Nutrition Grand Rounds

Syndrome X: Medical Nutrition Therapy Karen Roberts, M.S., C.N.S., Kathleen Dunn, M.P.H., R.D., Sandra K. Jean, M.S., and Claude K. Lardinois, M.D.

A significant number of Americans are at risk for developing a condition of insulin resistance termed Syndrome X. Dyslipidemia, resistance to insulin, obesity, and blood pressure elevation-the deadly quartet-describe Syndrome X, which increases atherogenic risk and contributes to coronary ar- tery disease. Lifestyle factors such as overeating and physical inactivity play a pivotal role in Syn- drome X. This deadly duet has been aptly coined “hyperactive fork” and “hypoactive foot, ” respec- tivelv In addition, emerging evidence suggests that certain nutrients may help protect against Syn- drome X. This review provides a brief discussion of diet and lifestyle factors related to Syndrome X.

Introduction

It has been estimated that as many as 1 in 4 apparently healthy Americans are at risk of developing “Syndrome X,” a metabolic derangement that is a major contributor to coronary artery disease.’ Gerald Reaven first coined the term Syndrome X, in 1988, to describe a cluster of athero- genic risk factors including hyperinsulinemia, obesity with an abdominal pattern of distribution, some degree of car- bohydrate intolerance, hypertension, and an abnormal blood lipid pattern of increased triglyceride and decreased high-density lipoprotein (HDL) subkactions. The deadly quartet of dyslipidemia, resistance to insulin, obesity, and pressure elevation (abbreviated as DROP) describes Syn- drome X. Newer features of Syndrome X include easily oxidized, small, low-density lipoprotein (LDL) particles, heightened blood-clotting activity (e.g., increased plas- minogen-activating inhibitor- I), and elevated serum uric acid concentration. Central to Syndrome X is insulin re- sistance, a condition in which body cells lose sensitivity to insulin action, and insulin-stimulated glucose disposal

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Ms. Roberts, Ms. Dunn, and Ms. Jean are with the Department of Nutrition Science, Leiner Science Center, Carson, CA 90745, USA. Dr. Lardinois is with the Veterans Affairs Sierra Nevada Health Care System and the University of Nevada School of Medicine, Reno, NV 89502, USA.

is compromised. Syndrome X is also known as the insulin resistance syndrome and the cardiovascular dysmetabolic syndrome.

Although genetic predisposition is a determinant of insulin resistance and probably accounts for the variation in insulin sensitivity observed in apparently healthy people,* diet and lifestyle play a pivotal role in the devel- opment of Syndrome X. The typical Western diet, charac- terized by excessive intake of nutrient-poor, low-fiber, re- fined carbohydrate-rich foods combined with physical inactivity and smolung, promotes the insulin resistance that precedes Syndrome X. The deadly duet of overeating (“hyperactive fork”) and physical inactivity (“hypoactive foot”) contributes substantially to the development of Syndrome X. Establishing dietary recommendations to reduce the prevalence of Syndrome X is premature given the relative lack of research addressing the potential ben- efits of dietary changes or dietary supplementation for reducing insulin resistance. However, some nutritional factors may have therapeutic value in protecting against Syndrome X. The purpose of this review is to provide a brief discussion of such factors and the physiologic con- sequences of these factors on insulin resistance.

Insulin Resistance in Syndrome X

Although considerable evidence has characterized insu- lin resistance in diabetes and obesity, few studies have specifically examined insulin resistance related to Syn- drome X. In insulin resistance, the body becomes insensi- tive to insulin action, which compromises insulin-stimu- lated glucose disposal. Pancreatic beta cells offer the first line of defense against developing insulin resistance by increasing insulin secretion to maintain glucose homeo- stasis. Although hyperglycemia and diabetes are an end result of beta cell failure, more often in Syndrome X pan- creatic h c t i o n compensates for insulin resistance by cre- ating a condition of hyperinsulinemia. Hyperinsulinemia and insulin resistance are the dominant factors that link the clinical features of Syndrome X.3

Insulin targets several tissue sites and cellular path- ways where defects can manifest as Syndrome X. In muscle, the binding of insulin to its cellular receptor sets off a

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chain of events that ultimately results in translocation of glucose transporters, glucose uptake and phosphoryla- tion, and storage as glycogen. Consequently, in insulin resistance, muscle glycogen synthesis is reduced and the release of substrates (e.g., lactate) taken up by the liver for hepatic glucose synthesis is enhanced.2 Furthermore, in nondiabetic insulin resistance such as that which oc- curs with obesity, there may be a decrease in fatty acid oxidation in muscle!

