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

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

Depletion of intracellular free magnesium (Mg_i) is a characteristic feature of insulin resistance in essential hypertension, but it is not clear to what extent low Mg_i 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 Mg_i responsiveness to insulin in hypertension, and whether this effect was related to any direct IGF-I effect on Mg_i. ³¹P-Nuclear magnetic resonance spectroscopy was used to measure Mg_i 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 Mg_i (P < 0.05) in a dose- and time-dependent fashion, as did insulin (P < 0.05). However, in hypertensive subjects, maximal Mg_i 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 Mg_i responsiveness was closely and directly related to basal Mg_i levels (insulin: r = 0.72; P < 0.01; IGF-I: r = 0.18; P = NS). Lastly, blunted Mg_i 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 Mg_i levels; 2) cellular Mg_i responses to insulin, but not to IGF-I, depend on basal Mg_i levels, i.e. the higher the Mg_i the greater the sensitivity to insulin; and 3) IGF-I potentiates insulin-induced stimulation of Mg_i at doses that themselves do not raise Mg_i. 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.

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