J Diub Cony,
6:143-249
Scholarly Review
The Role of Magnesium Mellitus A Possible Mechanism Complications
in Diabetes
for the Development
of Diabetic
G. Grafton M. A. Baxter
INTRODUCTION eaths from the acute effects of diabetes mellitus are now relatively rare, however, the long-term complications of diabetes have increasingly become recognized as a major threat to the length and quality of life of the patient with diabetes mellitus. Macroangiopathic complications account for the increased mortality and morbidity from coronary artery, cerebrovascular, and peripheral vascular disease seen in patients with diabetes mellitus when compared with the nondiabetic popu1ation.l Similarly, microangiopathic complications account for the increased incidence of blindness2 and renal failure3 seen in the diabetic population. Microangiopathy is also implicated in the development of neuropathy, a condition commonly seen in patients with diabetes mellitus, which has profound effects on the quality of life.4 Retinopathy, nephropathy, and neuropathy appear to be closely related, and many patients develop more than one of these complications.4 This association has led to speculation that all diabetic complications are a manifestation of one, common, generalized and progressive underlying process.5,6 A number of theories have been proposed to account for the development of diabetic complications. It has been noted that there is a direct relationship between the degree of control
D
Reprint requests to be sent to: Dr. M. A. Baxter, Department of Medicine, Queen Elizabeth Hospital, Birmingham, B15 2HT, England. Department of Medicine, Queen Elizabeth Hospital, Birmingham, England 0 1992 Journal
ofDiabetes
and Its Complications
of the diabetes (i.e., the control of serum glucose concentrations) and the incidence of diabetic complications. As yet, however, a direct causal relationship has not been established.4*7,8 In addition, it has been variously reported that nonenzymatic glycosylation,’ growth hormone and related peptides (e.g., insulinlike growth factor 1 (IGF-1) and growth hormone binding proteins),*O genetic predisposition,‘*-I3 oxidative stress, l4 and inhibition of inositol transport (the polyol theory)*5,16 are all involved in the pathogenesis of diabetic complications. The plethora of hypotheses serves to underlie the fact that no consensus exists on the probable mechanisms underlying the development of diabetic complications, In addition to the commonly quoted theories, a number of interesting observations, which seek to implicate a variety of effecters in the pathogenesis of diabetic complications, have been reported. Currently, many of these observations remain unexplained and unexplored. Perhaps the most notable and interesting of these are the suggestions of a relationship between the diabetic state and the serum and/or intracellular concentrations of various metal ions. Studies*7-21 have reported that diabetes is associated with decreased concentrations of magnesium, zinc, and potassium; however, the most frequent and consistent observation appears to be the correlation between diabetes mellitus and hypomagnesemia. MAGNESIUM
HOMEOSTASIS
Magnesium is an abundant ion and it has been estimated that a 73-kg man contains 1.2 moles (29.2 g) of magnesium that is distributed between the skeleton
144
GRAFTON
AND BAXTER
(65%), the intracellular fluid (34%), and the extracellular fluid (l%).= Serum magnesium concentrations have been shown to be 0.810 ? 0.057 mmol/L (n = 140)17 with approximately one-third bound to protein (approximately 25% to albumin and 8% to globulin).23 It should be stressed that serum magnesium concentrations do not necessarily accurately reflect the total body content of magnesium. The control of magnesium homeostasis appears to be a balance between dietary intake, redistribution between tissues, and renal excretion with no one factor playing a dominant role. Factors influencing urinary magnesium excretion include hypercalcemia, hyperglycemia, increased extracellular volume, diuretics, parathyroid hormone levels, and hypermagnesemia (possibly through suppression of parathyroid hormone (PTH) levels). 22~24~25 PTH is reported to increase the renal tubular reabsorption of magnesium,22 and insulin has been shown to influence the distribution of magnesium by stimulating the active transport of magnesium from the extracellular medium into cells.26,27 Magnesium concentrations may also be affected by calcitonin, glucocorticoids, mineralocorticoids, vitamin D, and thyroid hormones.22
J Diab Camp 1992; 6:2
not yet available, however, the observation that erythrocytes from patients with essential hypertension show a reduced magnesium uptake in response to insulin and that magnesium promotes smooth muscle relaxation may be of significance.37,38 The relationship between hypomagnesemia, hypertension, and the retinal microcirculation has also been investigated. Cohen et a1.39showed that, in patients with high-renin essential hypertension, oral magnesium supplements could completely reverse retinal vasospasm without effecting a change in systemic blood pressure. They commented that the retinal vascular changes seen in hypertensive patients were probably secondary to hypomagnesemia. Hypomagnesemia has also been implicated in the development of ischemic heart disease.38,40,4’ An indirect mechanism linking ischemic heart disease and hypomagnesemia may arise from the association of hypomagnesemia with hypertension; however, circumstantial evidence for an independent role of magnesium in ischemic heart disease has been provided by a study of white South African males that reported an inverse relationship between deaths from ischemic heart disease and the magnesium content of drinking water.42 Similarly, studies have also noted the greater HYPOMAGNESEMIA, INSULIN RESISTANCE, incidence of ischemic heart disease in white, as comHYPERTENSION, AND ISCHEMIC HEART pared with black, Africans.43,44 These workers have DISEASE commented that the higher serum magnesium concentrations seen in blacks may be a protective facInsulin resistance has been reported during treatment tor against the development of ischemic heart for diabetic ketoacidosis and is known to be associated disease. with aging, impaired glucose tolerance, and essential Hypomagnesemia has also been demonstrated in hypertension. 