In adipose tissue, insulin resistance results in an el- evated concentration of circulating free fatty acids (FFA), which enhances hepatic secretion of triglyceride-rich li- poproteins and impairs endothelium-dependent vasodila- tion.2 FFAs oppose insulin’s action on the liver; in re- sponse to an increased circulating FFA concentration, hepatic glucose fluxes are altered, and glucose produc- tion is maintained even in the face of an adequate and rising glucose ~ 0 0 1 . ~ Elevated FFA and insulin resistance in adipose tissue are probably not the major defects in insulin resistance associated with diabetes5 However, the clinical consequences of elevated FFA suggest a more prominent role of adipose insulin resistance in Syndrome X

Although the kidney is not considered an insulin- sensitive tissue, insulin resistance in Syndrome X has been suggested to influence renal function. Hyperinsulinemia, as hypothesized by Reaven,6 may enhance sodium reten- tion and decrease uric acid clearance, thereby contribut- ing to hypertension and elevated uric acid concentration, which are common in Syndrome X.

Dietary and Lifestyle Factors in Syndrome X

Experimental evidence indicates that the typical Western diet, which is high in fat and refined carbohydrate and low in fiber, induces insulin resistance and precedes other as- pects of Syndrome X, including obesity. Long-term feed- ing studies in rats indicate that a diet high in fat and re- fined carbohydrate reduces insulin-stimulated glucose transport; increases plasma insulin, triglyceride, and glyc- erol concentrations; and induces hypertension and ab- dominal obesity compared with a low-fat, high-complex carbohydrate diet. Negative effects on glucose transport and plasma insulin were observed within 2 weeks-well before the development of obesity-and continued throughout the 2-year experimental period.’

Animal studies suggest that a high-fat, high-refined carbohydrate diet can trigger insulin resistance. Short- term regulated feeding studies in humans indicate that isoenergetically substituting dietary carbohydrate for satu- rated fat increases fasting and postprandial triglyceride concentrations and decreases HDL concentration, which are factors associated with increased coronary heart dis- ease risk.s The negative effect of carbohydrate feeding may be greater in people who are more insulin resistant

and at greater risk of heart disease? These findings have led to the suggestion that a high-carbohydrate diet should be avoided in insulin-resistant people with Syndrome X. The clinical value of these findings has been questioned, however, and they may have been a function of experi- mental design.I0

The long-term benefit of a low-carbohydrate diet in reducing chronic disease and promoting insulin sensitiv- ity has yet to be shown under ad libitum conditions. How- ever, ad libitum consumption of the alternative-a higher- fat diet-increases total energy intake and contributes to weight gain.” Indeed, the negative metabolic effects of high carbohydrate consumption disappear when fed un- der real life conditions’* or when combined with physical activity.I3 Furthermore, consumption of isoenergetic diets high in either monounsaturated fat or carbohydrate and adequate in fiber has been shown to have similar effects on cardiovascular risk factors and insulin sensitivity in apparently healthy relatives of subjects with type 2 diabe- tes.14

Epidemiologic evidence indicates that a diet rich in fruits, vegetables, and high-fiber complex carbohydrates is associated with a lower risk of chronic disease.lSJ6 A public health recommendation to increase fat consump- tion at the expense of dietary carbohydrate in an effort to reduce insulin resistance and prevent Syndrome X is pre- mature. Such recommendations would likely increase en- ergy intake and contribute to obesity and greater athero- genic risk. A more prudent recommendation would be to consume a diet low in refined carbohydrates and high in fiber. Results from the Coronary Artery Risk Development in Young Adults Study indicate that dietary fiber intake is inversely associated with insulin concentration and, com- pared with fat intake, is a stronger predictor of weight gain and cardiovascular disease risk factors (e.g., elevated trig- lyceride, LDL cholesterol, and fibrinogen concentrations and decreased HDL cholesterol concentration).I6 Frost et al.’7J8 showed that the consumption of a low-glycemic index, high-fiber diet improves insulin sensitivity in sub- jects with or at risk for coronary heart disease.

