Hypertension and abnormal glucose homeostasis

Hypertension Homeostasis

and Abnormal

Glucose

Possible Role of Divalent Ion Metabolism LAWRENCE

M. RESNICK, M.D. hew York,

NW York

Recent epidemiologic and clinical evidence emphasizes the association of hypertension, peripheral insulin resistance, hyperinsulinemia, and/or frank diabetes mellitus. The underlying basis for this clinical association remains unknown, and much attention has been focused on a possible role for hyperinsulinemia in these processes. However, evidence also suggests direct hypotensive effects of insulin. It is therefore unclear to what extent hyperinsulinemia contributes to, rather than merely reflects, these multiple metabolic abnormalities. Recent research links both hypertension and diabetes to common defects in calcium and magnesium metabolism, at least in part described by increased cytosolic free calcium, suppressed intracellular free magnesium, and their associated intracellular and hormonal alterations. Thus, hypertension, peripheral insulin resistance, and hyperinsulinemia may be different clinical manifestations of a common underlying cellular defect in divalent ion metabolism.

he clinical association of abnormal glucose tolerT ance and/or frank diabetes mellitus with hypertension is the focus of increasing attention. Early epidemiologic studies suggested that within normal populations, plasma glucose values one hour after a 50-g oral glucose load were closely related to blood pressure, independent of weight and heart rate [l]. This was confirmed soon thereafter in two English populations-the Wrighthall and Bedford surveys [2]. In the former, positive significant correlations were found between basal blood pressure and the blood sugar level two hours after a 50-g oral glucose load. In the Bedford survey, it was among newly deteeted and borderline diabetic subjects that blood pressure was most significantly elevated [2]. In the Framingham study, the prevalence of hypertension was greater in diabetic than in non-diabetic subjects within the 50- to 79-year-old age range [3]. Similarly in a study by the DuPont Company, Pell and D’Alonzo [4] found that blood pressures were significantly elevated, especially in the pre-clinical stages of diabetes mellitus, when only glucose tolerance was abnormal. This suggested that hypertension may itself predispose subjects to altered glucose tolerance and/or diabetes mellitus [4]. Indeed, hypertension was a predictor for the development of diabetes mellitus in a group of 10,000 men [5]. These epidemiologic studies have been complemented by studies in laboratory hypertensive rat models, and by clinical studies in essential hypertensive subjects, which confirm that altered glucose and insulin metabolism are characteristic of the hypertensive state. Long-term combined sucrose and salt loading in spontaneously hypertensive rats (SHR) but not in normotensive Wistar-Kyoto (WKY) rats significantly potentiated increased blood pressure and heart size, even though each nutrient alone had no effect [6]. An oral glucose challenge given to SHR and WKY rats resulted in a significantly greater insulin response in the SHR rat despite indistinguishable postload glucose values [7]. Furthermore, the ability of exogenously administered insulin to stimulate glucose disposal was decreased in the SHR. These observations suggest the presence of peripheral insulin resistance in this hypertensive animal model [7]. However, at least one recent report suggests the opposite, demonstrating lower ghxcose and insulin responses to intravenous glucose loads in SHR compared with WKY rats, when studied in the unrestrained conscious state

[a.

From the Cardiovascular Center, New York Hospital-Cornell University Medical Center, New York, New York. Requests for reprints should be addressed to Dr. Lawrence M. Resnlck, Cardiovascular Center, New York Hospital-Cornell University Medical Center, 525 East 68th Street, Starr 4, New York, New York 10021.

December

Clinical studies in human hypertension have more uniformly demonstrated alterations of blood pressure linked to impaired glucose metabolism. Verza et al [9] studied hypertension in elderly subjects and observed higher plasma glucose and insulin responses to a standard 75-g oral glucose load among hypertensive com8, 1989

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(11.1)

7 5 i

175(9.71)'

3 ;

150 (8.32)'

140(1004)120(861)-

? loO(717) i ; 3 I ii ab

125 wg3) lOO(5.55)'

80(574)80(574)

75(4.16)'

60(430)60(430)

50 (2.78)'

40(267)SO(267)

25 (1.39)t

20(143)20(143)

-

1

0

60

120

180

0

60

120

180

Time, min

L

Figure 1. Plasma glucose and insulin levels after a 75-g oral glucose load given to hypertensive (solid circles) and normotensive insulin responses were significantly elevated in hypertension (p 4000) Data are from [ll].