28,29All of these conditions are also aspatients following acute myocardial infarct.45 Several sociated with hypomagnesemia.30 The mechanism by studies have shown that the magnesium content of which hypomagnesemia may induce insulin resisventricular muscle, particularly that which had tance is unknown; however, several studies have reundergone infarction, was significantly lower in paported that lowering magnesium concentrations in- tients who died from myocardial infarction than in duces an increase in erythrocyte plasma membrane those patients who had suffered noncardiac deaths4 microviscosity. It has been suggested that this pheThe possibility that magnesium leaks from infarcted nomenon may impair the interaction of the insulin myocardium is supported by the observation that molecule with its receptor.31 If hypomagnesemia serum concentrations of magnesium rise some 8-11 h prompted a general reduction in insulin-receptor following myocardial infarction.46 It is well reported binding, a state of insulin resistance-with hyperinthat patients with diabetes mellitus have a higher sulinemia-would be generated. mortality following acute myocardial infarction than Significantly lowered serum magnesium concentrathe nondiabetic population.’ The possibility that this tions have been observed in patients with essential is related to myocardial magnesium depletion is suphypertension,32 and one study has reported an in- ported by the report of Laurendeau and DuRuisseau verse correlation between serum magnesium levels who also noted that the intracellular magnesium conand mean arterial blood pressure.33 It has also been centration was very low in heart muscle obtained from demonstrated that infusion of magnesium into hyperdiabetic patients who died with cardiomyopathy.40 tensive patients can produce a transient fall in sys- Further support for the possible adverse effects of hytemic arterial pressure and a more sustained drop in pomagnesemia in myocardial infarction comes from peripheral vascular resistance.34,35 Similarly, magnethe study of Rasmussen et a1.47 which showed that the infusion of magnesium into diabetic patients, folsium deficiency may result in increased peripheral vascular resistance and systemic hypertension.36 A lowing acute myocardial infarction, reduced their mechanistic role for magnesium in hypertension is mortality by 50%.
J Diab Comp 1992; 6:2
HYPOMAGNESEMIA AND DIABETIC COMPLICATIONS Magnesium deficiency can occur acutely during vigorous intravenous rehydration, e.g., therapy for diabetic ketoacidosis. More chronic magnesium deficiency can develop as a consequence of long-standing diabetes and is also seen in starvation, diarrhea, alcoholism, and cirrhosis. Despite these many associations hypomagnesemia had traditionally been regarded as a relatively rare clinical finding.48 In the late 197Os, however, several studies reported significant hypomagnesemia in a large percentage of patients with diabetes mellitus. Typical of these reports was the study of Mather et al. l7 which showed that, compared with control values, 25% of all diabetic patients attending one outpatient clinic over a 4.5-month period had low serum concentrations of magnesium.17 Although it had been reported in earlier studies that, in patients with diabetes mellitus, the degree of hypomagnesemia does not correlate with age, sex, body weight, or ethnic origin17,20,49 (with the exception of black African patients who show no significant hypomagnesemia,50 several recent studies have reported that the degree of hypomagnesemia is inversely related to the level of glycemic contro1.24,51 This observation is supported by Mather et a15’ who reported an inverse relationship between serum glucose and magnesium concentrations in 9 of 14 patients with diabetes mellitus during a study of the diurnal variation of these parameters. The mechanism for the development of hypomagnesemia in diabetes is unknown; however, the correlation of hypomagnesemia with glycemic control and the observation that diabetes is associated with hypermagnesuria20,53 has led to the proposal that glucose inhibits the renal tubular reabsorption of magnesium. McNair et als5* also demonstrated a lowered serum magnesium concentration in patients with diabetes mellitus and noted that the degree of hypomagnesemia was more pronounced in a subgroup of patients who suffered from diabetic retinopathy.54 Furthermore, these workers demonstrated a direct correlation between the degree of hypomagnesemia and the severity of retinopathy and proposed that hypomagnesemia may be an independent risk factor for the development and progression of diabetic retinopathy. The association between retinopathy and hypomagnesemia has been reaffirmed in several independent studies.20,49,54*55 Indirect support for this assertion also came from the study of Erasmus et ale5’ who found no significant hypomagnesemia in black Africans with diabetes mellitus, a population in which there is a low incidence of retinopathy (and coronary artery disease). 5o These workers suggested that the low incidence of retinopathy and coronary artery dis-
MAGNESIUM AND DIABETIC COMPLICATIONS
145
