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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 12 4402-4407
Copyright © 1998 by The Endocrine Society

Original Studies

Magnesium Responsiveness to Insulin and Insulin-Like Growth Factor I in Erythrocytes from Normotensive and Hypertensive Subjects

Ligia J. Dominguez, Mario Barbagallo, James R. Sowers and Lawrence M. Resnick

Division of Endocrinology, Metabolism, and Hypertension, Wayne State University (L.J.D., J.R.S., L.M.R.), Detroit, Michigan 48201; and the Institute of Internal Medicine and Geriatrics, University of Palermo (M.B.), 90144 Palermo, Italy

Address all correspondence and requests for reprints to: Prof. Mario Barbagallo, Viale F. Scaduto 6/c, 90144 Palermo, Italy. E-mail: mabar{at}unipa.it


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Depletion of intracellular free magnesium (Mgi) is a characteristic feature of insulin resistance in essential hypertension, but it is not clear to what extent low Mgi levels contribute to insulin resistance, result from it, or both. As insulin-like growth factor I (IGF-I) may improve insulin resistance, we investigated whether this peptide could similarly improve Mgi responsiveness to insulin in hypertension, and whether this effect was related to any direct IGF-I effect on Mgi. 31P-Nuclear magnetic resonance spectroscopy was used to measure Mgi in erythrocytes from 13 fasting normotensive and 10 essential hypertensive subjects before and 30, 60, and 120 min after incubation with a physiologically maximal dose of insulin (200 µU/mL) and with different doses of recombinant human IGF-I (0.1–100 nmol/L).

In normotensive subjects, IGF-I elevated Mgi (P < 0.05) in a dose- and time-dependent fashion, as did insulin (P < 0.05). However, in hypertensive subjects, maximal Mgi responses to insulin, but not to IGF-I, were blunted [insulin, 163 ± 11 to 177 ± 10 µmol/L (P = NS); IGF-I, 164 ± 6 to 190 ± 11.7 µmol/L (P < 0.05)]. Furthermore, for insulin, but not for IGF-I, cellular Mgi responsiveness was closely and directly related to basal Mgi levels (insulin: r = 0.72; P < 0.01; IGF-I: r = 0.18; P = NS). Lastly, blunted Mgi responses to insulin could be reversed by preincubation of hypertensive cells with IGF-I.

We conclude that 1) both IGF-I and insulin stimulate erythrocyte Mgi levels; 2) cellular Mgi responses to insulin, but not to IGF-I, depend on basal Mgi levels, i.e. the higher the Mgi the greater the sensitivity to insulin; and 3) IGF-I potentiates insulin-induced stimulation of Mgi at doses that themselves do not raise Mgi. These effects of IGF-I may underlie at least in part its ability to improve insulin sensitivity clinically. Together, these data support a role for IGF-I in cellular magnesium metabolism and emphasize the importance of magnesium as a determinant of insulin action.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE CLINICAL and epidemiological association between syndromes characterized by insulin resistance, such as essential hypertension, obesity, and noninsulin-dependent diabetes mellitus (NIDDM), is well known (1, 2, 3, 4). Erythrocytes and other cells from subjects with these syndromes display higher cytosolic free calcium levels (Cai), reciprocally lower cytosolic free magnesium (Mgi) levels, altered intracellular pH (pHi), and other ionic abnormalities (5, 6, 7). These abnormalities have, in turn, been closely related to the level of blood pressure (5), the extent of cardiac hypertrophy (8), and the degree of insulin resistance present in these clinical states (6). On the basis of these and other data, our group has proposed an ionic hypothesis in which the above cellular abnormalities explain the association of these syndromes as different clinical manifestations of a common shared ionic defect (9). According to this hypothesis, the insulin resistance of hypertension, obesity, and NIDDM results at least in part from a cellular Mgi deficiency. However, it has been difficult to determine the precise role of the cellular Mg deficit in causing insulin resistance, as this deficit might also be the secondary result of resistance to the direct Mgi-elevating actions of insulin (10, 11).

To help resolve this question, we have begun to investigate the cellular ionic actions of insulin-like growth factor I (IGF-I), a circulating polypeptide with vasoactive (12, 13), growth-promoting, and metabolic properties similar to those of insulin (14, 15). IGF-I can exert its biological action both through specific IGF-I receptors and, because of sequence homology with insulin, through the insulin receptor (16). Acute and long term metabolic effects of human recombinant (rh) IGF-I have been demonstrated in vitro (17) and in vivo (18, 19), including its ability to ameliorate insulin resistance in diabetes (20, 21).