pared with normotensive subjects. These results suggested insulin resistance in the hypertensive patients, which was confirmed by glucose clamp studies [9]. Similar results were obtained by Swislocki et al [lo], showing exaggerated glucose and insulin responses to oral glucose loads among middle-aged hypertensive patients, who also had higher steady-state plasma glucose concentrations during an insulin suppression test. Both of these results were indicative of insulin resistance [9,10]. Furthermore, in another study by the same group demonstrating exaggerated plasma glucose and insulin responses to an oral glucose load (Figure l), there was also a significant correlation between systolic and diastolic blood pressure and insulin responses [ll]. Moreover, in a study of high-risk third-trimester pregnant women, 50 percent of the hypertensive subjects had marked hyperinsulinemia after oral glucose ingestion, in contrast to the normotensive pregnant group [12]. Finally, the presence of insulin resistance has been directly addressed via utilization of the euglycemic insulin clamp technique, glucose turnover, and whole body glucose oxidationtechniques by Ferrannini et al (131. Hypertensive subjects were reported to have impaired insulin-induced glucose uptake, which was inversely related to the blood pressure, suggesting that hypertension is an insulin-resistant state [13]. INSULIN AND BLOOD PRESSURE: TOO MUCH OR TOO LlllLE INSULIN ACTION IN HYPERTENSION? Peripheral insulin resistance in subjects who are not frankly diabetic is normally compensated for by increased circulating insulin concentrations. A variety of recent clinical studies have emphasized the association of hyperinsulinemia per se with blood pressure. In the San Antonio heart study, hyperinsulinemia was correlated directly with systolic and diastolic blood pressure in men [14]. Lucas et al [15] reported fasting serum insulin levels to be positively associated with 6A-18s

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(open circles) subjects. Both glucose ar

systolic and diastolic blood pressure in obese women, independent of age, weight, and blood glucose values. Bonora et al [16] found a direct relationship between post-glucose insulin values and systolic and diastolic blood pressure in non-obese, normotensive, and essential hypertensive subjects. As a result of this commonly observed association of insulin resistance and hyperinsulinemia with elevated blood pressure, the question arises-to what extent do peripheral insulin resistance and hyperinsulinemia directly contribute to and/or reflect hypertension? On the basis of epidemiologic studies, Modan et al [17] suggested hyperinsulinemia as a key intermediary in linking obesity, hypertension, and diabetes mellitus. Similarly, Landsberg [la] postulated a role for hyperinsulinemia and the sympathetic nervous system in the development of obesity and hypertension. Most workers who suggest an active role for hyperinsulinemia in the development of hypertension focus on insulin effects on sodium metabolism and specifically, the renal sodium-retaining properties of insulin as described by DeFronzo and colleagues [19]. Indeed, insulin receptors have been mapped throughout the nephron, and the highest concentration of receptors is located in the proximal convoluted tubule [20]. These findings are consistent with increased proximal tubular sodium reabsorption, for which evidence has been presented in both experimental and human essential hypertension [21,22]. These data are also consistent with the increased total body exchangeable sodium present in diabetic patients, especially with co-existent hypertension [23]. Moreover, central volume expansion and saline infusion result in a blunted natriuretie response among diabetic subjects, despite adequate glycemic control. The molecular mechanisms underlying insulin effects on sodium metabolism have also been investigated. A direct effect of insulin on sodium/hydrogen exchange has been demonstrated in vitro in a variety