ease was related to the maintenance of normal magnesium levels and further proposed that magnesium may provide protection against the development of diabetic complications. The involvement of hypomagnesemia in the development of retinopathy can also be implied by the study of Cohen et a1.39These workers have shown that the retinal vasospasm, observed in patients with essential hypertension, was related to hypomagnesemia. The implication for the development of retinopathy in a patient with diabetes mellitus particularly in the presence of coexisting hypertension, is clear. The correlation of hypomagnesemia in diabetes mellitus, diabetic microangiopathic complications, hypertension, and ischemic heart disease has led to the speculation that at least some of these conditions may be prevented or alleviated by administration of magnesium. 56,57 The long-term effects of chronic magnesium administration on the development of diabetic complications are currently unknown and require the results of long-term, prospective, randomized, placebo-controlled double-blind trials. Despite the interest in magnesium therapy no tenable hypothesis for the mechanism of action of magnesium in diabetes or associated conditions, has yet been proposed. POSSIBLE MECHANISMS FOR THE ACTION MAGNESIUM
OF
Intracellular magnesium is necessary for the activity of membrane-bound Na + /K+ /ATPase. This enzyme is responsible for the maintenance of the transmembrane concentration gradients of both sodium and potassium and is a potential target enzyme for many hormones and growth factors.58 A reduction in the activity of Na +/K+/ATPase has also been implicated in the development of diabetic complications.15,‘6 It has been argued that magnesium deficiency would lead to decreased activity of Na +/K + /ATPase with implications for those tissues, most notably cardiac muscle and neural tissues, which are dependent on Na+/ K+/ATPase activity for their normal functioning.*’ The hypothesis that magnesium may affect the activity of the Na +/K+/ATPase enzyme is supported by the observation that intracellular hypomagnesemia is often associated with intracellular hypokalemia,ls a consequence of inhibition of Na +/K+/ATPase activity .
It has also been suggested that magnesium may exert its effects on the macrovasculature via changes in serum lipid concentrations. In support of this contention it has been noted that magnesium therapy is associated with a fall in the serum concentrations of both @lipoproteins and cholesterol while a-lipoproteins concentrations are increased.59,60 Nevertheless, direct evidence correlating hypomagnesemia with hyperlipidemia is scant. Indeed, a number of contradic-
146 GRAFTON AND BAXTER
tory studies have shown lowered, raised, or unaltered serum lipid concentrations in response to hypomagnesemia.40 It has also been shown that free fatty acids can bind serum magnesium forming an insoluble magnesium-lipid complex. This observation raises the possibility that hypomagnesemia may be a consequence of hyperlipidemia and not its causes41 Furthermore, hypomagnesemia is known to be a risk factor for the development of diabetic complications even in the absence of elevated serum lipids.17 It would therefore appear that the interaction of magnesium and lipids cannot be the sole explanation for the association of hypomagnesemia and diabetic complications. An increase in the thrombotic tendency of blood is known to be associated with macrovascular disease and myocardial infarcti0n.r Anticoagulants and antiplatelet drugs (e.g., aspirin) are known to confer protection against myocardial infarction and stroke. It is therefore of interest that magnesium has been shown to have antithrombotic activity. Magnesium administration to patients with non-insulin-dependent diabetes mellitus (NIDDM) is reported to decrease the hyperaggregability of platelets that is characteristic of this condition.61 In addition, magnesium appears to have anticoagulant activity, which may result from its antagonism of the effects of calcium on the clotting cascade.40 The antagonism between the activities of magnesium and calcium has also been proposed as a mechanism to explain other observations. In smooth muscle, it is proposed that magnesium competes for calcium-binding sites on the cell membrane thus limiting the availability of calcium to the cell and promoting relaxation of the muscle cells. A fall in the serum magnesium concentration would result in an increased availability of calcium-binding sites on the cell membrane. It is argued that an increase in calcium binding leads to smooth muscle contraction with a consequent rise in vascular tone, peripheral vascular resistance, and systemic blood pressure.38 Although this mechanism may explain the role of magnesium in the development of hypertension, it does not explain the effects of magnesium in all cells and is unlikely to be the mechanism by which specific diabetic complications are generated. POSSIBLE MECHANISMS LINKING HYPOMAGNESEMIA AND DIABETIC COMPLICATIONS Insulin resistance, hyperinsulinemia, hypertension, hyperlipidemia, and an increased thrombotic tendency are recognized as independent risk factors for the development of macrovascular disease. The association of these conditions with non-insulin-dependent diabetes has been recognized previously and has led to the suggestion that the coexistence of these con-
] Diub Comp 1992; 6:2
ditions constitutes a distinct clinical entity, now termed the Reaven-Modan syndrome.28,2g The observation that hypomagnesemia may be independently implicated in the etiology of each of these conditions (see previous discussion) provides a tenable explanation for their association. Hypomagnesemia may therefore underlie the development of macrovascular disease in NIDDM. The possibility that hypomagnesemia may be implicated in the development of the more specific diabetic complications (particularly retinopathy) is also of interest. To date, one of the most attractive theories for the development of diabetic complications is the polyol theory. In brief, the polyol theory suggests that increased activity of the enzyme aldose reductase leads to the intracellular accumulation of sorbitol. Sorbitol inhibits inositol transport leading to a fall in the intracellular concentration of inositol resulting in the inhibition of Na +/K+/ATPase activity. On the basis of