Diabetes Treatments

The term diabetes mellitus, derived from the Greek words Diabetes Mellitus and. Magnesium ficiency and diabetes mellitus will be reviewed with …

Diabetes Mellitus and Magnesium: Unlikely Partners

This continuing education program was made possible by an unrestricted educational grant from Geist Pharmaceuticals, LLC and is approved for 1 contact hour 01 CEU of continuing pharmaceutical education credit and 1 hour in AMA PRA Category 1 continuing medical education credit

DIABETES MELLITUS DIABETES

Mg

More copies of this home study module are available to health-care professionals by contacting the Department of Continuing Education at the Massachusetts College of Pharmacy and Health Sciences: 617-732-2081 phone ce@mcpedu email The opinions in this publication represent those of the authors and do not necessarily reflect the opinions of the Massachusetts College of Pharmacy and Health Sciences and Boston University School of Medicine Copyright 2000 MCPHS All rights reserved

Introduction
Scientists and clinicians are becoming increasingly aware of the critical role magnesium plays in diabetes mellitus DM A deficiency of this mineral, which is involved in more than 300 enzymatic reactions throughout the body, would be expected to negatively impact essential biochemical processes Insulin secretion and action, for example,
depend on adequate cellular magnesium Polyuria–a characteristic of the hyperglycemic state of DM– results in a significant amount of magnesium being excreted in the urine, leading to total-body magnesium deficiency Experimental and clinical studies have demonstrated significant associations between decreased magnesium levels and increased insulin resistance as well as increased severity of DM complications Magnesium supplementation can be an effective, safe and inexpensive way to insure adequate magnesium status for DM patients The term diabetes mellitus, derived from the Greek words meaning siphon and sweet, refers to a group of metabolic disorders characterized by elevated blood glucose resulting from inadequate insulin secretion or insulin action In some cases the primary defect is the synthesis, release or action of insulin; in other instances a metabolic defect beyond insulin is responsible The chronic hyperglycemia that results may eventually lead to dysfunction, damage and eventual failure of various organ systems, especially the heart, kidneys, blood vessels, nerves and eyes Because the primary symptoms typically include polyuria, polydipsia and polyphagia, the early
descriptions of DM referred to this disease as the great pissing evil Secondary symptoms associated with a defect in glucose homeostasis include fatigue, susceptibility to infections, impaired growth and blurred vision Although most health care providers primarily associate DM with abnormal carbohydrate metabolism, protein and lipid metabolism are also adversely affected by the inadequate insulin secretion or decreased tissue responsiveness to insulin insulin resistance The tissue damage that results from glycosylation of various proteins and the accumulation of polyols produced from chronically elevated glucose levels are believed to contribute to the

3

Mg Diabetes Mellitus and Magnesium: Unlikely Partners

early development of atherosclerosis, cataracts, cerebrovascular disease and neuropathies DMs long-term microvascular and macrovascular complications account for the tremendous morbidity and resultant health care costs associated with DM patient care In the United States it has been estimated that more than 16 million people 59 of the population have one of the various forms of DM, and of these individuals approximately one-third are unaware that they have the disease Men and
women appear to be equally affected; however, minority groups such as African Americans, Asians and Latinos have a disproportionately higher rate of DM1 In 1997, the costs associated with DM in the United States were approximately 100 billion The direct health care costs were 44 billion, a value that represented approximately 6 of the total annual health care expenditures Lost productivity in school and at work accounted for an additional 54 billion of indirect costs In the year 2000, the costs associated with DM continue to escalate

Diabetes Mellitus and Magnesium: Unlikely Partners
Classifications of Diabetes Mellitus
Recently the American Diabetes Association, delineated DM into categories including 2 type 1, type 2, gestational and several others Type 1 DM is typically a result of an autoimmune-mediated process in which pancreatic beta-cells in the Islets of Langerhans are destroyed resulting in little if any insulin production Previously, this form of DM was called juvenile-onset or insulin-dependent DM IDDM The most prevalent form of DM is type 2, previously called maturity-onset or non-insulin-dependent DM NIDDM, and is generally characterized by insulin resistance Although
type 2 DM may be associated with some degree of an insulin secretion defect, patients are often overweight and do not usually have evidence of circulating autoantibodies against the pancreatic beta-cells Other forms of DM include gestational, iatrogenic eg, corticosteroids, thiazides, thyroid hormone, betaadrenoceptor blockers, endocrinologic eg, acromegaly, Cushings disease, glucagonoma, hyperthyroidism, pheochromocytoma and many specific genetic defects of beta-cell function or insulin action

Diabetes Mellitus and Magnesium: Unlikely Partners
Timothy J Maher, PhD Sawyer Professor of Pharmaceutical Sciences Dean, Research and Sponsored Programs Professor of Pharmacology, Massachusetts College of Pharmacy and Health Sciences Robert M Levin, MD Associate Professor of Medicine, Section of Endocrinology, Nutrition and Diabetes, Boston Medical Center Program Director, Continuing Medical Education Boston University School of Medicine

