occasions in the absence of history, physical examination, or laboratory evidence of secondary forms of hypertensive disease. EH subjects were previously either unmedicated or had been off antihypertensive therapy for at least 4 weeks before blood sampling. Other than blood pressure, no age, race, or gender differences were present in EH vs. NT subjects. Blood for each sample was processed, using ³¹P- and ¹⁹F-nuclear magnetic resonance (NMR) techniques as described below, for analysis of Ca_i and Mg_i levels before (basal, 0 min) and 30, 60, 120, and 180 min after the addition of regular human insulin (200 µU/mL, final tube concentration) to isolated cells at 37 C. The dose of 200 µU/mL was chosen according to a dose-response curve showing maximal effects at this concentration (10), which also corresponds to a maximal physiological insulin response. NMR-derived basal ion values were stable for the time course of the experiments.

To investigate whether different insulin responses in cells from EH vs. NT subjects were due to differences in basal cellular ion levels, we also measured ionic responses to insulin in red cells from NT after depleting these cells of Mg_i with either of two treatments (n = 7 for each): 1) A23187 (10 µmol/L) plus ethylenediamine tetraacetate (1 mmol/L) in a calcium-free medium, or 2) an extracellular glucose concentration of 15 mmol/L, which consistently lowers Mg_i and raises Ca_i (14).

³¹P-NMR analysis of Mg_i

As described in detail previously (7, 14), 10 mL heparinized blood were spun at 2000 rpm for 10 min, the plasma was discarded, and the remaining erythrocyte fraction was decanted into a 12-mm NMR tube. ³¹P-NMR spectra were recorded at 81 MHz and 37 C for 30 min on an XL200 spectrometer (Varian Associates, Sunnyvale, CA) in the Fourier transform mode with wide band proton noise decoupling.

Mg_i was determined according to the following equation (15): Mg_i = [K_d (MgATP)] x (^-1 - 1), where K_d (MgATP) is the apparent dissociation constant for the reaction MgATP = Mg²⁺ + ATP (= 0.4 x 10^-5 M under physiological conditions at 37 C and pH 7.2), and = (ATP)_free/(ATP)_total, as determined from the chemical shift difference in the - and ß-phosphoryl group resonances of ATP in the ³¹P-NMR spectrum.

¹⁹F-NMR analysis of Ca_i

Ca_i was determined in by a modification of the method of Levy et al. (16), using the fluorinated, membrane-permeable calcium chelator quin-MF/AM, as previously described (7, 10). Blood (10 mL) was spun at 2000 rpm for 10 min, the plasma was separated, and the packed cells were suspended in 100 mL Hanks’ Balanced Salt Solution buffer (HBSS) with 0.35 g NaHCO₃ to achieve a pH of 7.4. Cells were loaded in a shaking water bath with 20 µmol/L quin-MF/AM for 25 min at 37 C and then spun at 2000 rpm for 10 min. The medium was aspirated, and the cells were resuspended in fresh HBSS together with the subject’s plasma and then incubated at 37 C for 90 min. Cells were recentrifuged, washed again with fresh HBSS together with plasma, and after a final centrifugation were decanted into 10-mm NMR tubes. ¹⁹F-NMR spectra were run on a Varian VXR-500 NMR spectometer operating at 470 MHz at 37 C. Free cytosolic calcium was calculated according to the formula: Ca_i = K_d,app x (Ca-quin-MF)/(quin-MF) (7), where K_d,app is the apparent dissociation constant of Ca²⁺ and quin-MF = 139 nmol/L in red cell hemolysates at 37 C; (Ca-quin-MF)/(quin-MF) was calculated from the ratio of the areas of the quin-MF vs. Ca-quin-MF resonances peaks on the ¹⁹F-NMR spectrum.

Statistical analysis

Data for the responses of each cellular ion species to insulin were analyzed for statistical significance using repeated measures ANOVA and subsequent post-hoc t tests (Super-Anova, Abacus Concepts, Berkeley, CA) for the effects of insulin over time at 0, 30, 60, 120, and 180 min. The relations of insulin-induced changes in Ca_i and Mg_i to the basal Ca_i and Mg_i levels were analyzed by linear regression analysis with Pearson correlation coefficients. The percent change in the response of each ion to insulin was calculated for each subject as the maximal increment from basal levels of both Ca_i and Mg_i. All values are reported as the mean ± SEM.

	Results

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For both NT and EH subjects, Ca_i and Mg_i levels in red cells before and after incubation with insulin are displayed in Figs. 1 and 2. Among NT, Ca_i averaged 19.8 ± 2.5 nmol/L and rose with insulin at 30, 60, 120, and 180 min to 39.8 ± 8.0, 50.1 ± 8.2, 69.3 ± 11.1, and 50.9 ± 13.4 nmol/L, respectively (P < 0.05 at all times vs. 0 min; Fig. 1, top). Basal Mg_i levels in NT were 208.9 ± 8.4 µmol/L and rose with insulin to 238.4 ± 9.74, 264.1 ± 14.5, 225.8 ± 11.3, and 216.2 ± 10.0 µmol/L, respectively, at 30, 60, 120, and 180 min (P < 0.05 at all times vs. 0 min, except 180 min; Fig. 2, top).