data that show that the Na+/K+/ATPase complex requires phosphatidylinositol for its structure and functiorVj2 and that inositol transport in sodium dependent, it has been proposed that inositol transport and Na +/K+ /ATPase activity are functionally linked.15,16 This contention has been supported by the observation that ouabain, an inhibitor of Na + IK + /ATPase activity, also impairs inositol transport.63 It is proposed that a self-perpetuating cycle is generated whereby a reduced rate of inositol transport leads to intracellular inositol depletion and further inhibition of Na+/K+/ATPase activity. It is argued that such a cycle would exacerbate the biochemical abnormalities promoting the development of diabetic complications.15,16 The observation that magnesium is required for Na +/K+/ATPase activity38,40,48 is of some interest in the context of this theory and warrants further study. Despite many attractions, however, the polyol theory remains unproven. Recently, concern about the theory has focused on the lack of experimental evidence supporting the proposed sequence of biochemical abnormalities.64-66 In particular, the proposed interaction between sorbitol and the inositol transporter is based solely on the observation that in rats, aldose reductase inhibitors reduce both neuronal accumulation of sorbitol and depletion of inositol.66 The possibility that another, physiologically important, effector of inositol transport exists has recently been raised following the discovery that magnesium is a positive effector of inositol transport.67 MAGNESIUM
AND INOSITOL
TRANSPORT
The affinity of the inositol transporter for inositol is acutely affected by magnesium over the concentration range O-l.0 mmol/L67 This is of particular interest, as the normal concentration (mean + SD) of serum magnesium is 0.81 + 0.057 mmol/L, whereas in dia-
MAGNESIUM AND DIABETIC COMPLICATIONS
/ Diab Comp 1992; 6:2
betics this value can be as low as 0.5 mmol/L.17 Consideration of the kinetics of inositol transport suggests that at the concentration of magnesium seen in many diabetic patients (and at physiological concentrations of inositol) the rate of inositol transport would be onehalf that seen in nondiabetic, normomagnesemic controls. It is argued that limitation of inositol supply would eventually lead to intracellular inositol depletion.68 The polyol theory suggests that the consequence of intracellular inositol depletion would be impaired activity of certain regulatory proteins thereby altering cellular function, and, in the diabetic state, predispose to the development of diabetic complications. The exact nature of the interaction of the inositol transporter with magnesium is not fully elucidated but the kinetic studies strongly suggest the magnesium is an allosteric effector.This observation presents some problems. Although all tissues are exposed to hypomagnesemia, not all develop diabetic complications. This may reflect the fact that many tissues do not have an active inositol transport system (for example, hepatocytes and skeletal muscle)69,70 and other cells, such as peripheral blood neutrophils have low rates of inositol transport.7’ Presumably, these tissues have reduced inositol requirements and/or are capable of de-novo inositol synthesis and would not be compromised by a reduced rate of inositol supply. Second, a reduction in the rate of inositol transport may only be important in cells that have been stimulated to undergo growth or differentiation.68*7z Diabetes is a condition known to be associated with an elevated concentration of a variety of growth and differentiation factors.9*66 It can be argued that diabetic complications develop in cells promoted to respond to growth factors present as a consequence of the diabetic state, which have a hypomagnesemia-induced inhibition of inositol transport. Such a hypothesis gives a tenable explanation of the disease and tissue specificity of diabetic complications. The data discussed in this review strongly support the view that hypomagnesemia may have an important role in both the development of macrovascular and microvascular disease. The recent observation that magnesium is an effector of inositol transport allows a number of theories concerning the etiology of diabetic complications to be linked together in a single unifying hypothesis. Resolution of the importance of magnesium requires a clinical trial to correlate hypomagnesemia, inositol transport rates, and the incidence of diabetic complications. Nevertheless, this hypothesis provides theoretical support for the studies that are currently evaluating the role of magnesium-supplemented diets as an adjunct to treatment of patients with diabetes.37,61
147
CONCLUSIONS Many theories seek to explain the pathogenesis of diabetic complications, but, as yet, none has provided a complete and satisfactory answer to this problem. The observation that diabetes mellitus is associated with hypomagnesemia is not new but, possibly due to a lack of a convincing mechanistic explanation, has until recently been largely neglected. The recognition that hypomagnesemia is associated with essential hypertension, insulin resistance, hyperinsulinemia, hyperlipidemia, and ischemic heart disease is of interest and may provide mechanistic support for the currently proposed theory that the association of these conditions constitutes a distinct clinical syndrome. The report of the effects of magnesium on inositol transport attempts to correlate data from two distinct lines of clinical research into a single theory for the development of diabetic complications. The suggestion of a link between hypomagnesemia and inositol transport provides a testable hypothesis that may produce new insight into the pathogenesis of diabetic complications. REFERENCES 1.
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59.
Malkiel-Shapiro B, Bersohn I: Magnesium sulphate in coronary thrombosis. BY Med J [Clin Res] 1:292, 1960.
60.