Therefore, using 31P-nuclear magnetic resonance (31P-NMR) spectroscopic techniques, we examined intracellular free magnesium responses to insulin and IGF-I in erythrocytes from normal and essential hypertensive individuals. Our results demonstrate that both IGF-I and insulin stimulate Mgi; that in hypertensive subjects the action of insulin, but not that of IGF-I, is blunted; and that the cellular ionic effects of insulin appear closely linked to basal Mgi levels. These data suggest that the ability of IGF-I to improve insulin sensitivity clinically may be related at least in part to its effect on cellular Mg metabolism.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Twenty milliliters of venous blood were drawn from unmedicated normotensive (NT; n = 13) and hypertensive (HTN; n = 10) subjects in the morning (0900–1200 h) after an overnight fast. The patients included in the study were randomly selected from the outpatient hypertension clinic at Wayne State University (Detroit, MI). Previous medications were withdrawn for at least 3 weeks, and diuretics were withdrawn for at least 3 months before the study. Essential hypertension was previously diagnosed on the basis of a minimum of three blood pressure readings greater than 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. NT subjects were chosen from among laboratory personnel and from among patients found not to have hypertensive disease. Clinical and laboratory characteristics of study subjects are shown in Table 1Go.


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  		Table 1. Clinical and laboratory characteristics of study subjects

 
All blood cell incubations with the two peptides were performed in a water bath maintained at 37 C. Cells from both NT and HTN subjects were incubated in the presence of varying doses of IGF-I (0.1–100 nmol/L), and Mgi concentrations were measured serially over a period of 120 min. The IGF-I dose inducing a maximal Mgi response was then compared with a physiologically maximal dose of insulin (200 µU/mL) (10) in separate experiments.

To study the interaction of IGF-I and insulin effects on Mgi, cells were preincubated with 1 nmol/L IGF-I, a dose at which no binding of IGF-I to insulin receptors occurs (22), for 60 min. Insulin at a physiological maximal dose (200 µU/mL) was added to this system for a further 60 min. Mgi levels at 120 min were measured in tubes containing no hormone (basal), 1 nmol/L IGF-I alone, 200 µU/mL insulin alone, and the combination of both IGF-I and insulin.

31P-NMR analysis of free Mgi and pHi

Erythrocyte Mgi levels were measured according to previously described methods (5, 6). Briefly, blood samples were spun at 2000 rpm for 10 min, and the plasma was discarded. The remaining packed erythrocyte fraction was decanted into a 12-mm NMR tube, and 31P-NMR spectra were recorded at 81 MHz and 37 C with a GE 300-MHz NMR spectrometer in the Fourier transform mode with wide-band proton noise decoupling. As the relative separation between the {alpha}- and ß-phosphoryl group resonances (chemical shift {delta}{alpha}ß) of ATP in a 31P-NMR spectrum depends on the state of ATP complex formation with Mg2+, a comparison of {delta}{alpha}ß for a cell ({delta}{alpha}ßcell) with that for free ATP and the MgATP complex ({delta}{alpha}ßATP and {delta}{alpha}ßMgATP, respectively) allows calculation of the fraction of total ATP that is uncomplexed, i.e. f = (ATP)free/(ATP)total can be calculated as: f = ({delta}{alpha}ßcell - {delta}{alpha}ßMgATP)/({delta}{alpha}ßATP - {delta}{alpha}ßMgATP).

Intracellular free magnesium level concentrations can then be calculated from these NMR spectra and a knowledge of the dissociation constant for the reaction MgATP = Mg2+ + ATP (KdMgATP = 3.8 ± 0.4 x 10-5 mmol/L, at 37 C and pH 7.2), according to the equation: Mgi = KdMgATP (f-1 - 1).

At 37 C and pH 7.2, {delta}{alpha}ßATP and {delta}{alpha}ßMgATP = 0.832 and 8.255 pp, respectively, and KdMgATP = 3.8 ± 0.4 x 10-5 mmol/L (23). Under these conditions, measurements of Mgi levels remain stable for 8–12 h.

Intracellular pH was determined by measuring the chemical shift difference of the 3- and 2-phosphoryl resonances of the 2,3-diphosphoglycerate on the 31P spectra (24). 31P-NMR and the chemical shift difference of the 3- and 2-phosphoryl resonances of 2,3-diphosphoglycerate were plotted against the pH value at which the spectrum was obtained. A titration curve, prepared by analyzing spectra obtained at various known pH values, was linear within the pH range tested and was used to determine the pH of unknowns.