Target Audience
Pharmacists, Primary Care Physicians, Physician Assistants, Nurse Practitioners and other healthcare providers

Educational Needs Addressed Diabetes Mellitus and Magnesium
Disorders of mineral metabolism are among the less well-understood
clinical problems encountered by clinicians, and magnesium deficiency leads that list Magnesium is one of the most important minerals in the body It serves as a co-factor in more than 300 bodily reactions A deficiency of magnesium may lead to a number of serious consequences, such as hypocalcemia, hypokalemia, hyponatremia, and life-threatening arrhythmias This module is intended to update the reader on the causes of magnesium deficiency, how to prevent the disorder, and how to replace deficits in a safe and effective fashion The association of magnesium deficiency and diabetes mellitus will be reviewed with specific emphasis on how poorly controlled diabetes leads to a deficiency of magnesium

Goal
T review the role of magnesium in health and disease o states, with a special emphasis on using this mineral to optimize the action of insulin and alter development of long-term complications of diabetes mellitus

Objectives

The Role of Minerals
A growing body of research shows an association between DM and alterations in the homeostasis of several trace minerals Impaired insulin release, altered insulin action and increased glucose intolerance in experimental

After completing this
lesson the health care provider will be able to: Identify nutritional sources of magnesium and describe its role in normal and pathophysiological states, especially diabetes mellitus;
Continued overleaf

5

Mg Diabetes Mellitus and Magnesium: Unlikely Partners

Explain the evidence linking suboptimal magnesium status with diabetes mellitus and its associated long-term complications; Describe recent studies that use supplemental magnesium as a pharmacotherapeutic adjunct treatment for diabetes mellitus; Describe the processes that regulate magnesiums absorption, distribution and excretion; and List the side effects and precautions associated with supplemental magnesium use in diabetes mellitus patients

Accreditation Statements
Massachusetts College of Pharmacy and Health Sciences is accredited by the American Council on Pharmaceutical Education ACPE to provide continuing pharmaceutical education Massachusetts College of Pharmacy and Health Sciences will grant 1 contact hour 01 CEUs to pharmacists who read this supplement, correctly answer 70 of the accompanying questions and submit the completed examination to Massachusetts College of Pharmacy and Health Sciences Boston
University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians Boston University School of Medicine designates this educational activity for a maximum of 1 hour in category 1 credit towards the AMA Physicians Recognition Award, provided it is used and completed according to instructions, and providing a score of 70 or better is achieved Each physician should claim only those hours of credit that he/ she actually spent on the educational activity

Disclosure Statement
It is the policy of Massachusetts College of Pharmacy and Health Sciences Boston University School of Medicine, Departments of Continuing Education, that faculty disclose to program participants any real or apparent conflict of interest In addition, faculty are asked to disclose when any discussion of unapproved use of pharmaceuticals and devices is being discussed Faculty members for this program have nothing to disclose

animals and human subjects with DM have been linked to a deficit in the cellular availability of magnesium as well as other minerals including chromium, selenium, vanadium and zinc DMs characteristic
polyuria, which results from the glucose-mediated hyperosmotic glomerular filtrate, may be largely responsible for the observed higher-than-normal excretion rates of some of these minerals, especially magnesium Depending on dietary and supplemental magnesium intake, this enhanced mineral loss may result in a state of negative balance As a result, there is less magnesium available for optimal insulin secretion or action and this, we expect, would lead to altered, and presumably less-than-optimal, metabolic functioning In such cases it would be important to correct the altered mineral status by increasing dietary intake of the particular mineral or using supplemental mineral sources As you will see later in the discussion, many magnesium-rich foods are not optimal for patients with DM In this case, supplemental magnesium may be the most effective way to insure adequate magnesium levels In addition to its involvement in insulins release and activity, magnesium also plays an important role in other essential biochemical processes Of significant importance, magnesium is required to activate sodium-potassium adenosine triphosphatase Na-K ATPase, which maintains electrical gradients
across all cell membranes When hypomagnesemia is present, decreased intracellular potassium distribution can alter cell excitability such as QT-interval prolongation Magnesium is also an essential cofactor in the action of parathyroid hormone on bone A magnesium deficiency may result in hypocalcemia, which also can contribute to QT-interval prolongation