Malkiel-Shapiro B, Bersohn I, Terner PE: Parenteral magnesium sulphate therapy in coronary heart disease. A preliminary report on its clinical and laboratory aspects. Med PYOC2:455-462, 1956.
61.
F’aolisso G, Tirelli A, Coppola L, Verrazzo G, Pizza G,
6:143-249
Scholarly Review
The Role of Magnesium Mellitus A Possible Mechanism Complications
in Diabetes
for the Development
of Diabetic
G. Grafton M. A. Baxter
INTRODUCTION eaths from the acute effects of diabetes mellitus are now relatively rare, however, the long-term complications of diabetes have increasingly become recognized as a major threat to the length and quality of life of the patient with diabetes mellitus. Macroangiopathic complications account for the increased mortality and morbidity from coronary artery, cerebrovascular, and peripheral vascular disease seen in patients with diabetes mellitus when compared with the nondiabetic popu1ation.l Similarly, microangiopathic complications account for the increased incidence of blindness2 and renal failure3 seen in the diabetic population. Microangiopathy is also implicated in the development of neuropathy, a condition commonly seen in patients with diabetes mellitus, which has profound effects on the quality of life.4 Retinopathy, nephropathy, and neuropathy appear to be closely related, and many patients develop more than one of these complications.4 This association has led to speculation that all diabetic complications are a manifestation of one, common, generalized and progressive underlying process.5,6 A number of theories have been proposed to account for the development of diabetic complications. It has been noted that there is a direct relationship between the degree of control
D
Reprint requests to be sent to: Dr. M. A. Baxter, Department of Medicine, Queen Elizabeth Hospital, Birmingham, B15 2HT, England. Department of Medicine, Queen Elizabeth Hospital, Birmingham, England 0 1992 Journal
ofDiabetes
and Its Complications
of the diabetes (i.e., the control of serum glucose concentrations) and the incidence of diabetic complications. As yet, however, a direct causal relationship has not been established.4*7,8 In addition, it has been variously reported that nonenzymatic glycosylation,’ growth hormone and related peptides (e.g., insulinlike growth factor 1 (IGF-1) and growth hormone binding proteins),*O genetic predisposition,‘*-I3 oxidative stress, l4 and inhibition of inositol transport (the polyol theory)*5,16 are all involved in the pathogenesis of diabetic complications. The plethora of hypotheses serves to underlie the fact that no consensus exists on the probable mechanisms underlying the development of diabetic complications, In addition to the commonly quoted theories, a number of interesting observations, which seek to implicate a variety of effecters in the pathogenesis of diabetic complications, have been reported. Currently, many of these observations remain unexplained and unexplored. Perhaps the most notable and interesting of these are the suggestions of a relationship between the diabetic state and the serum and/or intracellular concentrations of various metal ions. Studies*7-21 have reported that diabetes is associated with decreased concentrations of magnesium, zinc, and potassium; however, the most frequent and consistent observation appears to be the correlation between diabetes mellitus and hypomagnesemia. MAGNESIUM
HOMEOSTASIS
Magnesium is an abundant ion and it has been estimated that a 73-kg man contains 1.2 moles (29.2 g) of magnesium that is distributed between the skeleton
144
GRAFTON
AND BAXTER
(65%), the intracellular fluid (34%), and the extracellular fluid (l%).= Serum magnesium concentrations have been shown to be 0.810 ? 0.057 mmol/L (n = 140)17 with approximately one-third bound to protein (approximately 25% to albumin and 8% to globulin).23 It should be stressed that serum magnesium concentrations do not necessarily accurately reflect the total body content of magnesium. The control of magnesium homeostasis appears to be a balance between dietary intake, redistribution between tissues, and renal excretion with no one factor playing a dominant role. Factors influencing urinary magnesium excretion include hypercalcemia, hyperglycemia, increased extracellular volume, diuretics, parathyroid hormone levels, and hypermagnesemia (possibly through suppression of parathyroid hormone (PTH) levels). 22~24~25 PTH is reported to increase the renal tubular reabsorption of magnesium,22 and insulin has been shown to influence the distribution of magnesium by stimulating the active transport of magnesium from the extracellular medium into cells.26,27 Magnesium concentrations may also be affected by calcitonin, glucocorticoids, mineralocorticoids, vitamin D, and thyroid hormones.22
J Diab Camp 1992; 6:2
not yet available, however, the observation that erythrocytes from patients with essential hypertension show a reduced magnesium uptake in response to insulin and that magnesium promotes smooth muscle relaxation may be of significance.37,38 The relationship between hypomagnesemia, hypertension, and the retinal microcirculation has also been investigated. Cohen et a1.39showed that, in patients with high-renin essential hypertension, oral magnesium supplements could completely reverse retinal vasospasm without effecting a change in systemic blood pressure. They commented that the retinal vascular changes seen in hypertensive patients were probably secondary to hypomagnesemia. Hypomagnesemia has also been implicated in the development of ischemic heart disease.38,40,4’ An indirect mechanism linking ischemic heart disease and hypomagnesemia may arise from the association of hypomagnesemia with hypertension; however, circumstantial evidence for an independent role of magnesium in ischemic heart disease has been provided by a study of white South African males that reported an inverse relationship between deaths from ischemic heart disease and the magnesium content of drinking water.42 Similarly, studies have also noted the greater HYPOMAGNESEMIA, INSULIN RESISTANCE, incidence of ischemic heart disease in white, as comHYPERTENSION, AND ISCHEMIC HEART pared with black, Africans.43,44 These workers have DISEASE commented that the higher serum magnesium concentrations seen in blacks may be a protective facInsulin resistance has been reported during treatment tor against the development of ischemic heart for diabetic ketoacidosis and is known to be associated disease. with aging, impaired glucose tolerance, and essential Hypomagnesemia has also been demonstrated in hypertension. 