Regular physical activity can prevent insulin resis- tance and help protect against Syndrome X. Recent re- v i e w ~ ~ . ’ ~ demonstrate that physical activity has an appar- ent “insulin-saving effect,” in which regular exercise may improve insulin sensitivity by enhancing insulin action and reducing plasma insulin concentration. Physical ac- tivity appears to have the greatest effect on muscle, al- though improved insulin responsiveness is also observed in adipose and peripheral tissues. Improvements in insu- lin responsiveness can last up to 2 weeks in trained sub- jects but begin to decline within 1 week in untrained or obese subjects. This indicates that regular physical activ- ity is required to have a lasting effect on insulin respon- siveness.

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Alcohol consumption may indirectly affect Syndrome X. Although moderate alcohol consumption of one to three drinks per day has been suggested to reduce fasting insu- lin concentration, enhance insulin sensitivity, increase HDL cholesterol concentration, and reduce disease risk:" 23 chronic intake of greater amounts may contribute to Syndrome X. Consuming alcohol in large amounts sup- presses fat 0xidation,2~ elevates insulin and free fatty acid concentration^,^^ and increases concentrations of sub- strates such as lactate that potentially influence hepatic glucose production.26 The regular consumption of three or more alcoholic drinks per day has been found to in- crease the risk of hypertensi~n.~~ Thus nutrient losses or deficiencies induced by a high alcohol intake may con- tribute to Syndrome X.

Cigarette smoking has long been recognized as a dis- ease risk factor and appears to be a strong contributor to Syndrome X. Smoking reduces insulin sensitivity,28 and cigarette smokers show classic symptoms of Syndrome X, including hyperin~ulinemia~~ and dy~lipidemia.~~ A recent cross-sectional study3' indicates that cigarette smoking aggravates insulin resistance in subjects with type 2 dia- betes in a dose-dependent manner. Furthermore, subjects with diabetes who smoke exhibit classic signs of Syn- drome X, including elevated triglycerides and lower HDL concentrations with a tendency toward higher blood pres- sure, compared with nonsmoking patients with diabete~.~'

Specific Nutrient Considerations in Syndrome X

Emerging experimental and clinical evidence suggests that some nutrients may help protect against Syndrome X. Al- though preliminary research suggests that several botani- cals may affect Syndrome X, few have been examined clini- cally, and a review of these materials is not included. Of par- ticular interest are certain nutrients including antioxidants, essential fatty acids, minerals, and the amino acid arginine, which are described below and outlined in Table 1.

Antioxidants Vitamin C appears to play an integral role in insulin h n c - tion and glucose metabolism and may be important nn the insulin resistant state. Vitamin C is necessary for glucose- stimulated insulin release,32 and it may compete with glu- cose for cellular uptake.33 In addition, vitamin C may pro- tect vessel function, restore nitric oxide activity, and main- tain endothelium-dependent va~odilation.~~ Inhsion with vitamin C at a cumulative dose of less than 1000 mg im- proves endothelium vasodilation in subjects with diabe- tes.3s.36 Supplementation to maximize tissue concentration of vitamin C may be necessary in insulin resistance. Com- pared with placebo, vitamin C supplementation (500 mg/ day for 30 days) reduces blood pressure in subjects with hypertension, which correlates with an increase in plasma ascorbic acid c~ncentration,~~ However, megadosing with vitamin C appears to be ill advised. Daily supplementation with 2000 mg of vitamin C for 2 weeks delays the insulin response to an oral glucose challenge in healthy subjects.38 In addition, vitamin C in amounts greater than 500 mg/day may compromise the ability of folic acid to reduce elevated plasma homocysteine con~entration,3~ an independent risk factor for cardiovascular disease.