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of tissues [24,25]. In each instance, insulin increased intracellular pH and intracellular sodium values. Furthermore, in streptozotocin-induced diabetic rats, amiloride-sensitive sodium hydrogen exchange appears to be impaired [26]. In humans, food ingestion or insulin infusion also stimulated (Na+-K+-ATPase) activity in normal subjects [27]. On the other hand, renal stimulation of Na+-K’-ATPase was observed in insulin-deficient, streptozotocin-induced, diabetic rats [28]. Tedde et al [29] have also disputed the notion of direct insulin stimulation of Nat-K+-ATPase and emphasize its action in stimulating Nat, K+, co-transport in erythrocytes. The studies mentioned earlier all suggest that hyperinsulinemia plays a role in linking hypertension and altered glucose metabolism. Although this may seem paradoxical, since the inciting cause for hyperinsulinemia is presumably peripheral insulin resistance, a recent preliminary study in obese adolescents demonstrated a dissociation between the renal and peripheral glucose end organ effects of insulin. Infused insulin decreased urinary sodium excretion despite the presence of peripheral insulin resistance [30]. Hence, (‘too much” sodium and perhaps catecholamine-related insulin actions may predispose subjects to hypertension [311. While a role for hyperinsulinemia in mediating the clinical association of insulin resistance and hypertension is an attractive hypothesis, it is opposed by certain direct observations. At the cellular level, insulin directly blocks calcium currents and shortens calciumdriven action potentials [32]. Indeed, insulin itself may induce frank hypotension in the absence of an adequate, compensatory rise in catecholamine activity [33]. Furthermore, glucose ingestion associated with significant hyperinsulinemia may significantly reduce blood pressure. Conversely, fructose ingestion, which changes insulin concentrations minimally, had no effect on blood pressure 1341. Secondly, insulin may more generally antagonize the cardiovascular actions of circulating catecholamines [35]. Indeed, the wellknown inhibitory effect of insulin on catecholamineinduced lipolysis is associated with a rapid, dosedependent translocation of beta-adrenergic receptors from external to internal cytoplasmic sites [36]. Third, long-term insulin infusions in normal dogs, although causing renal sodium retention, does not change blood pressure [37]. Furthermore, the renal sodium retention often observed in patients with diabetes mellitus may derive from hyperglycemia itself, and thus not be insulin-related. Sodium-linked glucose transport is widely distributed in various tissues 1381, and hyperglycemia alone is sufficient to increase intracellular sodium concentration studied in proximal tubule preparations from streptozotocin-induced diabetic rats [39]. These observations suggest that insulin deficiency and/or “too little effective insulin action” may underlie the predisposition to hypertension among subjects with insulin resistance and/or frank diabetes mellitus.

INSULIN AND DIVALENT CATIONS: NEW INSIGHTS LINKING HYPERTENSION TO GLUCOSE METABOLISM Alterations of cellular and hormonal aspects of calcium metabolism have been reported in hypertension

ON DIABETES AND HYPERTENSION / RESNICK

[40]. Since these same alterations may also affect glucose metabolism and pancreatic insulin secretion [41], it is reasonable to consider whether an ionic basis exists that could help explain the clinical linkage of hypertension and peripheral insulin resistance.

CALCIUM Parallels exist between the calcium metabolic abnormalities present in hypertensive patients and those that characterize diabetes mellitus. Hypercalciuria is present in insulin-deficient streptozotocininduced diabetic rats. In this model, it appears that both increased caloric intake and specific defects in renal tubular calcium reabsorption occur. The loop of Henle as well as the distal nephron appear to be sites at which these latter defects occur [42]. Similarly, normal human subjects demonstrate a consistent hypercalcuric response to oral sucrose loading, in proportion to the induced hyperinsulinemia-the more insulin is stimulated by sucrose, the more urine calcium excretion increases (r = 0.82, p ~0.01) [431 (Figure 2). Diabetic hypercalciuria is also associated with low-normal serum ionized calcium levels, as well as with decreased duodenal calcium transport (44,451. These defects highlight the impaired calcium balance of diabetes, and may help to explain the increased incidence of osteoporosis observed in diabetes mellitus patients [46]. Interestingly, these renal and gastrointestinal defects are also found in hypertension [47]. In keeping with current hypotheses invoking renal glomerular hyperfiltration in the development of both hypertension and diabetic nephropathy, Bank [411 has shown insulin infusion in the presence of calcium reduces the single nephron glomerular filtration rate of diabetic rats to normal levels. Although lower-than-normal circulating levels of 1,25-dihydroxyvitamin D have also been reported in diabetes mellitus patients [48], circulating levels of vitamin D binding protein are abnormally low in diabetic patients and hence, free 1,25-dihydroxyvitamin D may actually be increased [491. Conversely, insulin stimulates the renal 25-hydroxyvitamin D-l alphahydroxylase, and thus, increases renal 1,25-dihydroxyvitamin D production. Since 1,25-dihydroxyvitamin D is now appreciated to increase calcium uptake in both cardiac and vascular smooth muscle, altered circulating levels of 1,25-dihydroxyvitamin D may contribute to the development of some forms of hypertension [50]. This same calcium metabolic “profile”-high 1,25-dihydroxyvitamin D, and low circulating ionized calcium, is characteristic of low renin essential hypertension, the very same form of hypertension most characteristic of the diabetic state [51-531. At the cellular level, insulin was shown by Draznin and colleagues [54] to elevate cytosolic free calcium levels in adipocytes of normal subjects, although this was not confirmed by other workers [55]. Despite the findings by Zierler and Wu [32] that insulin directly decreases calcium currents, in cardiac sareolemmal membranes, insulin stimulated sodium-dependent calcium uptake [56!, providing a possible basis for the positive ionotropic action of insulin, and for the linkage of insulin to sodium-dependent hypertension. Conversely, increased cytosolic free calcium may cause insulin resistance, decreasing insulin-stimulated glucose transport at values greater than 200 to 300 nM