Tracing the Magnesium-DM Connection
The association between magnesium and diabetes has been known for some time The earliest suggestion, made in 1952 by Stutzman and Amatuzio, was based on their observation of lower serum magnesium levels in DM 3 patients Studies in experimental animals demonstrate that magnesium can retard or prevent the induction of insulin resistance and DM, while a magnesium deficit can predispose to hyperglycemia Based on studies in humans, we can estimate that a significant proportion of patients 25 to 40 with DM are hypomagnesemic, or 4 have suboptimal magnesium status In the Atherosclerosis Risk in Communities ARIC study, Ma and colleagues investigated the relationship between serum and dietary magne5 sium and DM The researchers tested 15,248 subjects and found significantly lower serum magnesium levels in
those with DM compared to those without the disease Researchers also found associations between magnesium levels and both cardio-vascular disease and hypertension, probably as a result of the common biochemical mechanisms underlying the damage observed in each of the diseases Duplicating the results of the above study, Sasaki and colleagues demonstrated that the DM patients in their study had lower serum levels of ionized 6 magnesium than healthy controls In another recent study, researchers examined the serum levels of magnesium in patients with malnutrition-related DM MR-DM 7 from Bangladesh This type of DM is further divided into two categories–fibrocalculus pancreatic diabetes and protein-deficient DM–and constitutes 55 of all patients with DM in Bangladesh Patients with MR-DM had significantly decreased serum magnesium levels com-

pared with controls or malnourished patients without DM Almost 70 of those patients with MR-DM had clinically defined hypomagnesemia serum levels 070 mmol/L and 90 had hypermagnesuria urinary magnesium 335 mmol Mg/mol creatinine Of the patients who had type 2 DM not related to malnutrition, 42 exhibited hypomagnesemia The researchers suggested
these patients observed alterations in magnesium status resulted primarily from urinary loss of the mineral associated with an osmotic diuresis, which is characteristic of this disease Malnutrition, with its associated poor dietary magnesium intake, further contributes to the magnesium deficit in MR-DM patients

Magnesium and Diabetes Mortality
Diabetes mellitus is the seventh leading cause of death in the United States A number of investigations have demonstrated an association between mortality rates among DM patients and the magnesium content of drinking water One such US study reported a significant negative correlation r056 between the magnesium content of drinking 8 water and the mortality rate of DM patients Similarly, patients with DM from more than 2,633 different locations in Canada demonstrated a negative correlation between the magnesium content of their drinking water and DM-related mortality rates Another more recent study illustrated the association between the magnesium content of Taiwanese drinking water and the risk of dying from DM The authors reported a significant protective effect of magnesium for patients with DM compared to those without the disease In this
study of more than 13,000 subjects,

7

Mg Diabetes Mellitus and Magnesium: Unlikely Partners

the odds of dying from DM significantly decreased as the magnesium level in drinking 9 water increased

Magnesium and Insulin Action
In support of clinical findings showing an association between hypomagnesemia and the poor glucose control observed in DM patients, numerous studies have demonstrated an important relationship between magnesium and insulin release and activity The release of insulin caused by a glucose challenge is partly dependent on adequate magnesium Insulin, via its interaction with ligand-activated tyrosine protein kinase-associated receptors, initiates a cascade of biochemical interactions that result in several physiological, biochemical and molecular events that are involved in carbohydrate, 10 lipid and protein metabolism Although the binding of insulin to its receptor does not appear to be altered by magnesium status, the ability of insulin once bound to the receptor to activate tyrosine kinase is reduced in hypo11 magnesemic states As a result, reduced peripheral glucose uptake and oxidation are often noted in subjects with hypomagnesemia Decrements in the
enzymatic activities of several metabolic pathways are seen in DM patients as 12 a result of the relative magnesium deficiency In an animal study involving genetically obese diabetic Zucker rats, magnesium supplementation prevented insulin resistance induced by fructose administration and delayed the on13 set of insulin resistance and hyperglycemia In patients with type 2 DM, Yajnik and colleagues found that there was a direct relationship between serum magnesium levels and the efficiency with which glucose was cleared 14 following an intravenous glucose load Patients with low magnesium levels were much less ef-

ficient at handling a glucose challenge Similarly, insulin-induced magnesium accumulation by erythrocytes from patients with type 2 DM is markedly impaired and correlates well with the poor insulin-induced glucose disposal observed 15 in these patients In a double-blind, randomized, crossover study, Paolisso and colleagues investigated the effects of magnesium supplementation in elderly subjects average age was 78 years with insulin resistance on the handling of glucose following an intravenous glucose load and an euglycemic hyperinsulinemic glucose clamp procedure They
also determined the effects of magnesium on erythrocyte magnesium content, which had been shown to be depressed, and membrane microviscosity Magnesium pidolate at 45 g per day 158 mmol per day for four weeks significantly improved insulin action, enhanced total-body and oxidative-glucose metabolism, increased erythrocyte magnesium concentrations and decreased 16 erythrocyte membrane microviscosity Similarly, in another double-blind placebocontrolled study of older patients with type 2 DM Paolisso and colleagues administered magnesium 2 g per day in the diet for four weeks Magnesium treatment significantly increased plasma and erythrocyte magnesium levels, as well as increased the insulin response and glucose disappearance following a pulse of glucose During the euglycemic-hyperglycemic glucoseclamp testing in these subjects, those who received chronic magnesium therapy withstood a significantly greater glucose infusion rate These changes correlated well with the increases in erythrocyte magnesium Chronic magnesium treatment also significantly decreased the resting plasma glucose levels in 17 these patients with type 2 DM