Vitamin E may be of particular benefit in the insulin- resistant state. In subjects with diabetes, supplementa- tion with a modest amount of vitamin E (1 00-200 IU/day) reduces free radical stressM and improves concentrations of the water-soluble antioxidants vitamin C and glu- tathi0ne.4'~~~ Supplementation with 1200 TU/day of vita- min E reduces LDL cholesterol oxidation in healthy men43 and reduces soluble adhesion factors in subjects with dia- betes," thereby reducing the risk of vascular complica- tions of insulin resistance. The antioxidant activity of vi- tamin E may help preserve the integrity of beta cells, which are highly susceptible to oxidative stress. In newly diag- nosed subjects with type 1 diabetes, vitamin E supple- mentation (1 5 mgkg body weight) protects beta cell func-

Table 1. Potential Beneficial Roles of Selected Nutrients in Syndrome X Promotes Reduces Improves Improves Improves Reduces

Blood Vessel Elevated Blood Blood Glucose Insulin Blood Lipid Oxidative Nutrient Health Pressure Control Action Profiles Stress Alpha-lipoic acid Arginine chromium CoenzymeQlO Magnesium Omega-3 fatty acids Selenium Vanadium VitaIIlinC VitaIIlinE ** * Although vitamin E supplementation has been shown to improve insulin action in subjects with diabetes and in healthy subjects, it has been associated with a decline in insulin action in obese subjects.

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tion.*5 Vitamin E also may have a more direct effect on insulin sensitivity. In controlled trials, daily supplementa- tion with 900 mg of vitamin E improves insulin action in subjects with diabetes and in healthy mature and elderly s ~ b j e c t s . ~ ~ . ~ ~ In obese subjects with diabetes, however, supplementation with 600 mg/day of vitamin E for 3 months is associated with a decline in insulin

The benefit of vitamin E for Syndrome X may be en- hanced by combining it with selenium. Because selenium works with vitamin E as part of the body's antioxidant defense system, it may help protect against LDL oxida- tion, improve glucose control, and enhance insulin activ- ity. Although clinical research is lacking, experimental evi- dence from animal models is encouraging. In experimental diabetes, selenium was found to reduce oxidation, nor- malize hepatic lipid metabolism, and protect the kidneys from damage.49ss0 In obese Zucker rats-a model for insu- lin resistance-selenium supplementation reduces plasma insulin concentration and protects against oxidative stress.s1 In each study, greater benefits were found when selenium was combined with vitamin E, confirming its sup- portive role in vitamin E activity.

Although not considered nutritionally essential, other antioxidants such as alpha-lipoic acid and coenzyme QlO may protect against Syndrome X. Alpha-lipoic acid supple- mentation improves diabetic neuropathy, may enhance glucose d i s p o ~ a l ~ ~ . ~ ~ and utilization,% and may prevent the chemically induced development of diabetes in ani- m a l ~ . ~ ~ Although coenzyme QlO may not directly affect the insulin response, it may protect against Syndrome X. Administration of 100 mg/day of coenzyme Q 10 increases HDL cholesterol and reduces blood pressure in subjects with essential hypertension.s6 In subjects with hyperten- sion and coronary artery disease, supplementation with 120 mg/day of coenzyme Q 10 reduces blood pressure, trig- lycerides, glucose, lipid peroxidation, and fasting and 2- hour plasma insulin concentration^.^^

Omega-3 Fatty Acids Although omega-3 fatty acid supplementation is often recommended to reduce an elevated triglyceride concen- tration, evidence suggests a limited effect on insulin re- sistance. In fructose-fed rats, fish oil supplementation ameliorates the metabolic defects of insulin res i~tance.~~ In sucrose-fed rats, fish oil supplementation prevents in- duced insulin resistance but has no effect on pre-existing insulin in~ensitivity.~~ In subjects with type 2 diabetes, fish oil supplementation may cause a reversible deteriora- tion in glucose tolerance,60 but this effect may be transi- tional.61 Results from the Oslo Diet and Exercise Study are more encouraging and suggest that adding fish to a low- fat diet reduces insulin resistance when combined with regular endurance exercise.62