28,29All of these conditions are also aspatients following acute myocardial infarct.45 Several sociated with hypomagnesemia.30 The mechanism by studies have shown that the magnesium content of which hypomagnesemia may induce insulin resisventricular muscle, particularly that which had tance is unknown; however, several studies have reundergone infarction, was significantly lower in paported that lowering magnesium concentrations in- tients who died from myocardial infarction than in duces an increase in erythrocyte plasma membrane those patients who had suffered noncardiac deaths4 microviscosity. It has been suggested that this pheThe possibility that magnesium leaks from infarcted nomenon may impair the interaction of the insulin myocardium is supported by the observation that molecule with its receptor.31 If hypomagnesemia serum concentrations of magnesium rise some 8-11 h prompted a general reduction in insulin-receptor following myocardial infarction.46 It is well reported binding, a state of insulin resistance-with hyperinthat patients with diabetes mellitus have a higher sulinemia-would be generated. mortality following acute myocardial infarction than Significantly lowered serum magnesium concentrathe nondiabetic population.’ The possibility that this tions have been observed in patients with essential is related to myocardial magnesium depletion is suphypertension,32 and one study has reported an in- ported by the report of Laurendeau and DuRuisseau verse correlation between serum magnesium levels who also noted that the intracellular magnesium conand mean arterial blood pressure.33 It has also been centration was very low in heart muscle obtained from demonstrated that infusion of magnesium into hyperdiabetic patients who died with cardiomyopathy.40 tensive patients can produce a transient fall in sys- Further support for the possible adverse effects of hytemic arterial pressure and a more sustained drop in pomagnesemia in myocardial infarction comes from peripheral vascular resistance.34,35 Similarly, magnethe study of Rasmussen et a1.47 which showed that the infusion of magnesium into diabetic patients, folsium deficiency may result in increased peripheral vascular resistance and systemic hypertension.36 A lowing acute myocardial infarction, reduced their mechanistic role for magnesium in hypertension is mortality by 50%.
J Diab Comp 1992; 6:2
HYPOMAGNESEMIA AND DIABETIC COMPLICATIONS Magnesium deficiency can occur acutely during vigorous intravenous rehydration, e.g., therapy for diabetic ketoacidosis. More chronic magnesium deficiency can develop as a consequence of long-standing diabetes and is also seen in starvation, diarrhea, alcoholism, and cirrhosis. Despite these many associations hypomagnesemia had traditionally been regarded as a relatively rare clinical finding.48 In the late 197Os, however, several studies reported significant hypomagnesemia in a large percentage of patients with diabetes mellitus. Typical of these reports was the study of Mather et al. l7 which showed that, compared with control values, 25% of all diabetic patients attending one outpatient clinic over a 4.5-month period had low serum concentrations of magnesium.17 Although it had been reported in earlier studies that, in patients with diabetes mellitus, the degree of hypomagnesemia does not correlate with age, sex, body weight, or ethnic origin17,20,49 (with the exception of black African patients who show no significant hypomagnesemia,50 several recent studies have reported that the degree of hypomagnesemia is inversely related to the level of glycemic contro1.24,51 This observation is supported by Mather et a15’ who reported an inverse relationship between serum glucose and magnesium concentrations in 9 of 14 patients with diabetes mellitus during a study of the diurnal variation of these parameters. The mechanism for the development of hypomagnesemia in diabetes is unknown; however, the correlation of hypomagnesemia with glycemic control and the observation that diabetes is associated with hypermagnesuria20,53 has led to the proposal that glucose inhibits the renal tubular reabsorption of magnesium. McNair et als5* also demonstrated a lowered serum magnesium concentration in patients with diabetes mellitus and noted that the degree of hypomagnesemia was more pronounced in a subgroup of patients who suffered from diabetic retinopathy.54 Furthermore, these workers demonstrated a direct correlation between the degree of hypomagnesemia and the severity of retinopathy and proposed that hypomagnesemia may be an independent risk factor for the development and progression of diabetic retinopathy. The association between retinopathy and hypomagnesemia has been reaffirmed in several independent studies.20,49,54*55 Indirect support for this assertion also came from the study of Erasmus et ale5’ who found no significant hypomagnesemia in black Africans with diabetes mellitus, a population in which there is a low incidence of retinopathy (and coronary artery disease). 5o These workers suggested that the low incidence of retinopathy and coronary artery dis-
MAGNESIUM AND DIABETIC COMPLICATIONS
145
ease was related to the maintenance of normal magnesium levels and further proposed that magnesium may provide protection against the development of diabetic complications. The involvement of hypomagnesemia in the development of retinopathy can also be implied by the study of Cohen et a1.39These workers have shown that the retinal vasospasm, observed in patients with essential hypertension, was related to hypomagnesemia. The implication for the development of retinopathy in a patient with diabetes mellitus particularly in the presence of coexisting hypertension, is clear. The correlation of hypomagnesemia in diabetes mellitus, diabetic microangiopathic complications, hypertension, and ischemic heart disease has led to the speculation that at least some of these conditions may be prevented or alleviated by administration of magnesium. 56,57 The long-term effects of chronic magnesium administration on the development of diabetic complications are currently unknown and require the results of long-term, prospective, randomized, placebo-controlled double-blind trials. Despite the interest in magnesium therapy no tenable hypothesis for the mechanism of action of magnesium in diabetes or associated conditions, has yet been proposed. POSSIBLE MECHANISMS FOR THE ACTION MAGNESIUM
OF
Intracellular magnesium is necessary for the activity of membrane-bound Na + /K+ /ATPase. This enzyme is responsible for the maintenance of the transmembrane concentration gradients of both sodium and potassium and is a potential target enzyme for many hormones and growth factors.58 A reduction in the activity of Na +/K+/ATPase has also been implicated in the development of diabetic complications.15,‘6 It has been argued that magnesium deficiency would lead to decreased activity of Na +/K + /ATPase with implications for those tissues, most notably cardiac muscle and neural tissues, which are dependent on Na+/ K+/ATPase activity for their normal functioning.*’ The hypothesis that magnesium may affect the activity of the Na +/K+/ATPase enzyme is supported by the observation that intracellular hypomagnesemia is often associated with intracellular hypokalemia,ls a consequence of inhibition of Na +/K+/ATPase activity .
It has also been suggested that magnesium may exert its effects on the macrovasculature via changes in serum lipid concentrations. In support of this contention it has been noted that magnesium therapy is associated with a fall in the serum concentrations of both @lipoproteins and cholesterol while a-lipoproteins concentrations are increased.59,60 Nevertheless, direct evidence correlating hypomagnesemia with hyperlipidemia is scant. Indeed, a number of contradic-
146 GRAFTON AND BAXTER
tory studies have shown lowered, raised, or unaltered serum lipid concentrations in response to hypomagnesemia.40 It has also been shown that free fatty acids can bind serum magnesium forming an insoluble magnesium-lipid complex. This observation raises the possibility that hypomagnesemia may be a consequence of hyperlipidemia and not its causes41 Furthermore, hypomagnesemia is known to be a risk factor for the development of diabetic complications even in the absence of elevated serum lipids.17 It would therefore appear that the interaction of magnesium and lipids cannot be the sole explanation for the association of hypomagnesemia and diabetic complications. An increase in the thrombotic tendency of blood is known to be associated with macrovascular disease and myocardial infarcti0n.r Anticoagulants and antiplatelet drugs (e.g., aspirin) are known to confer protection against myocardial infarction and stroke. It is therefore of interest that magnesium has been shown to have antithrombotic activity. Magnesium administration to patients with non-insulin-dependent diabetes mellitus (NIDDM) is reported to decrease the hyperaggregability of platelets that is characteristic of this condition.61 In addition, magnesium appears to have anticoagulant activity, which may result from its antagonism of the effects of calcium on the clotting cascade.40 The antagonism between the activities of magnesium and calcium has also been proposed as a mechanism to explain other observations. In smooth muscle, it is proposed that magnesium competes for calcium-binding sites on the cell membrane thus limiting the availability of calcium to the cell and promoting relaxation of the muscle cells. A fall in the serum magnesium concentration would result in an increased availability of calcium-binding sites on the cell membrane. It is argued that an increase in calcium binding leads to smooth muscle contraction with a consequent rise in vascular tone, peripheral vascular resistance, and systemic blood pressure.38 Although this mechanism may explain the role of magnesium in the development of hypertension, it does not explain the effects of magnesium in all cells and is unlikely to be the mechanism by which specific diabetic complications are generated. POSSIBLE MECHANISMS LINKING HYPOMAGNESEMIA AND DIABETIC COMPLICATIONS Insulin resistance, hyperinsulinemia, hypertension, hyperlipidemia, and an increased thrombotic tendency are recognized as independent risk factors for the development of macrovascular disease. The association of these conditions with non-insulin-dependent diabetes has been recognized previously and has led to the suggestion that the coexistence of these con-
] Diub Comp 1992; 6:2
ditions constitutes a distinct clinical entity, now termed the Reaven-Modan syndrome.28,2g The observation that hypomagnesemia may be independently implicated in the etiology of each of these conditions (see previous discussion) provides a tenable explanation for their association. Hypomagnesemia may therefore underlie the development of macrovascular disease in NIDDM. The possibility that hypomagnesemia may be implicated in the development of the more specific diabetic complications (particularly retinopathy) is also of interest. To date, one of the most attractive theories for the development of diabetic complications is the polyol theory. In brief, the polyol theory suggests that increased activity of the enzyme aldose reductase leads to the intracellular accumulation of sorbitol. Sorbitol inhibits inositol transport leading to a fall in the intracellular concentration of inositol resulting in the inhibition of Na +/K+/ATPase activity. On the basis of data that show that the Na+/K+/ATPase complex requires phosphatidylinositol for its structure and functiorVj2 and that inositol transport in sodium dependent, it has been proposed that inositol transport and Na +/K+ /ATPase activity are functionally linked.15,16 This contention has been supported by the observation that ouabain, an inhibitor of Na + IK + /ATPase activity, also impairs inositol transport.63 It is proposed that a self-perpetuating cycle is generated whereby a reduced rate of inositol transport leads to intracellular inositol depletion and further inhibition of Na+/K+/ATPase activity. It is argued that such a cycle would exacerbate the biochemical abnormalities promoting the development of diabetic complications.15,16 The observation that magnesium is required for Na +/K+/ATPase activity38,40,48 is of some interest in the context of this theory and warrants further study. Despite many attractions, however, the polyol theory remains unproven. Recently, concern about the theory has focused on the lack of experimental evidence supporting the proposed sequence of biochemical abnormalities.64-66 In particular, the proposed interaction between sorbitol and the inositol transporter is based solely on the observation that in rats, aldose reductase inhibitors reduce both neuronal accumulation of sorbitol and depletion of inositol.66 The possibility that another, physiologically important, effector of inositol transport exists has recently been raised following the discovery that magnesium is a positive effector of inositol transport.67 MAGNESIUM
AND INOSITOL
TRANSPORT
The affinity of the inositol transporter for inositol is acutely affected by magnesium over the concentration range O-l.0 mmol/L67 This is of particular interest, as the normal concentration (mean + SD) of serum magnesium is 0.81 + 0.057 mmol/L, whereas in dia-
MAGNESIUM AND DIABETIC COMPLICATIONS
/ Diab Comp 1992; 6:2
betics this value can be as low as 0.5 mmol/L.17 Consideration of the kinetics of inositol transport suggests that at the concentration of magnesium seen in many diabetic patients (and at physiological concentrations of inositol) the rate of inositol transport would be onehalf that seen in nondiabetic, normomagnesemic controls. It is argued that limitation of inositol supply would eventually lead to intracellular inositol depletion.68 The polyol theory suggests that the consequence of intracellular inositol depletion would be impaired activity of certain regulatory proteins thereby altering cellular function, and, in the diabetic state, predispose to the development of diabetic complications. The exact nature of the interaction of the inositol transporter with magnesium is not fully elucidated but the kinetic studies strongly suggest the magnesium is an allosteric effector.This observation presents some problems. Although all tissues are exposed to hypomagnesemia, not all develop diabetic complications. This may reflect the fact that many tissues do not have an active inositol transport system (for example, hepatocytes and skeletal muscle)69,70 and other cells, such as peripheral blood neutrophils have low rates of inositol transport.7’ Presumably, these tissues have reduced inositol requirements and/or are capable of de-novo inositol synthesis and would not be compromised by a reduced rate of inositol supply. Second, a reduction in the rate of inositol transport may only be important in cells that have been stimulated to undergo growth or differentiation.68*7z Diabetes is a condition known to be associated with an elevated concentration of a variety of growth and differentiation factors.9*66 It can be argued that diabetic complications develop in cells promoted to respond to growth factors present as a consequence of the diabetic state, which have a hypomagnesemia-induced inhibition of inositol transport. Such a hypothesis gives a tenable explanation of the disease and tissue specificity of diabetic complications. The data discussed in this review strongly support the view that hypomagnesemia may have an important role in both the development of macrovascular and microvascular disease. The recent observation that magnesium is an effector of inositol transport allows a number of theories concerning the etiology of diabetic complications to be linked together in a single unifying hypothesis. Resolution of the importance of magnesium requires a clinical trial to correlate hypomagnesemia, inositol transport rates, and the incidence of diabetic complications. Nevertheless, this hypothesis provides theoretical support for the studies that are currently evaluating the role of magnesium-supplemented diets as an adjunct to treatment of patients with diabetes.37,61
147
CONCLUSIONS Many theories seek to explain the pathogenesis of diabetic complications, but, as yet, none has provided a complete and satisfactory answer to this problem. The observation that diabetes mellitus is associated with hypomagnesemia is not new but, possibly due to a lack of a convincing mechanistic explanation, has until recently been largely neglected. The recognition that hypomagnesemia is associated with essential hypertension, insulin resistance, hyperinsulinemia, hyperlipidemia, and ischemic heart disease is of interest and may provide mechanistic support for the currently proposed theory that the association of these conditions constitutes a distinct clinical syndrome. The report of the effects of magnesium on inositol transport attempts to correlate data from two distinct lines of clinical research into a single theory for the development of diabetic complications. The suggestion of a link between hypomagnesemia and inositol transport provides a testable hypothesis that may produce new insight into the pathogenesis of diabetic complications. REFERENCES 1.
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