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I

I

50

100

I 150

I

200

SERUM INSULIN (uU/ml) 1

Figure 2. Relation of serum insulin to urinary calcium responses following oral sucrose loading. Data are from [41]

COORDINATE CONTROL OF BP AND INSULIN SENSITIVITY BY Mgi

Mg++-

NO+,

NO+-K+

ATPose,

BP Figure 3. Hypothetical

Insulin sensitivity

relation of both peripheral tissue insulin sensitivity

and blood pressure to intracellular free magnesium levels

[571. Furthermore, verapamil may prevent the insulin resistance induced by long-term glucose and insulin loading of cells in vitro [58]. It thus appears that insulin may directly increase cytosolic free calcium and/or potentiate sodium-dependent calcium uptake, which, in turn, can induce cellular resistance to insulin action. Hence, altered cytosolic free calcium levels rather than hyperinsulinemia per se, may underlie the clinical association of hypertension, obesity, and other peripheral insulin-resistant states. 6A-20s

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MAGNESIUM Although magnesium has received less attention than calcium, its role in both hypertension and in insulin action suggests that it too may be a link between hypertension, peripheral insulin resistance, and frank diabetes mellitus. Paolisso et aZ [59] demonstrated that total red blood cell magnesium levels increase in normal subjects after an oral glucose load. This was also observed during hyperinsulinemic glucose clamp experiments, as well as when insulin was incubated in

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vitro with red blood cells [59]. These authors have since reported that these insulin effects on cellular magnesium uptake are impaired in both hypertensive and in non-insulin-dependent diabetic subjects [60,61]. Thus, the stimulation of Na+-K+-ATPase attributed to insulin may very well be due to the action of magnesium, which within the physiologic range, stimulates this enzyme [62]. Hence, a decrease of insulin action due to either insulin deficiency or peripheral insulin resistance, might decrease intracellular magnesium levels. Indeed, Resnick et al [63] demonstrated decreased levels of intracellular free magnesium in experimental and human hypertension. Levels of intracellular-free magnesium were also linearly and inversely related to the height of the blood pressure. Recently, these authors reported that intracellular free magnesium also appeared to be closely and inversely related to the insulinemic response to oral glucose loads. The lower the free magnesium, the more insulin it took to metabolize the glucose. Since magnesium regulates the activity of all the rate-limiting glycolytic enzymes, they have postulated that the link between peripheral insulin resistance, hyperinsulinemia, and hypertension may, at least in part, be mediated by decreased levels of intracellular free magnesium [64] (Figure 3). It is possible that impaired glucose tolerance and hypertension may be different clinical manifestations of a common underlying mechanism-altered intracellular calcium and/or magnesium metabolism. Under different genetic andlor environmental influences, hypertension or diabetes may predominate clinically, each associated with a predisposition to the other on an intracellular ionic basis.

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ON DIABETES AND HYPERTENSION i RESNICK

18. Landsberg i: Diet, obesity and hypertension: an hypothesis Involving rnsulrn, the sympathetic nervous system, and adaphve thermogenesrs. Q J Med 1986; 61: 1081-1090. 19. DeFronzo RA, Cooke C, Andres R, et a/: The effect of insulin in renal handling of sodium, potassrum, calcium, and phosphate rn men. J Clin Invest 1975; 55: 845-855. 20. Butler D, Vadrot S, Roseau S, Morel F: lnsulrn receptors along the rat nephron [1251j~nsulin binding rn microdrsected glomeruli and tubules. Phugers Arch 1988; 412: 604-612. 21. Brenchi G, Nrutte E, Farrari P, et at A possrble primary role for the kidney in essenbal hypertension. Am J Hypertens 1989; 2: 2S-6S (Part 2). 22. Weder AB: Red cell lrthium countertransport and renal lithium clearance rn hypertenslon. N Engl J Med 1986; 314: 198-201. 23. O’Hare JA, Ferris J, Twomey B, Brady D, Sullivan D: Essential hypertension and hyper tension in diabetic patients wrthout nephropathy. J Hypertens 1983; 1: 200-203. 24. Morrrll GA, Weinstein SP, Kostellow AB, Gupta RK: Studies of insulin actron on the amphibian oocyte plasma membrane using NMR, electrophysrological, and Ion flux technrque. Broth Biophys Acta 1985; 844: 37i-392. 25. Moore RD: The case for Intracellular pH in insulin action. In: Czech MP, ed. Molecular basis of insulin action. New York: Plenum Press, 1985; 145-170. 26. Lagadie-Gossmann D, Chesnais JM, Fewray D, lntracelluar pH regulahon in paprllary muscle cells from streptozotocrn in drabetrc rats: an ron-sensltrve microelectrode study. Pflugers Arch 1988; 412: 613-617. 27. Ng LL, Bruce MA, Hochaday TDR: Leucocyte sodrum pump activity after meals, or insulin in normal and obese subjects: cause for increased energetic efficiency rn obesity? Br Med J 1987; 295: 1369-1373. 28. Khadouri C, Barlet-Bas C, Doucet A: Mechanism of universal increased tubular Na-KATPase durrng streptozotocin-Induced diabetes. Pflugers Arch 1987; 409: 296-301. 29. Tedde R, Sechi LA, Mariglrano A, Scano L, Pala A: in wtroaction of lnsulln on erythrocyte sodrum transport mechanisms: Its possrble role rn the pathogenesrs of arterral hypertension. Clan Exp Hypertens 1988; AlO: 545-559. 30. Rocchini A, Kvesalis D, Moorehead C: Insulin and renal sodium handling in obese adolescents a cause of hypertension (abstr). Hypertension 1987; 10: 358. 31. Reaven GM, Hoffman BB: A role for insulrn in the aetiology and course of hypertension? Lancet 1987; II: 435-436. 32. Zierler K. Wu FS: Insulin acts on Na. K. and Ca currents. Trans Assoc Am Phvs I 1988: 101: 320-3i5. 33. Mathias CJ, daCosta DF, Fosbraey P, Chnstensen NJ, Banrxter R: Hypotensive and sedative effects of insulin in autonomic failure. Br Med J 1987; 295: 161-163. 34. Jansen RWMM. Pentermen BJM. VanLier HJJ. Hoefnazels HL: Blood pressure reduction after oral glucose loadrng and its relation to age, blood pressure, and insuirn. Am J Cardrol 1987; 60: 1087-1091. 35. Alexander WD, Oake RJ: The effect of lnsulln on vascular reactrvrty to noreprnephrrne diabetes. Drabetes 19n; 26: 611-614. 36. Enefeldt P. Helimer J. Wahrenberg H. Armer P: Effects of insulin on adrenoreceotor brndingand the rate of catecholamineyinduced lipolysis in Isolated human fat cells. J Biol Chem 1988; 263: 15553-15560. 37. Hall JE, Coleman TG, Mrzzelle HL: Does chrome hyperinsulrnemla cause hypertension? Am J Hypertens 1989; 2: 171-173. 38. Mierson S, DeSimone SK, Heck GL, DeSimone JA: Sugar-activated ion transport in canine lkngual epithelium. J Gen Physiol 1988; 92: 87-111. 39. Kumar AM, Gupta RK, Spitzer A Intracellular sodium In proxrmal tubules of diabetrc rats, Role of glucose. Kidney Int 1988; 33: 792-797. 40. Resntck LM: Uniformity and drversrty of calcrum metabolism In hypertension: a conceptual framework. Am J Med 1987; 82 (suppl 1B): 16-26. 41. Bank N: Mulhple abnormalitres of calcrum metabolism in insulin-dependent diabetes. J Clin Hypertens 1986; 3: 295-299. 42. Guruprakash GA, Krothapalli RK, Rouse D, Babrno H, Suki W: The mechanism of hypercalcuria in Streptozotocrn-induced diabetic rats. Metabolism 1988; 37: 30631 1 __.. 43. Hall MG, Allen LH: Sucrose ingestion, rnsulrn response, and mineral metabolism in humans. J Nutr 1987; 117: 1229-1233. 44. Fogh-Andersen N: McNain P, Moller-Paterson J, Medsbad S: Serum calcium fractrons In diabetes mellitus. Clin Chem 1982; 28: 2073-2076. 45. Panto JT: Intestinal adaptatron to a dietary calcium deficiency In the diabetic rat. Med SCI Res 1987; 15: 917-918. 46. McNair P, Madsbad S, Christensen MS, et ai Bone mineral loss In Insulrn-treated diabetes mellitus. Acta Endocrinol 1979. 90: 463468. 47. Young EW, Bukoski RD: Calcrum metabolrsm in essenhal hypertension. Proc Sot Exp 8101Med 1988; 187: 123-141. 48. Schneider LE, Schedl HP, McCann T, Hausaler MR: Experrmental drabetes reduces circulating 1,25-drhydroxyvrtamrn D in the rat. Science 1977 196: 1452-1453. 49. Nyomba BL, Bouillon R, VISSUWJ, et a/: Calcrum and bone homeostasls rn diabetic BB rats. Transplant Proc 1986; 18: 1502-1503. 50. Resnlck LM: Calcrum and vitamin D metabolism in the pathophyslology of human hypertension. American Institute of Nutrition Proceedings. Nutritron 1987; 87: 110-l 15. 51. Resnick LM, Laragh JH, Sealey JE, Alderman MH: Drvalent cahons in essentral hypertension. Relations between serum ionized calcium, magnesium, and plasma renrn actrvrty. N Engl .I Med 1983; 309: 888-891. 52. Resnick LM, Muller FB, Laragh JH: Calcium regulatory hormones rn essential hypertensron: relation to plasma renin activity and sodium metabolrsm. Am Intern Med 1986; 105: 649-654. 53. Chrlstlleb AR, Kaldany A, E’Elia JA: Plasma renrn activity and hypertensron in drabetes mellitus. Diabetes 1976; 25: 969-973. 54. Draznin B, Kao M, Sussman KE: lnsul~n and glyburide increase in cytosolrc free calcrum concentration in isolated rat adipocytes. Diabetes 1987; 36: 174-178. 55. Klrp A, Ramlal T: Cytoplasmic calcium during differentiation of 3T3-Ll adipoqtes. Effect of rnsulln and relation to glucose transport J Brol Chem 1987; 262: 9141-9146.

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56. Gupta M, lnnes IR, Dhalla NS: Characterization of insulin receptors in cardiac sarcolemmel and sarcoplasmic retrcular membranes. J Cardiovasc Pharmacol 1987; 10: 259267. 57. Draznin 6, Sussman K, Kao M, Lewis D, Sherman N: The existence of an optional range of cytosolic free calcium for insulin-stimulated glucose transport in rat adrpocyies. J Biol Chem 1987; 262: 14385-14388. 58. Draznin B, Sussman KE, Eckel R, Kao M, Yost T, Sherman NA: Possible role of cytosolrc free calcium concentration in mediating insulin resistance of obesity and hyperinsulinemia. J Clin Invest 1988; 82: 1848-1852. 59. Paolisso G, Szambato S, Passeriello N, et a/: Insulin induces opposite changes in plasma and erythrocyte magnesium concentratrons in normal men. Diabetologia 1986; 29: 644-647.

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60. Paolisso G, Passerrello N, Sgembato JS, ei a/: Impaired Insulin-mediated erythrocyte magnesium accumulation in essential hypertension. Clin Sci 1987; 73: 535-539. 61. Paolisso G, Sgambato S, Giugliano D, ef a/: lmparred rnsulrn-induced erythrocyte mag nesium accumulation is correlated to impaired insulin-mediated glucose disposal in type 2 (non-Insulin-dependent) diabetic patients. Diabetologia 1988; 31: 910-915. 62. Fischer PWF, Giroux A: Effects of dretary magnesrum on sodium-potassium pump action in the heart of rats. J Nutr 1987; 117: 2091-2095. 63. Resnick LM, Gupta RK, Laragh JH: Intracellular free magnesium in erythrocyte of essential hypertension. Proc Nat1 Acad Sci USA 1984; 81: 6511-6515. 64. Resnick LM, Gupta RK, Gruenspan H, Laragh JH: Intracellular free magnesium in hypertension: relation to peripheral insulin resistance and obesity (abstr). Clin Res 1988; 36: 431A.

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