Statistical analyses

The statistical significance of differences in Mgi responses to each hormone treatment vs. basal (no treatment) was estimated by ANOVA, using the 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 using the CRUNCH software package on an IBM-compatible computer. All data are presented as the mean ± SEM. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Basal Mgi values (in micromoles per L) were lower in erythrocytes from HTN compared to erythrocytes from NT subjects (168 ± 7.8 vs. 187 ± 8.8; P < 0.05). IGF-I elevated Mgi in erythrocytes from NT and HTN subjects at a threshold dose of 10 nmol/L (Fig. 1Go). The effect of IGF-I was observed at 60 and 120 min of incubation (P < 0.05 at each time vs. basal; Fig. 2Go). By contrast, insulin-stimulated Mgi levels in cells from NT, but not HTN, subjects (Fig. 2Go). These different Mgi responses to IGF-I vs. insulin in HTN and NT cells were sufficient both for maximal absolute Mgi levels attained and for the change at 30, 60, and 120 min in Mgi (in micromoles per L) from baseline values ({Delta}Mgi for insulin: in NT, 28.9 ± 5.0, 30.0 ± 8.0, and 28.3 ± 2.0; in HTN, 0.2 ± 3.1, 2.8 ± 3.4, and -2.9 ± 3.0; {Delta}Mgi for IGF-I: in NT, 7.1 ± 5.1, 25.5 ± 5.2, and 41.9 ± 5.6; in HTN, 2.0 ± 2.0, 18.8 ± 6.8, and 20.6 ± 7.5). No significant effects of IGF-I or insulin on pHi levels were detected in this in vitro erythrocyte system at any of the times examined (Table 2Go).



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  		Figure 1. Dose-response curve of the effect of IGF-I on erythrocyte 31P-NMR-determined Mgi levels in NT (A) and HTN (B) individuals. Each point represents the mean ± SEM of 13 and 10 subjects, respectively. *, P < 0.05; **, P < 0.01 (vs. basal Mgi levels).

 


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  		Figure 2. Time course of insulin (200 µU/mL; A) and recombinant human IGF-I (100 nmol/L; B) effects on Mgi levels in NT and HTN subjects. *, P < 0.05; **, P < 0.01 (vs. basal Mgi levels).

 

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  		Table 2. Intracellular pH measurements after insulin and IGF-I incubations

 
For all subjects, regardless of diagnostic clinical blood pressure category, the cellular Mgi responsiveness to insulin was closely linked to basal Mgi (r = 0.72; P < 0.01); the lower the basal Mgi level, the more blunted the cell Mgi response (Fig. 3AGo). This was not true for IGF-I, where stimulation of Mgi occurred independently of basal Mgi levels (r = 0.18; P = NS; Fig. 3BGo).



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  		Figure 3. Effects of basal Mgi on insulin-induced (A) and recombinant human IGF-I-induced (B) changes in 31P-NMR-determined Mgi. Insulin-stimulated Mgi was significantly correlated with basal Mgi, whereas the response to IGF-I was independent of basal Mgi.

 
Lastly, using doses of insulin (200 µU/mL) and IGF-I (1 nmol/L) that did not themselves alter Mgi levels individually, a significant rise in Mgi was observed when insulin was added to IGF-I-preincubated cells (Fig. 4Go).



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  		Figure 4. Interaction of recombinant human IGF-I (1 nmol/L) and insulin (200 µmol/L/mL) effects on Mgi in erythrocytes from HTN subjects. *, P < 0.05 (vs. basal Mgi levels).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this investigation we compared insulin’s ionic effects with those of IGF-I, whose effect on Mgi levels has not been previously studied. We observed 1) that insulin at physiologically maximal concentrations, which significantly elevate Mgi levels in cells from NT subjects, failed to elevate Mgi in cells from HTN subjects; 2) that for all subjects, independently of their designation as NT or HTN, Mgi responsiveness to insulin was closely and directly related to basal Mgi levels, i.e. the lower the basal Mgi, the less responsive was the cell to insulin; 3) that IGF-I also stimulates Mgi levels in erythrocytes; and 4) that this effect differs somewhat from that of insulin itself, because IGF-I was equally effective in stimulating Mgi levels in cells from NT and HTN subjects in a manner not dependent on basal Mgi levels, and preincubation of HTN cells with IGF-I partially reversed the blunted Mgi responses to insulin. Together, these results suggest that IGF-I may contribute to regulate Mgi levels, and that IGF-I induced increases in Mgi levels may at least in part explain the previously described ability of IGF-I to enhance tissue insulin sensitivity.