Magnesium An abnormal decrease in the intracellular concentration of magnesium induced by the typical Westem diet, alterations in glucose regulation, or a high-insulin state may result in insulin resistance and hyperten~ion.6~~" Some but not all human trials suggest that supplementation with magnesium (480 m g / d a ~ ) ~ ~ reduces blood pressure in subjects with hy- pertension. Low magnesium intake is associated with indica- tors of insulin resistance in apparently healthy subjects.66 Otherwise healthy subjects with low plasma magnesium re- spond to'a glucose challenge with higher plasma glucose and insulin concentrations and maintain higher steady state glucose and insulin concentrations compared with age- and obesity-matched controls with normal plasma magnesium.67 Insulin may impair cellular magnesium uptake, which may worsen insulin resistance." Furthermore, magnesium supple- mentation in experimental animals corrects insulin resistance induced by a high-hctose diet.69 Considered together, these data suggest that insulin resistance may potentiate magne- sium deficiency, and magnesium supplementatiqn may help protect against Syndrome X.

Chromium and Vanadium Vanadium and chromium are involved in insulin action and glucose homeostasis and have been suggested as potential nutriceutical interventions for diabetes.70 Lim- ited clinical data suggest that daily administration of ap- proximately 100 mg of vanadium salt to subjects with dia- betes improves glucose control and insulin ~ensitivity.'~ However, the glucose-normalizing dose of vanadium greatly exceeds the typical dietary intake and the upper limit of safe intake (1 000 mg/day)."

Clinical investigations suggest that supplementation with 200 mg/day of chromium improves carbohydrate me- tabolism and blood glucose control in subjects with dia- betes or impaired glucose tolerance but has little effect in healthy s ~ b j e c t s . ~ ~ , ~ ~ These data suggest chromium may be beneficial for people with altered glucose metabolism, but supplementation probably has a minimal, if any, effect in healthy people. Chromium supplementation improves insulin sensitivity in rats fed a high-fat, low-chromium diet,7s which suggests a potential role in alleviating diet- induced insulin resistance.

Arginine Arginine is a precursor for nitric oxide. Nitric oxide was previously identified as an endothelium-derived relaxing factor and is known to mediate insulin's vasodilating ef- fects on the endothelium. Arginine-derived nitric oxide also has been shown to potentiate nutrient-stimulated in- sulin secretion.76 The benefit of arginine in alleviating Syndrome X in humans is not known, although oral supple- mentation improves endothelial function in apparently

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healthy subject^,'^ improves endothelium-dependent di- lation and reduces monocyte adhesion in men with coro- nary artery disease,78 and improves insulin sensitivity in subjects with diabete~.’~

Summary

Certain lifestyle choices such as consuming a typical Western diet, lacking adequate physical activity, and smok- ing greatly contribute to Syndrome X. Diet appears to play a pivotal role; the typical Western diet, high in re- fined carbohydrates, low in fiber, and high in saturated fat, is associated with increased risk of obesity leading to insulin resistance and Syndrome X. This diet is typically devoid of or low in fruits, vegetables, whole grains, and nuts, which are significant sources of many essential nu- trients, suggesting the possibility that nutrient deficien- cies are involved in the development of Syndrome X. How and to what extent potential diet-induced nutrient defi- ciencies contribute to Syndrome X have not been system- atically examined. However, nutrients such as antioxidants, essential fatty acids, minerals, and the amino acid arginine have been shown to affect various features of Syndrome X. Although these findings are encouraging and suggest potential therapeutic applications, more research is needed to clearly define the role of specific nutrients in the pre- vention and treatment of Syndrome X and to establish dietary guidelines to reduce its prevalence. Public health efforts must be initiated to promote a reasonable body weight (hypoactive fork) and encourage a regular exercise program (hyperactive foot) to reverse the serious health consequences of the deadly duet.

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