View larger version (22K): [in this window] [in a new window]   Figure 1. Cai levels before (basal, 0 min) and 30, 60, 120, and 180 min after the addition of regular human insulin (200 µU/mL) to red blood cells from NT (top panel) and hypertensive (middle panel) subjects. The lower panel shows the insulin-induced change in Cai (Cai) at the listed times compared to that at 0 min in hypertensive (HT) vs. NT subjects.

View larger version (23K): [in this window] [in a new window]   Figure 2. Mgi levels before (basal, 0 min) and 30, 60, 120, and 180 min after the addition of regular human insulin (200 µU/mL) to red blood cells from NT (top panel) and hypertensive (middle panel) subjects. The lower panel shows the insulin-induced change in Mgi (MgI) at the listed times compared to that at 0 min in hypertensive (HT) vs. NT subjects.

The differences between the ionic responsiveness to insulin of EH compared to NT cells were further analyzed by comparing the induced changes in both Ca_i and Mg_i values at each time point (i.e. Ca_i at 30 vs. 0 min, Ca_i at 60 vs. 0 min, etc.; Figs. 1 and 2, lower panel) and by comparing the integrated, area under the curve, total change in Ca_i and Mg_i levels for both NT and EH cells (Fig. 3). Ca_i responses to insulin appeared blunted in the EH vs. NT subjects throughout, although the changes were significantly different only at 60 and 120 min. Similarly, insulin-induced changes in Mg_i values were significantly blunted in cells from EH vs. NT subjects at 30, 60, and 120 min.

View larger version (20K): [in this window] [in a new window]   Figure 3. Integrated, area under the curve maximal responses of Cai (AUC-Cai) and Mgi (AUC-Mgi) to insulin in cells from NT (NlBP) and EH (HiBP) subjects.

View larger version (10K): [in this window] [in a new window]   Figure 4. Ion dependence of cellular insulin responses: relationship between basal Cai values and the maximal calcium response (%Cai) to insulin in both hypertensive and NT subjects (n = 18).

View larger version (11K): [in this window] [in a new window]   Figure 5. Ion dependence of cellular insulin responses: relationship between basal Mgi values and the maximal magnesium response (%Mgi) to insulin in both hypertensive and NT subjects (n = 18).

Insulin added to cells from NT subjects that were depleted of Mg_i displayed a blunted response pattern similar to that observed in cells from EH subjects. Each treatment resulted in equivalent lower preinsulin Mg_i levels (A23187, 161 ± 3 µmol/L; hyperglycemia, 159 ± 5 µmol/L; P < 0.001 for both treatments vs. untreated cells) and resulted in a similar blunting of insulin action on Mg_i [maximum change in Mg_i, 13 ± 2 µmol/L (A23187) vs. 15 ± 3 µmol/L (hyperglycemia); P = NS] compared to those in EH cells (maximum change in Mg_i, 17 ± 6.1 µmol/L; Fig. 6). Once again, for all NT cells, Mg_i responses closely followed basal preinsulin Mg_i (r = 0.637; P < 0.001; Fig. 7).

View larger version (29K): [in this window] [in a new window]   Figure 6. Maximal responses of Mgi (Mgi) after incubation with insulin (Ins-NlBP; 200 µU/mL) in normal cells (n = 7) compared with that in cells from subjects with EH (Ins-HiBP) and after Mgi depletion of normal cells with hyperglycemia (I + Glu; 15 mmol/L; n = 7) or with A23187 (I + A23187; n = 7).

View larger version (14K): [in this window] [in a new window]   Figure 7. Relationship between basal Mgi values and the Mgi responses to insulin in magnesium-replete and magnesium-depleted red blood cells from NT subjects (n = 21).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

As peripheral vasoconstrictor tone is critically dependent on intracellular cation content (17, 18), we wondered to what extent the hypothesized contribution of insulin resistance and hyperinsulinemia to the hypertensive process (19) might be mediated by alterations of insulin’s ionic actions (10) rather than its effects on glucose utilization (5). Our present results suggest that insulin resistance is indeed an ionic phenomenon. Specifically, the effects of insulin on Ca_i and Mg_i levels in cells from EH and NT subjects were significantly different. Thus, in red blood cells from EH subjects, exhibiting elevated basal Ca_i and reduced basal Mg_i values, the ability of insulin to stimulate Ca_i was blunted, and the effect of insulin to stimulate Mg_i levels was completely suppressed. Lastly, depleting Mg_i levels in cells from NT subjects rendered them insulin resistant to an extent similar to that found in cells from EH subjects. These observations not only demonstrate an ionic component to cellular insulin resistance that has not been adequately appreciated, but further suggest that basal alterations in the cellular free divalent cation content in hypertension may at least in part be responsible for the blunted insulin responsiveness observed in these subjects.

That the lower Mg_i and/or elevated Ca_i content reported in hypertensive and diabetic cells (7) may directly cause insulin resistance (6) is also consistent with previous reports in the literature. Thus, fasting insulin levels as well as the endogenous hyperinsulinemic response to oral glucose loading in patients with EH closely follow fasting Mg_i and Ca_i levels (9, 20). The higher the fasting Ca_i and/or the lower the basal Mg_i, the greater the hyperinsulinemia. Conversely, Draznin demonstrated that increasing the Ca_i content produces insulin resistance in adipocytes from normal subjects (21, 22) and inhibits the effect of insulin on glucose transport in isolated adipocytes from NIDDM and obese patients as well (23). Clinically, decreases in Ca_i levels after infusions of the calcium channel antagonist nifedipine were associated with an improved insulin-mediated glucose uptake (24). A reduced magnesium content may also contribute to insulin resistance, as magnesium is important in the regulation of glucose utilization and in the action of the rate-limiting enzymes of glycolysis (25, 26). Using different techniques, Paolisso et al. reported defective insulin-mediated total cellular magnesium accumulation in both EH and NIDDM (27, 28). Alzaid et al. demonstrated a similar blunting of insulin action on circulating magnesium in diabetes (29). Lastly, magnesium depletion may underlie the hypertensive response to dietary fructose loading in rats (30).

Our data, although preliminary, may be clinically significant. First, the demonstration here of ionic aspects of insulin resistance in hypertension helps to explain more directly the link between altered insulin action and vascular disease; increased Ca_i as well as lower Mg_i both cause vasoconstriction and/or frank hypertension (25, 31). Secondly, our data provide circumstantial evidence that the ionic defects described here are a primary lesion, rather than secondary to insulin resistance itself, as 1) the decreased ability of insulin to elevate Ca_i cannot explain the basal elevation of Ca_i characteristic of insulin resistance states such as hypertension, obesity, and NIDDM (7, 31); and 2) inducing Mg_i deficiency in normal cells reproduced the same hypertensive pattern of blunted insulin responses.

Thirdly, the marked dissociation of Mg_i vs. Ca_i responses to insulin in EH suggests that different reported vascular actions of insulin, to constrict or dilate (13), would be the expected outcome of an unopposed elevation of Ca_i in insulin-resistant states such as hypertension, obesity, and NIDDM, promoting vasoconstriction compared to the balanced normal effects of insulin to stimulate both intracellular calcium and magnesium levels (10).

Lastly, we were impressed by the overall relations, independent of diagnostic assignment, between basal cellular ion content and ion responses to insulin. Indeed, as prior magnesium depletion of normal cells rendered these cells insulin ‘resistant’, the property of cellular insulin resistance may not be related to the disease state per se in which it occurs, such as hypertension, as much as to the underlying cellular ionic lesion characteristic of those disease states, including NIDDM and obesity as well as hypertension, in which insulin resistance is known to occur (7, 8). A similar pattern of ion-dependent insulin hyporesponsiveness has also been recently reported by our group in peripheral white cells in pregnant NT and hypertensive subjects (32). Furthermore, basal Mg_i levels in situ in skeletal muscle have been recently reported to predict the rate of extracellular glucose disposal after oral glucose loading (20).

This study also has limitations that should be acknowledged. First, in this in vitro study, we did not assess indices of endogenous glucose and insulin metabolism among the various normal and hypertensive subjects; thus, we cannot comment on the relation of cellular ionic responses to basal insulin and/or insulin to glucose ratios. Second, we have not addressed the mechanism(s) of insulin’s ionic actions in this study. Thus, although no intracellular storage sites for calcium and/or magnesium exist in peripheral red cells, we can only presume that insulin-induced elevations of Mg_i and Ca_i reflect cellular uptake from the extracellular space, rather than altered distribution of these ions intracellularly. The participation of other transduction systems, such as kinases, phosphatases, lipases, cyclic nucleotides, etc., was also not investigated. Lastly, we cannot determine the extent to which this behavior is unique to insulin or to the peripheral red cell. Nevertheless, we consider it a reasonable hypothesis that our results reflect a more general property of cellular ion homeostasis, in which steady state levels of divalent cations regulate cellular responsiveness to a variety of stimuli (33). This latter hypothesis is consistent with enhanced cellular calcium responses to agonist stimulation observed after weight reduction lowered basal cytosolic free calcium levels (34). All of these possibilities need to be addressed by future studies.

Received October 24, 1996.

Revised March 3, 1997.

Accepted March 10, 1997.

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