Magnesium deficiency has been shown to produce insulin
resistance in healthy human subjects In one study by Nadler and colleagues, lean non-diabetic subjects receiving a low-dose magnesium liquid diet 05 mmol per day for three weeks, had a significant reduction in intracellular free magnesium in erythrocytes 186 10 to 127 9 mM and serum magnesium levels 078 008 18 to 053 008 mmol/L However, serum sodium, calcium and potassium were unchanged An intravenous glucose tolerance test revealed significantly reduced tolerance on the Insulin Sensitivity Index when patients received the low-dose magnesium treatment compared with when they were magnesium replete In this study, magnesium deficiency also led to increased urinary thromboxane levels and enhanced aldosterone-secreting effects of angiotensin II The changes on both of these observed indices probably reflect increased activity of processes that can contribute to the underlying pathological changes associated with microvascular and macrovascular damage, therefore, the authors suggest that magnesium deficiency may be a common factor in both insulin resistance and vascular diseases A recent human, placebo-controlled study by deValk and colleagues reported the effects of supplemental
magnesium 15 mmol per day for three months in 50 type 2 DM patients requiring insulin While plasma magnesium and urinary magnesium excretion increased with magnesium therapy, other parameters measured HbA1c, blood glucose, lipids did not change There was, however, a slight reduction in diastolic blood pressure in the patients who experienced increased plasma magnesium1 9 Although individuals with compromised magnesium status have reported reduced insulin

release, most of the focus on magnesium supplementation for DM involves preventing long-term complications Magnesium deficiency has been associated with hypertension, dyslipidemia and retinopathy, all common to DM20

Magnesium and Diabetic Complications
It is estimated that less than 10 of DM patients die from acute problems associated with the disease such as diabetic ketoacidosis or hypoglycemia The greatest morbidity and mortality result from long-term complications These long-term complications are believed to develop when cells and cellular components are chronically exposed to elevated glucose levels, as seen in poorly controlled DM The nonenzymatic glycosylation of proteins and the accumulation of polyols eg, sorbitol
results in the formation of advanced glycation end products and ultimately cell damage Hyperlipidemia and hypertension are examples of macrovascular complications associated with DM The microvascular complications include neuropathies, retinopathy and nephropathy The association between magnesium deficiency and the risk of developing diabetic ret21 inopathy was first suggested in 1978 Approximately 75 of patients with type 1 DM will develop some degree of retinopathy after 15 years of diabetic symptoms In the most extensive study to date, Hartwal and colleagues examined 100 patients with type 2 DM and compared them with 100 controls without 22 DM Of the DM patients, 40 had no retinopathy, 40 had non-proliferative retinopathy and 20 had proliferative retinopathy, the most serious form see Table 1 When compared with controls, the DM patients had significantly lower serum magnesium levels Of the DM pa-

9

Mg Diabetes Mellitus and Magnesium: Unlikely Partners

a complete elimination of cramps in 20 of 24 Diabetic Retinopathy and Serum Magnesium patients after just a few Serum Magnesium days of magnesium GROUP N mmol/L therapy, 5mg/kg/day, Control 100 104 000 Mg aspartate
hydroDiabetics–no retinopathy 40 088 007 Diabetics–retinopathy chloride po Alnon-proliferative 40 077 007 though the remaining Diabetics–retinopathy subjects continued to proliferative 20 066 004 experience some leg 22 Significantly different from control Adapted from Hartwal, et al cramps, their intensity and frequency was 23 tients, serum magnesium levels were lower in markedly decreased Magnesium therapy has those patients with retinopathy than those also effectively treated leg cramps in patients without re tinopathy The lowest serum mag- without DM, even when serum magnesium level 24 nesium levels were observed in those patients appear normal Magnesium therapy should be with proliferative retinopathy Although re- considered for DM patients with leg cramps searchers have yet to establish a definitive when their renal function is adequate mechanism underlying the association between magnesium deficit and retinopathy, the com- Magnesium Basics– promised insulin release and consequent cel- Pharmacokinetics lular damage may contribute to disease Total body magnesium averages 20 to 28g progression as a result of chronic dysfunction with most 65 located in bone Of this of
glucose homeostasis amount, only 30 is exchangeable and the rest is tightly sequestered in the bone maSkeletal Muscle Cramps trix Intracellular magnesium constitutes apNumerous electrolyte disturbances are proximately 34 of the total, with only 1 known to adversely affect normal skeletal muscle located in the extracellular fluid While norfunction Of these, hypomagnesemia-induced mal serum values range from 08 to 12 mmol/ muscle cramps appear to be especially bother- L 14 to 20 mEq/L, serum magnesium measome to DM patients The nocturnal leg cramps surements, although routinely done, may not disrupt sleep causing excessive fatigue and fur- always accurately reflect intracellular levels ther reducing quality of life for DM patients Mag- Individuals may have serum magnesium levnesium therapy reportedly alleviates cramps with els well within the normal range and yet be a number of underlying causes total body magnesium deficient An accurate Hypomagnesemia patients with early-onset magnesium deficiency diagnosis, especially type 1 DM who complained of nocturnal leg the chronic latent variety, can be difficult to 25 cramps were studied for the ability of magne- make sium aspartate
hydrochloride to reduce sympThe small intestine absorbs most of the toms In this study Bachem and colleagues noted dietary magnesium Typically, about 35 to 60
Table 1

of an orally delivered magnesium load is absorbed, but this depends partly upon the individuals current magnesium status The transport mechanism across the intestinal wall is believed to be passive diffusion or facilitated transport There does not appear to be active magnesium transport in the small intestine, nor is the colon believed to absorb a significant amount of magnesium Serum magnesium levels increase as a result of oral magnesium supplementation with one of the many salts available including the amino acid chelates aspartate HCl, carbonate, chloride, gluconate and oxide Some studies have demonstrated differences in the bioavailability of the various salts in humans and experimental animals Research has shown aspartate HCl currently has the 26,27 greatest bioavailability Within the serum, magnesium is generally found in three distinct fractions: ionized magnesium 60, protein-bound magnesium 34 and complexed magnesium 6 Within cells, only 1 to 2 of the magnesium is free in the ionized form The largest
contributor to the protein-bound magnesium in serum is albumin, although a number of other proteins do contribute to magnesium binding Small amounts of magnesium are excreted in saliva and breast milk, but the body regulates magnesium predominantly by altering its excretion via the kidneys Ionized magnesium is freely filtered at the glomerulus and reabsorption takes place within the thick segment of the ascending limb of the loop of Henle 70, the proximal tubule 15 and the distal tubule 10 A number of hormones acting on the distal tubule–including various steroids, glucagon, vasopressin, parathyroid hormone and calcitonin–are likely to be involved in controlling magnesium reabsorption, which

attempts to maintain magnesium homeostasis Recent evidence suggests that the cells within the distal tubule, and possibly the thick ascending limb of the loop of Henle, are capable of adapting to magnesium and calcium availability through receptors that sense the concentration of these cations Thus, when magnesium status is suboptimal, these receptors sense the need for magnesium retention and cause more reabsorption

Drugs That Can Produce Magnesium Deficit
There are a number of clinically
useful drugs that can trigger magnesium loss largely because of their action on the kidneys see 28 Table 2 Important examples include corticosteroids, cyclosporine, digoxin, ethacrynic acid, ethanol, furosemide, methotrexate, oral contraceptives, tetracyclines and the thiazide diuretics Additionally, laxative abuse can cause magnesium deficiency by preventing intestinal absorption and enhancing gastrointestinal loss Because DM patients may either chronically or intermittently use some of these drugs, health care providers should pay special attention to the patients magnesium status
Table 2

Drugs Known to Deplete Magnesium
Benzthiazide Bumetanide Cholestyramine Corticosteroids Diethylstilbesterol Digoxin Estrogens Adapted from Pelton, et al
26

Ethacrynic acid Furosemide Minocycline Penicillamine Quinestrol Thiazide diuretics

11

Mg Diabetes Mellitus and Magnesium: Unlikely Partners

Magnesium deficiency is also seen in critically ill patients In such acute situations, assuming renal function is adequate, aggressive repletion with intravenous magnesium sulfate should be undertaken immediately to prevent serious cardiac arrhythmias and metabolic disturbances For magnesium
repletion, give 12 mg/kg of elemental magnesium intravenously during a 24-hour period during the first day, followed by 6 mg/kg on days two through five Serum magnesium levels should be monitored daily to avoid hypermagnesemia Many patients with hypomagnesemia will also be hypokalemic, so it may be necessary to add potassium chloride as well

Magnesium Toxicity
Magnesium has a very high therapeutic index The most common adverse effect associated with oral supplemental magnesium administration is diarrhea Toxicity from hypermagnesemia is usually only seen in those patients with significant renal impairment who have ingested excessive amounts of magnesium-containing products eg, laxatives, cathartics At magnesium serum levels of 15 to 25 mmol/L 3 to 5 mEq/L nausea, vomiting, bradycardia and hypotension can occur As serum levels approach 25 to 50 mmol/L 5 to 10 mEq/L hyporeflexia, EEG abnormalities and generalized central nervous system depression can occur At concentrations greater than 5 mmol/L 10 mEq/L severe respiratory depression, coma and asystolic arrest may occur Many of magnesiums actions at therapeutic concentrations, as well as at toxic concentrations, are caused by the
minerals ability to act at calcium channels Magnesium can be classified as an endogenous calciumchannel blocker Treating hypermagnesemia

typically involves stopping magnesium administration and starting calcium There is documented evidence that magnesium interacts with neuromuscular blocking agents and central nervous system depressants eg, opioids, general anesthetics and barbiturates However, in the absence of significant renal dysfunction, the most common adverse effects observed with magnesium supplementation involve its laxative effects Clinicians may use this observation to determine appropriate dosing A patient is usually started on a low magnesium dose and that dose is gradually increased If diarrhea occurs, adjust down the dose Magnesium is clinically useful for treating a number of disorders see Table 3 In addition to DM, magnesium has been used as an antiarrhythmic agent, an antihypertensive agent and to retard uterine contractions when beta-adrenoceptor agonists are contraindicated Additionally, magnesium has been used to treat asthma, headaches and barium poisoning

Daily Magnesium Requirements
The US Recommended Dietary Allowance RDA and Adequate Intake AI for
magnesium varies with age and physiological status
Table 3

Other Therapeutic Uses of Magnesium
Arrhythmias especially torsades de pointes Asthma Barium intoxication Constipation Adapted from Pelton, et al
26

Epilepsy Headache Hypertension and cardiovascular disease Peptic Ulcer Disease Uterine relaxation

see Table 4 For adults, the average daily intake should approach 5 mg/kg body weight Men older than 31 years have the highest requirement 420 mg daily, while the corresponding value for women in that age group is 320 mg daily Women between 14 and 18 years require 360 mg per day Pregnancy increases the requirement to 400 mg per day for those younger than 18 years and 350 to 360 mg per day for those older than 18 Similarly, lactation increases the values to 310 to 360 mg daily Most studies have demonstrated that the average magnesium intake is approximately 20 to 25 below the RDA Results of other studies suggest that 25 to 50 of the US population have suboptimal dietary magnesium intake Many of the foods we eat, whether of animal or plant origin, contain bioavailable magnesium Some foods with a generally desirable
Table 4

magnesium content include green leafy vegetables, grains,
various nuts almonds, soy, shrimp, various fish bluefish, cod, flounder, herring, mackerel, swordfish, wheat germ and chocolate Because some of the best dietary sources of magnesium are not the most appropriate food choices for DM patients because of the caloric or fat content eg, chocolate, nuts, supplementing with one of the available magnesium salts may be the easiest way to insure adequate magnesium intake Although the US RDA does not include a greater magnesium intake level for DM patients, supplementing with magnesium may be beneficial considering their tendency to excrete excessive urinary magnesium each day Numerous magnesium salts are available for use as dietary supplements

Recommended Dietary Allowance RDA for Magnesium
Category Infants Children Males Age years 005 051 13 4-8 913 14-18 19-30 30 913 14-18 19-30 30 18 19-30 31-50 Mg mg/day 30 75 80 130 240 410 400 420 240 360 310 320 400 360 350 310 360 320

Females

Pregnancy Lactation

Values represent the Adequate Intake AI because an RDA has not been established

13

Mg Diabetes Mellitus and Magnesium: Unlikely Partners

Recommendations and Conclusions
Early studies demonstrated an inverse relationship between plasma
magnesium levels and fasting blood-glucose levels in patients with DM Magnesium deficiency decreases insulin sensitivity via an alteration of the insulin-receptor associated tyrosine kinase, while supplementation with magnesium has been shown to benefit those with type 2 DM Monitoring the magnesium status of DM patients is important and should be part of their comprehensive therapy However, because such a small percentage of the totalbody magnesium is present in the compartment typically sampled the plasma or serum, diagnosing magnesium deficiency can be difficult Studies have demonstrated that despite a normal plasma or serum magnesium level, patients still may be deficient Magnesium deficiency can be treated in a number of ways Diet alone is usually not a practical approach because many of the foods rich in magnesium such as peanuts, soy beans, cashews, chocolate, dried fruits and shrimp should not be consumed in large quantities by DM patients because of the high caloric and lipid contents of these foods Supplemental magnesium is the better choice in this case Oral magnesium products should be taken with meals to minimize the likelihood of diarrhea The magnesium salts available
for oral use include the amino acid chelates eg, aspartate HCl, carbonate, chloride, gluconate and oxide Some studies have demonstrated significant differences in the bioavailability of the various salts in humans and experimental animals with the aspartate HCl having the 25,26 greatest absorption and bioavailability Magnesium aspartate HCl has also been reported

to cause less diarrhea than many of the other available magnesium supplements Supplementation with magnesium is obviously required for patients with low serum levels Many clinicians will also routinely recommend magnesium supplements even when serum levels are within the normal range because the diabetic state encourages elimination of magnesium, and because supplementation with this mineral is quite safe

References
1 Clark MJ, et al Diabetes guidelines: a summary and comparison of the recommendations of the American Diabetes Association, V eterans Health Administration, and the American Association of Clinical Endocrinologists Clin Therap 2000;22:899-910 2 Expert Committee on the Diagnosis and Classification of Diabetes Mellitus Report of the expert committee on the diagnosis and classification of diabetes mellitus
Diabetes Care 1997;20:1183-214 3 Stutzman FL, Amatuzio DS Blood and serum magnesium in portal cirrhosis and diabetes mellitus J Lab Clin Med 1952;41:215 4 McNair P, et al Renal hypomagnesaemia in human diabetes mellitus: its relation to glucose homeostasis Eur J Clin Invest 1982;12:81-5 5 Ma J, et al Associations of serum and dietary magnesium with cardiovascular disease, hypertension, diabetes, insulin, and carotid arterial wall thickness: the ARIC study J Clin Epidemiol 1995;48:927-40 6 Sasaki S, et al Abnormal magnesium status in patients with cardiovascular disease Clin Sci 2000;98:175-81 7 Khan LA, et al Serum and urinary magnesium in young diabetic subjects in Bangladesh Am J Clin Nutr 1999;69:70-3 8 Foster H Diabetes mellitus and low environmental magnesium levels Lancet 1987;2:633 9 Yang CY, et al Magnesium in drinking water and the risk of death from diabetes mellitus Magnesium Res 1999;12:131-7 10Lefebvre PJ, Scheen AJ Improving the action of insulin Clin Invest Med 1995;18:340-7 11Suarez A, et al Decreased insulin sensitivity in skeletal muscle of hypomagnesemic rats Diabetologia 1993;36Suppl 1:A82 12Laughlin MR, Thompson D The regulatory role for magnesium in glycolytic
flux of the human erythrocyte J Biol Chem 1996;271:28977-83 13Balon TW, et al Magnesium supplementation reduces development of diabetes in a rat model Am J Physiol 1995;269:E745-52 14Yajnik CS, et al Fasting plasma magnesium concentrations and glucose disposal in diabetes Br Med J 1993;288:1032-4 15Paolisso G, et al Impaired insulin-induced erythrocyte magnesium accumulation is correlated to impaired insulin-mediated glucose disposal in type 2 non-insulin-dependent diabetic patients Diabetologia 1988;31:910-5 16Paolisso G, et al Daily magnesium supplements improve glucose handling in elderly subjects Am J Clin Nutr 1992;55:1161-7 17Paolisso G, et al Improved insulin response and action by chronic magnesium administration in aged NIDDM subjects Diabetes Care 1989;12:265-9 18Nadler JL, et al Magnesium deficiency produces insulin resistance and increased thromboxane synthesis Hypertension 1993;21:1024-9 19DeValk HW, et al Oral magnesium supplementation in insulin-requiring type 2 diabetic patients Diabet Med 1998;15:503-7 20Seelig M Cardiovascular consequences of magnesium deficiency and loss: pathogenesis, prevalence and manifestations–magnesium and chloride loss in refractory
potassium repletion Am J Cardiol 1989;63:4G-21G 21McNair P, et al Hypomagnesemia, a risk factor in diabetic retinopathy Diabetes 1978;27:1075-7 22Hatwal A, et al Association of hypomagnesemia with diabetic retinopathy Acta Ophthalmol 1989; 67Copenh:714-6 23Bachem MG, et al Efficacy of oral magnesium supplementation in type 1 diabetics with nocturnal leg cramps Magnesium Bull 1986;8:280-3 24Haringer E Are nocturnal cramps in the calf due to magnesium deficiency? Normal serum magnesium concentrations do not rule out the presence of abnormally low intracellular magnesium levels Arztliche Praxis 1981;77:2653-4 25Gums JG Clinical significance of magnesium: a review Drug Intell Clin Pharm 1987;21:240-6 26Muhlbauer B, et al Magnesium-L-aspartate-HCl and magnesium-oxide: bioavailability in healthy volunteers Eur J Clin Pharmacol 1991;40:437-8 27Classen HG, et al Comparative animal studies on the absorption of magnesium in sulfate, chloride, aspartate and aspartate hydrochloride form from the gastrointestinal tract Arzneim-Forsch Drug Res 1973;23:267-71 28Pelton R, et al Drug-induced nutrient depletion handbook, 1999-2000 San DiegoCA: Natural Health Resources; 2000

15

Mg Diabetes Mellitus
and Magnesium: Unlikely Partners

Magnesium and Diabetes Mellitus Continuing Education Module Questions 1 The US Recommended Dietary Allowance RDA for magnesium for a male aged 31 years or older: a 75 mg b 1,200 mg c 5 mg/kg d 420 mg/kg 2 Therapeutically, magnesium can be used: a as a uterine relaxant b as an antiarrhythmic c for barium intoxication d all of the above 3 Which agents are known to enhance renal magnesium excretion: a cephalosporin antibiotics b testosterone c corticosteroids d HMG CoA reductase inhibitors 4 In patients with diabetes mellitus, the most compelling data to date supports an association between hypomagnesemia and: a the degree of urinary glucose spillage b HbA1c levels c severity of diabetic complications such as retinopathy d blood glucose levels 5 The most common adverse effect associated with magnesium supplementation in patients with diabetes mellitus is: a headache b arrhythmias c muscle pain d diarrhea 6 Normal serum magnesium levels are: a 0103 mmol/L b 0406 mmol/L c 0812 mmol/L d 2040 mmol/L 7 In patients with diabetes mellitus, magnesium deficiency: a increases insulin release b decreases insulin resistance c is commonly observed d leads to
hypercalcemia 8 Numerous studies have demonstrated that the level of magnesium in the drinking water of patients with diabetes mellitus is inversely correlated with: a serum potassium b diabetes mellitus-related mortality c tyrosine kinase activity d forced expiratory volume per minute FEV1 9 Most of the bodys magnesium is stored in the: a blood b bone c muscle d pancreas 10 Which magnesium salts, when administered orally, reportedly have greater bioavailability and fewer adverse gastrointestinal effects: a aspartate hydrochloride b carbonate c chloride d oxide

Answer Sheet and Post Test Instructions
Massachusetts College of Pharmacy and Health Sciences will grant 1 contact hours 01 CEUs to pharmacists who read this supplement, correctly answer 70 of the accompanying questions and submit the completed examination to Massachusetts College of Pharmacy and Health Sciences Boston University School of Medicine - Physicians may earn up to 1 AMA PRA Category 1 credit by reading this supplement, correctly answering at least 70 of the accompanying examination questions, and submitting the completed examination to Boston University School of Medicine This continuing education activity
expires on December, 2003 There is no charge for participating in this continuing education activity To receive statements/certificates of credit send or fax completed answer sheet to: Pharmacists: MCPHS-CE, 179 Longwood Ave, Boston, MA 02115 Fax: 617-732-2062 Physicians: Boston University School of Medicine - CME, 715 Albany Street, A305, Boston, MA 02118-2526 Fax: 617-638-4905 Massachusetts College of Pharmacy and Health Sciences is approved by the American Council on Pharmaceutical Education as a provider of continuing pharmaceutical education Pharmacists successfully participating in this program will receive a statement of credit for one 1 contact hours 01CEU within 3-4 weeks after receiving your completed answer sheet Initial release date: December, 2000 ACPE 026-999-00-215-H01 Boston University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians

Name _________________________________________________________________________________________ Address ____________________________________________________________________________ City __________________________ State _____ Zip Code
_________ Telephone _______________ State License Number ______________________ Pharmacist ________ Physician ________ Other ________ Please indicate your exam response by circling only ONE answer for each 1 A 2 A 3 A B B B C C C D D D 4 A 5 A 6 A B B B C C C D D D 7 A 8 A 9 A Agree Excellent 1 2 3 3 3 4 4 4 B B B C C C D D D 10 A B C D

Program Evaluation: Overall quality: Objectives: Relevance to practice:

Disagree Poor 5 None met 5 Not relevant 5

All met 1 2 Extremely relevant 1 2

It took me _____ hours _____ min to read this article and complete the exam

17

Mg Diabetes Mellitus and Magnesium: Unlikely Partners

Diabetes Mellitus and Magnesium: Unlikely Partners

This continuing medical education program is intended solely for educational purposes for qualified health care professionals In no event shall Massachusetts College of Pharmacy and Health Sciences or Boston University be liable for any decision made or action taken in reliance on the information contained in the program In no event should the information contained in the program be used as a substitute for professional care No physician-patient relationship is being established

19

Mg Diabetes Mellitus and
Magnesium: Unlikely Partners

The authors and accrediting bodies of this continuing education program have made all reasonable efforts to assure that all information contained herein is accurate in accordance with the latest available scientific knowledge at the time of acceptance for publication However, because information regarding drugs their administration, dosages, contraindications, adverse reactions, interactions, special warnings, and precautions, etc is subject to constant change, the reader is advised to check the manufacturers package insert for information concerning recommended dosages and potential problems and cautions prior to dispensing or administering the drug Special precautions should be taken when a drug is new, or highly toxic, or is unfamiliar to the dispenser or administrant

Massachusetts College of Pharmacy and Health Sciences Continuing Education 179 Longwood Avenue Boston, MA 02115

NON-PROFIT US POSTAGE PAID PERMIT NO 54285 BOSTON, MA

Source:mendosa.com