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 (25). The intracellular magnesium deficiency demonstrated in insulin-resistant states such as hypertension and type II diabetes may thus contribute to suppressed glucose metabolism and insulin action (5, 6, 7, 8). Conversely, insulin itself directly stimulates Mgi levels and may contribute to the regulation of Mgi levels (10, 11, 26). Thus, the shift from extra- to intracellular Mg observed in normal individuals after the ingestion of a glucose load was found to be smaller in type II diabetic patients, attributed to insulin resistance associated with NIDDM (27). Furthermore, insulin’s ability to increase levels of Mg was correlated with several parameters of insulin sensitivity (glucose uptake and disposal) and was negatively correlated with basal plasma insulin levels and excess body weight (28). Therefore, it is not clear to what extent the lower free magnesium levels in hypertension or diabetic syndromes (29, 30) directly contribute to insulin resistance, result from it, or both.

The ability of insulin to elevate cellular magnesium levels first reported by Lostroh (31, 32) has been also observed in erythrocytes and platelets (10, 11). Decreased magnesium responsiveness to insulin in cells from subjects with hypertension was demonstrated by measuring total magnesium content with atomic absorption spectroscopy (26, 27) and later by our group by measuring Mgi concentrations by NMR spectroscopy (33). Altered ionic actions of insulin in hypertension were linked with parallel alterations of insulin-mediated glucose uptake (27). These findings have been supported by similar recent studies of magnesium responses to insulin in NIDDM (34). Together, these results extend the concept of insulin resistance to include other, glucose-independent, ionic aspects of insulin action. Furthermore, altered magnesium responses to insulin may not necessarily be related to the hypertension per se, but may more generally reflect altered basal cellular magnesium levels. Indeed, as observed here, not only were insulin-induced changes in magnesium directly proportional to the initial Mgi level, but we have also reported previously that glucose disappearance after oral glucose loading is similarly directly related to basal in situ skeletal muscle Mgi; the lower the Mgi, the slower the fall in extracellular glucose (35). Additionally, depleting normal cells of magnesium also renders them insulin resistant (33). Hence, regardless of whether other primary abnormalities of insulin action exist in syndromes such as hypertension, these observations emphasize the potential contribution of altered cellular Mgi as an independent determinant of insulin action.

Although the effects of IGF-I on Cai in different cellular systems have been investigated, i.e. cardiomyocytes (36), vascular smooth muscle cells (37), and osteoblasts (38), among others, the direct effects of IGF-I on cellular Mg metabolism observed here have not been previously reported. That these effects are independent of insulin is suggested by 1) the dissociation of Mgi responses to insulin vis-à-vis IGF-I stimulation (in fact, for insulin, but not for IGF-I, cellular responsiveness depended on basal Mgi levels); and 2) the ability of IGF-I to improve insulin-induced stimulation of Mgi. These results are consistent with the presence of independent receptors for insulin and IGF-I in erythrocytes (39, 40). The effects on Mgi of IGF-I vis-à-vis insulin also parallel the effects of these two peptides on glucose metabolism. Indeed, similar to our results in cells from HTN subjects, metabolic responses to IGF-I in insulin-resistant diabetic rats were intact compared with impaired insulin-mediated effects on glucose uptake and intracellular glucose metabolism (41).

An interesting question is whether modifications in magnesium or other cation intake may alter basal Mgi levels and therefore change the cellular Mgi responsiveness to insulin. Two studies have demonstrated the ability of Mg supplementation to alter intracellular free Mgi values in NIDDM (42) and essential hypertension (43). Interestingly, in these reports the elevation of intracellular magnesium levels was paralleled with reduced platelet reactivity in response to a thromboxane A2 analog (42) and with decreased blood pressure and intracellular sodium (43). Future studies are needed to confirm the possible beneficial effects of magnesium supplementation on the ionic cellular environment as well as on the clinical manifestations of the associated conditions.

The ability of IGF-I to itself elevate Mgi in NT and HTN subjects may be clinically significant, as it would ameliorate the intracellular Mg deficiency that accompanies insulin-resistant states (6). Recently, IGF-I has been proposed as a therapeutic option in NIDDM and other insulin-resistant states, where it improves hyperglycemia despite an actual decrease in fasting insulin concentrations, suggesting an enhancement of insulin sensitivity (44, 45, 46). This may also be relevant to hypertension, because IGF-I is produced and acts locally in vascular tissue (47). Secondly, the ionic action of IGF-I to stimulate Mgi levels in cells from subjects with hypertension, another insulin-resistant state, not only suggests a mechanism by which IGF-I may improve tissue insulin sensitivity in that state as well, but may also help to explain lower basal Mgi levels observed in, for instance, NIDDM (6) as a reflection of the deficient circulating IGF-I levels found in that disease (48). The present study supports the overall hypothesis that the intracellular ionic milieu is at least one determinant of cellular responsiveness to insulin but not to all hormonal stimuli.

Received December 23, 1997.

Revised July 1, 1998.

Accepted August 18, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals