The metabolic syndrome represents the primary target of research for the Center for Human Nutrition. This syndrome is emerging as one of the major medical and public health problems both in the United States and worldwide. It has a strong nutritional component that makes it ripe for the Center's investigation. The metabolic syndrome is a precursor of both cardiovascular disease and diabetes. It emanates from a general derangement of the body's metabolic processes. The complexity of the metabolic syndrome presents a challenge to multidisciplinary research, which is a strong point of the Center for Human Nutrition.
Metabolic Syndrome as a Risk Factor for Coronary Heart Disease
Coronary heart disease is a condition that manifests as either heart attack (myocardial infarction) or chest pain (angina pectoris). It is caused by a narrowing and hardening of the coronary arteries (atherosclerosis). One of the primary features of atherosclerosis is the accumulation of cholesterol within the walls of the coronary arteries. Risk factors for coronary heart disease are the underlying causes of atherosclerosis. There are three major causes of coronary atherosclerosis along with some minor causes. The major causes are elevated LDL cholesterol (the "bad" cholesterol), cigarette smoking, and the metabolic syndrome. Among these LDL cholesterol is the primary cause of atherosclerosis. When the blood level of LDL is increased, atherosclerosis is initiated and sustained. Moreover, when LDL is elevated, cigarette smoking and the metabolic syndrome exaggerate the effects of LDL (see figure).
A syndrome is a collection of signs and/or symptoms occurring in a single person. The metabolic syndrome is constellation of individual risk factors that in aggregate greatly raise the risk for coronary heart disease. The metabolic risk factors that make up this syndrome are high triglycerides, small LDL particles, low HDL cholesterol (the "good" cholesterol), high blood pressure, high blood glucose, a tendency for blood clotting (thrombosis), and chronic inflammation.
Each risk factor of the metabolic syndrome appears to uniquely promote atherosclerosis; however, the relation of each to atherosclerosis is complex and not fully understood. Nonetheless, taken in aggregate, these risk factors accelerate the development of atherosclerosis when they occur in the presence of elevated LDL cholesterol. When LDL-cholesterol levels are very low, the risk factors of the metabolic syndrome have little effect on atherogenesis; but once LDL levels rise, these other risk factors become increasingly atherogenic. Each of these risk factors will be described in more detail subsequently.
Metabolic Syndrome and Type 2 Diabetes (Adult-Onset Diabetes)
Many persons with the metabolic syndrome will eventually develop type 2 diabetes (adult-onset diabetes). Type 2 diabetes is characterized by a fasting blood glucose level of 126 mg/dL or higher. Most persons with type 2 diabetes have two metabolic abnormalities that raise the blood glucose to the diabetes range. The first abnormality is a condition called insulin resistance; the other is a deficiency in production of insulin by the pancreas. Insulin is required for the uptake of the blood glucose by tissues of the body. The major site of glucose utilization is muscle, although other tissues use glucose. Insulin facilitates tissue uptake of glucose in all organs except the brain, which can use glucose without insulin. Insulin is produced in the beta-cells of the pancreas. If all beta-cells are lost, as in type 1 diabetes (juvenile diabetes), no insulin is produced. As a result, blood glucose levels are extremely elevated. However, even if insulin production is normal, the utilization of glucose by tissues may be impaired if a person has insulin resistance. Type 2 diabetes typically develops when insulin resistance is combined with a mild-to-moderate defect in the secretion of insulin.
Insulin resistance thus is a disorder in the metabolism of tissues that interferes with the normal action of insulin to promote glucose uptake and utilization. It usually precedes the development of type 2 diabetes by many years. There is a close connection between insulin resistance and the risk factors of the metabolic syndrome. The nature of this connection is not fully understood. One factor appears to be an overloading of tissues with fats (lipids). Patients with insulin resistance usually have a high level of free fatty acids, which are released from fat tissue (adipose tissue). When excess fatty acids enter muscle, lipid overload occurs, and this induces insulin resistance. Other factors may contribute to insulin resistance, but tissue overload of lipids appears to be a major factor.
This overload in various ways seems to engender the coronary risk factors of the metabolic syndrome. A full discussion of the causes of insulin resistance is given below.
When people have insulin resistance, the production of insulin rises to overcome the resistance. Thus, in the presence of insulin resistance, blood levels of insulin are high. One effect of higher blood levels of insulin is to "drive" more glucose into cells. This helps to prevent the development of high blood glucose. In addition, high blood insulin suppresses the release of fatty acids by adipose tissue. Conserving fat in adipose tissue by high insulin levels also dampens down insulin resistance by reducing fat overload of tissues.
As people age, their ability to produce insulin declines. The rate of decline is variable. In some persons it is more rapid than in others. When the production of insulin falls to the point that it cannot overcome insulin resistance, the blood glucose level rises. When the fasting glucose rises above 126 mg/dL, the person is said to have type 2 diabetes. Some people thus are more prone to diabetes than others because their beta-cells are less responsive to insulin resistance.
Insulin Resistance and the Metabolic Syndrome: Biological Role of Insulin
The major sites of insulin action are organs that primarily process body fuels--skeletal muscle, adipose tissue, and liver. Insulin action begins by its binding to the insulin receptor, a transmembrane glycoprotein having protein tyrosine kinase activity. Activation of receptor tyrosine kinase induces autophosphorylation of the receptor itself as well as phosphorylation of other proteins. The proteins in sequence to the receptor are the "docking proteins", insulin receptor substrates 1 and 2 (IRS-1 and IRS-2). Two proteins that bind to IRS-1 are phosphatidylinositol-3 kinase (PI-3 kinase) and Ras protein. Progressive phosphorylation lead to activation of several more serine/threonine protein kinases which results in branching cascades. Cascading activation accounts for the pleotrophic actions of insulin. Immediate actions of insulin regulate metabolism; delayed actions affect cellular growth and cellular differentiation. The actions of insulin can be divided into stimulatory actions and inhibitory actions.
The stimulatory actions include:
Promotes glucose transport into cells
Enhances glycogen synthesis
Increases fatty acid synthesis
Promotes protein synthesis
Modifies cellular differentiation and proliferation
Inhibitory actions consist of the following:
Reduces hepatic glucose output
Inhibits release of nonesterified fatty acids from adipose tissue
Suppresses lipid-related factors
In some people the cellular actions of insulin are impaired. This condition is called insulin resistance. There is a strong association between the presence of insulin resistance and the metabolic syndrome. Some investigators believe that insulin resistance is the primary cause of the metabolic syndrome. In the presence of insulin resistance, the stimulatory and inhibitors of actions of insulin are attenuated. These changes at least set the stage for the development of the risk factors of the metabolic syndrome.
Causes of Insulin Resistance
The factors that lead to insulin resistance can also be considered as causes of the metabolic syndrome, because insulin resistant is so strongly associated with the metabolic syndrome. The most prominent action of insulin is to promote the uptake of glucose by issues, but insulin has other actions as well. It can act to both stimulate and inhibit various metabolic pathways. Those that are stimulated include the cellular uptake of glucose, the synthesis of proteins, and cellular proliferation. Pathways that are inhibited include oxidation of fatty acids and formation of lipoproteins.
One of the major ways in which insulin resistance is introduced is by overload of tissues with lipids. Factors that contribute to tissue overload of lipid are obesity, especially upper body obesity, physical inactivity, fat-storage defects, male hormones, aging, and genetic factors. The latter three-male hormones, aging, and genetic factors-may lead to impairment of insulin action in ways other than through tissue lipid overload. These factors can be discussed briefly.
Obesity and Insulin Resistance
Perhaps the most common cause of insulin resistance is an excessive amount of fat in the body. Depending on the degree of excess, this is called overweight or obesity. Body fat is composed almost entirely of triglycerides, which in turn are composed of fatty acids and glycerol. Three fatty acid molecules combine with one glycerol molecule to form one molecule of triglyceride. Triglycerides are stored in fat tissue (adipose tissue). Adipose tissue breaks down triglyceride and releases fatty acids into the blood stream when they are needed for energy. In lean people, amounts of fatty acids released into the blood stream are just sufficient for their utilization as fuel, and tissues do not become overloaded with lipid. In obese persons, however, too much fatty acid is released, and tissues become overloaded with fat. Thus, obese persons acquire excess fat in tissues, particularly muscle and liver, as well as in adipose tissue. This excess tissue fat leads to insulin resistance. Recent work suggests that obese adipose tissue also releases other factors that worsen insulin resistance, although this possibility remains to be proven.
Regular exercise "burns" off excess fat in tissues. In this way, physical activity prevents insulin resistance. Conversely, with physical inactivity, fat tends to accumulate in tissues, particularly muscle. This promotes insulin resistance. Since most Americans engage in little physical activity, they are prone to insulin resistance. This resistance in an inactive person is exacerbated in the presence of obesity. This combination of obesity and physical inactivity explains why insulin resistance is a population characteristic of the United States. It also explains why so many older Americans develop coronary heart disease or type 2 diabetes.
Fat Storage Abnormalities
If adipose tissue can hold onto fat efficiently, excess fatty acids will not be released into the blood stream. In this case, tissues do not become overloaded with fat, and insulin resistance does not develop. On the other hand, if adipose tissue is unable to hold tightly to its fat, some fat will begin to accumulate in other tissues. The latter condition can be called a fat storage abnormality.
Upper body obesity. One common example of a fat storage abnormality is found in persons who have upper body obesity. Here the fat is stored mainly in adipose tissue in the abdominal region. The location can be either within the abdomen (visceral fat) or just beneath the skin (subcutaneous fat). For reasons not well understood, abdominal fat does not hold tightly to its fat, and excess fatty acids are released into the circulation. This leads to fat overload in tissues and hence to insulin resistance. In contrast, adipose tissue in the lower body holds more tightly to its fat. Tissue overload with fat does not occur, and insulin resistance does not develop.
Insulin resistance of adipose tissue. In some persons, adipose tissue appears to be defective in fat storage, regardless of fat distribution. These persons release excess fatty acids from adipose tissue which leads to fat overload in tissues. These persons can be said to have insulin resistance of adipose tissue. Normally, circulating insulin suppresses breakdown of adipose tissue fat and reduces fatty acid release. With insulin resistance of adipose tissue, circulating insulin fails to inhibit fatty acid release. This leads to high blood levels of fatty acids, tissue overload with fat, and increased insulin resistance. Studies in the Center for Human Nutrition have shown that many patients with high blood triglyceride have insulin resistance of adipose tissue. They have high levels of fatty acids that cannot be explained by upper body obesity. In these patients, high fatty acids presumably led to liver fat overload, leading to excessive production of triglycerides into the blood stream.
Lipodystrophy. A third category of fat storage defect occurs in patients who have a deficiency of adipose tissue. In such persons, there is not enough adipose tissue to store all of the fat coming into the body from the diet. As a result, excess fat enters tissues, particularly muscle and liver. This tissue fat overload leads to insulin resistance.
A deficiency of adipose tissue is called lipodystrophy. There are three forms of lipodystrophy. In one of these, congenital generalized lipodystrophy, is characterized by almost total loss of adipose tissue. The genetic basis of this disorder has been been determined, although the chromosomal location of it has been identified. Patients with congenital generalized lipodystrophy have very severe insulin resistance. The second form of lipodystrophy is called familial partial lipodystrophy. Patients with this disorder have lost their fat in the tissue beneath the skin (subcutaneous adipose tissue).
With familial partial lipodystrophy, fat also accumulates in tissues, and insulin resistance develops. Finally, patients with AIDS who are treated with drugs called protease inhibitors also develop a form of lipodystrophy in which most of the subcutaneous is lost. They have a clinical picture similar to patients with familial partial lipodystrophy, including severe insulin resistance.
Androgens (male hormones)
Androgens appear to affect adipose tissue metabolism. In men, adipose tissue appears to accumulate preferentially in the upper body. It is well known that men are prone to development of abdominal obesity (potbelly). Thus, in a sense, male hormones induce a form of fat storage defect because of the propensity of upper body obesity to release excessive amounts of free fatty acids. This leads to excess fat accumulation in liver and muscle. Men are inherently more prone to insulin resistance than are women, who tend to accumulate fat in the lower body. It must be kept in mind that women are prone to accumulate more total body fat than occur in men. This greater fat accumulation, even in the lower body, partially offsets upper body accumulation in men. Moreover, some women have abnormally high levels of androgens. These women, who often have polycystic ovaries, develop upper body obesity and develop insulin resistance.
Corticosteroids (cortisone-like hormones)
The corticosteroids produced by the adrenal gland also have the potential to cause insulin resistance. This action is observed most dramatically in patients who have Cushings disease, which is due to overproduction of corticosteriods. Patients with Cushings disease manifest insulin resistance, and many develop type 2 diabetes. Moreover, patients who receive corticosteroids in treatment of disease also show insulin resistance. The ways in which corticosteroids cause insulin resistance are not fully understood. One mechanism may be through corticosteroids effects on adipose tissue. Patients with corticosteroid excess develop upper body obesity, which suggests that they induce a fat-storage defect. However, it also is likely that corticosteroids produce a more generalized defect in insulin signaling pathways. Some investigators speculate that mild abnormalities in the metabolism of corticosteroids contribute to the development of upper body obesity and insulin resistance in humans.
In the population as a whole, insulin resistance increases with advancing age. This rise may occur for several reasons. First, muscle mass uniformly declines with age. Since muscle is the major site of insulin action, a reduction in muscle mass will allow for less total glucose utilization. This site of defect often is accentuated in the many older persons who adopt sedentary life habits. In addition, the percentage fat content of the body increases with age. Older people have a higher percent body fat even when there is no change in body mass index. This excess adipose tissue, relative to a reduction in muscle mass, probably combines to raise insulin resistance in older persons. Finally, the possibility exists that aging leads to loss of efficiency of the insulin signaling pathways.
The importance of genetics in the development of insulin resistance is strongly suggested by variation in insulin responsiveness in different populations. The highest levels of insulin resistance are found in people of South Asian origin. Metabolic studies show that South Asians on average are about twice as insulin resistant as Caucasians. Little is known about the genetic factors that contribute to population differences in insulin resistance.
Within the Caucasian population considerable variation in insulin resistance exists. Some of this variation is acquired through differences in nutrition, body weight, physical activity, age, and hormonal status. Beyond these differences, however, genetic variation also must influence insulin responsiveness. Interest currently is high in the genetic basis of insulin resistance, and several candidate genes have been proposed. To date, none of the candidate genes have been shown to be major genes for insulin resistance in humans; but many studies are in progress.
Levels of insulin resistance also may vary between other populations. Two populations of interest are peoples of African origin and East Asian origins. Some evidence suggests that these population do not have a high genetic (racial) baseline of insulin resistance. However, these populations have not been studied fully for baseline insulin responsiveness. In contrast, Native Americans appear to have a high genetic baseline of insulin resistance. Several studies have been carried out to identify the causes of insulin resistance in Native Americans; so far however no definite major genes responsible for insulin resistance in this population has not been identified.
Metabolic Risk Factors
Elevated Blood LDL: Primary Metabolic Risk Factor
An elevated blood LDL generally is not considered to be an integral component of the metabolic syndrome. Nevertheless, it is a major independent risk factor that must be present before the other components of the metabolic syndrome can come into play as atherogenic factors. In populations around the world in which the various components of the metabolic syndrome are present, atherosclerotic coronary heart disease is relatively rare when blood LDL levels are very low. In population studies, only when LDL levels begin to rise does the incidence of coronary heart disease begin to increase. The reason for this is that LDL is the primary pathogenic agent for atherosclerosis, whereas the other risk factors associated with the metabolic syndromes are aggravating agents. The link between blood LDL levels and insulin resistance has not been extensively studied. Clearly many factors other than insulin resistance contribute to elevated LDL. However, when there is fat overload in the liver, the production of lipoproteins by the liver appears to be increased; this overproduction of lipoproteins containing apolipoprotein B will lead to some rise in LDL levels. For example, obese persons have higher LDL-cholesterol levels than do lean persons. Thus it is not possible to remove elevated LDL entirely from the metabolic syndrome.
Other Blood Lipid Disorders (Atherogenic Dyslipidemia)
Other abnormalities in blood lipids are more characteristic of the metabolic syndrome. There typically are three abnormalities that group together, hence their name, the lipid triad. These include raised triglycerides, small dense LDL particles, and low HDL. The lipid triad also has been called the atherogenic lipoprotein phenotype or atherogenic dyslipidemia. Each component of atherogenic dyslipidemia appears to independently promote atherosclerosis. Raised triglycerides indicate the presence of remnant lipoproteins, which seemingly are as atherogenic as LDL. Small LDL slip into the arterial wall more readily than normal-sized atherosclerosis, and thus have enhanced atherogenicity. Low HDL probably promotes atherosclerosis in several ways. One notable example is the ability of HDL to remove excess cholesterol from the arterial wall (reverse cholesterol transport); when HDL is low, reverse cholesterol transport is retarded.
A fourth abnormality often accompanies the lipid triad. This is an elevation of apolipoprotein B (apo B). Apo B is the major lipoprotein of LDL and triglyceride-rich lipoproteins. Some investigators believe that the total apo B level is the single best indicator for the presence of atherogenic dyslipidemia. Certainly, when total apo B levels are high, a person is at increased risk for coronary heart disease.
Patients with insulin resistance often have atherogenic dyslipidemia. When the liver is overloaded with fat, there is an overproduction of apo-B containing lipoproteins. This leads to raised triglycerides, increased remnant lipoproteins, increased total apo B, and small LDL. All of these represent a compensatory response by the liver in its attempt to cope with and remove excess fat. In addition, an important liver enzyme, hepatic lipase, also is increased in the presence of insulin resistance. This enzyme degrades HDL and contributes to the low HDL associated with insulin resistance.
High Blood Pressure (Hypertension)
An association between insulin resistance and blood pressure has been observed in several studies. In addition, obesity, which is accompanied by insulin resistance, predisposes to elevated blood pressure. Other investigations show that elevated blood pressure often clusters with the other risk factors of the metabolic syndrome. Considerable research has been carried out to investigate the mechanisms behind the association between elevated blood pressure and insulin resistance. Studies in laboratories suggest that high insulin levels directly raise blood pressure. High insulin levels appear to cause over activity of the sympathetic nervous systems, which increases blood pressure. Also, excess insulin may cause sodium retention by the kidney. These mechanisms have been difficult to reproduce in humans. Moreover, some workers have questioned whether insulin resistance is causally related to elevated blood pressure. In some populations in which insulin resistance is common, e.g. South Asians and Native Americans, hypertension is not common. Thus, the jury is still out as to whether elevated blood pressure is related more closely to insulin resistance per se or to obesity. Regardless of the precise mechanisms involved, the fact remains that elevated blood pressure commonly is found in association with other metabolic risk factors and thus must be considered a component of the metabolic syndrome.
The ways in which high blood pressure promotes atherosclerosis has never been elucidated. Some workers propose that high blood pressure injures the arterial wall which provides a substratum upon which the other risk factors can act. Another possibility is that increased hydrostatic pressure "drives" more lipoproteins into the arterial wall, which in effect, increases lipoprotein concentrations. The need for high LDL for atherogenesis in persons with hypertension is shown by the low prevalence of coronary heart disease in hypertensive populations who have very low levels of LDL.
High Blood Glucose (Hyperglycemia)
Many patients with the metabolic syndrome eventually develop elevated blood glucose. The first stage of elevation is called impaired fasting glucose, with glucose levels in the range of 110-126 mg/dL. The occurrence of impaired fasting glucose is a strong indicator of the presence of the metabolic syndrome. Whether elevations of glucose in this range directly promote atherosclerosis is not known. However, once fasting glucose levels exceed 126 mg/dL, which is called type 2 diabetes, atherogenesis is accelerated. Several possible mechanisms have been proposed to explain the very high risk of coronary heart disease in patients with type 2 diabetes. One hypothesis is that excess glucose interacts with proteins in the arterial wall to produces advanced glycation products (AGEs). These products are polymeric products that are strongly proinflammatory. Although the mechanisms for atherogenesis are not fully understood, once a patient with the metabolic syndrome develops type 2 diabetes, the risk for coronary heart disease is increased greatly.
Tendency for Blood Clotting (Prothrombotic State)
Several coagulation factors commonly are increased in persons having the metabolic syndrome. These factors include fibrinogen, von Willebrand factor, factor VII, and plasminogen activator inhibitor -1 (PAI-1). The coagulation factor that is most consistently abnormal in persons with insulin resistance and the metabolic syndrome is an elevation of PAI-1. Excess PAI-1 may be derived from either the liver or adipose tissue. The synthesis of other coagulation factors may be stimulated in the presence of insulin resistance. The combination of coagulation factors gives rise to a prothrombotic state, which predisposes to coronary heart disease. Excess coagulation factors may promote the development of atherosclerosis; alternatively, they may lead to more severe thrombosis during small coronary plaque ruptures; thus, the presence of a prothrombotic state could greatly exacerbate acute coronary syndromes (unstable angina and acute myocardial infarction).
State of Chronic Inflammation (Proinflammatory State)
A newly emerging metabolic risk factor is a proinflammatory state. Atherosclerosis must be classified pathologically as chronic inflammation. In this regard it resembles other chronic inflammatory diseases such as those caused by bacteria (e.g. tuberculosis) or auto-immune diseases (lupus erythematosus). The difference is that atherosclerosis is located in the inner lining of the artery (intima), its causes are different from other causes of inflammation, and it is an indolent process. Chronic inflammation is characterized by the presence of inflammatory cells in tissues. The major inflammatory cell of atherosclerosis is the macrophage. In addition, the smooth muscle cells of the arterial wall can acquire inflammatory properties. One unique feature of atherosclerosis is that macrophages and smooth muscle cells acquire large amounts of cholesterol, which eventually kill the cells. The causes of chronic inflammation in the artery include lipoproteins, products of cigarette smoke, and elevated blood glucose. Ultimately, when coronary plaques grow large enough, they can rupture to produce heart attack. Plaque rupture appears to occur in areas where inflammation is most active.
In persons with the metabolic syndrome, chronic inflammation in the arterial wall appears to be enhanced. This is reflected in the blood by " inflammatory markers". One of these is called C-reactive protein, which is released by the liver in the presence of enhanced inflammation. High levels of cytokines, which are proteins that activate macrophages, are another indication of enhanced inflammation. Excess cytokines, which are commonly associated with the metabolic syndrome, may arise from an excess of adipose tissue. All of the features of the proinflammatory state have not been defined; however, the relation between inflammatory processes and the metabolic syndrome is becoming a topic in intense research. If a proinflammatory state is in fact one of the risk factors of the metabolic syndrome, as it appears to be, it could contribute importantly to the development of premature coronary heart disease, and perhaps even to type 2 diabetes.
Treatment: Life-Habit Changes
Of all the causes of the metabolic syndrome, overweight heads the list. By the same token prevention of overweight will prevent or delay the onset of the metabolic syndrome in most people. Further, if a person is already overweight, successful weight reduction will eliminate most of the risk factors of the metabolic syndrome. Prevention of overweight in the general population is a major goal for public health. Treatment of overweight is a clinical problem. Recently, the National Institutes of Health have provided guidelines for clinical management of obesity.
Physical inactivity is the second major cause of the metabolic syndrome. Regular exercise is the remedy. Many research studies show that regular exercise reduces the risk factors of the metabolic syndrome. Physical activity has other benefits. It improves overall cardiovascular function. It reduces risk for heart disease, stroke, and even cancer. Moderate exercise provides almost as much health benefit as heavy exercise. The foundation of a healthy physical activity program is 30 minutes of moderate exercise (brisk walking, swimming, biking) daily. Additional and more vigorous exercise, if carried out in a safe manner, provide some additional benefit. Nonetheless care must be taken not to sustain injury during exercise; injury from strenuous exercise can interfere with even a moderate exercise program. The Surgeon General of the United States has provided a consensus report on the health benefits of different levels of exercise.
Evidence is growing that "what you eat" can affect the metabolic syndrome as well as "how much you eat". One of the major unresolved issues in nutrition that has a direct bearing on the metabolic syndrome is the optimal relationship of carbohydrate-to-fat in the diet. A long-held view maintains that a high proportion of fat energy to total energy intake favors the development of several chronic diseases, e.g. obesity, heart disease, diabetes and cancer.
Data can be mounted from both animal research and population studies to support this view. There is no question that the type of fat consumed is important. If dietary fat is high in saturated fatty acids (e.g. animal fats), the serum LDL cholesterol will rise; this predisposes to the development of coronary heart disease. However, if the dietary fat is mainly unsaturated fat, the risk for coronary heart disease is not elevated. For example, in the Mediterranean region, where high-fat diets in the form of olive oil is consumed, rates of coronary heart disease are relative low. So are cancer rates. Olive oil is rich in monounsaturated fatty acids.
Even if fats high in unsaturated fats do not raise the risk for heart disease and cancer, some researchers contend that they still may promote obesity. Studies in laboratory animals show that some species develop obesity when fed high-fat diets. On the other hand, it has been difficult to document in human studies that a high percentage of fat in the diet is associated with obesity. Controlled clinical trials on this question generally are lacking. There is little doubt that excess fat calories can contribute to obesity; but so can excess carbohydrate. Thus, the claim that a high ratio of fat-to-carbohydrate, independent of total caloric intake, promotes obesity remains to be substantiated.
Further, from the point of view of the metabolic syndrome, there are disadvantages to low-fat, high-carbohydrate diets. These diets can cause atherogenic dyslipidemia, i.e., they can raise triglycerides, lower HDL cholesterol, and induce small LDL particles. In addition, following a meal that is high in carbohydrate, there is transitory hyperglycemia (high serum glucose) and hyperinsulinemia (high serum insulin). Some investigators believe that these responses are detrimental, in that they mimic the abnormalities in lipid and glucose metabolism seen in the metabolic syndrome. These investigators thus would favor more balance between fat and carbohydrate in the diet, provided that the fat is of the unsaturated variety.
Treatment: Nutriceuticals (Supplements)
Lower LDL with Plant Stanols
A major advance for LDL lowering was the introduction of plant stanols. They are derived from plant sterols. Plants do not contain cholesterol, but require cholesterol-like molecules for cell function. These "plant cholesterols" are called plant sterols. The major plant sterol is called sitosterol. It has been known for many years that plant sterols will interfere with the absorption of cholesterol. This action produces a lowering of blood LDL-cholesterol levels. For a long time, the potential for plant sterols in cholesterol control was reexamined. Further, plant sterols have been modified to make them more effective. One modification product is called plant stanol esters. Plant stanol esters are sold commercially in the form of a margarine called Benecol.
Another product, Take Control, is a margarine containing plant sterol esters. The plant stanol product may be a somewhat better LDL lowering margarine than the plant sterol product. Moreover, none of the plant stanol is absorbed, whereas small amounts of the plant sterol product are absorbed, which theoretically could have detrimental effects. Therefore plant stanols may be preferred over plant sterols. Regardless, the daily ingestion of three grams per day of the plant stanol (or sterol) will lower the LDL cholesterol by 10-15 percent. These product make an ideal supplement to use with a cholesterol-lowering diet.
Several lines of evidence point to oxidative damage to the organic molecules as a pathological process. Particularly vulnerable to oxidation are DNA, proteins, and lipids. Oxidative damage occurs continuously, and the body has mechanisms for repair. However, should damage exceed the body's ability to repair, then pathological consequences may result. Foremost on the list of possible diseases are atherosclerosis and coronary heart disease, cancer, Alzheimer disease, and aging itself. In reference to the metabolic syndrome, excessive oxidation comes under the category of a pro-inflammatory state.
For example, oxidized lipoproteins in the arterial wall set off an inflammatory reaction that promotes the development of atherosclerosis. This inflammatory component of atherosclerosis raises the question of whether antioxidants might slow down the development of this disease.
One antioxidant that delays oxidation of low density lipoproteins (LDL) is vitamin E. This vitamin is a lipid which is carried in LDL. If oxidation of LDL within the arterial wall really is an important factor in atherogenesis, then high doses of vitamin E could retard this process. Studies in laboratory animals provide suggestive evidence that vitamin E and other antioxidants will slow down development of atherosclerosis. Moreover, epidemiological studies indicate that populations that consume large amounts of antioxidants have less coronary heart disease than those with low antioxidant intakes do. To date, however, the value of vitamin E for reducing risk for coronary heart disease has not been proved through controlled clinical trials.
A variety of other substances have antioxidant properties, for example, vitamin C, beta-carotene, and flavonoids. Vitamin C has long been thought to be protective against various diseases, in part due to its antioxidant properties. In contrast to vitamin E, which is fat-soluble, vitamin C is water-soluble. The story with vitamin C is similar to that for vitamin E. Research in laboratory animals is suggestive of some protective effect. Moreover, populations that consume liberal quantities of vitamin C, in the form of fruits and vegetables, have lower rates of heart disease and cancer. It must be noted that not all epidemiological studies however find evidence of a beneficial effect from high intakes of vitamin C. And perhaps more important, controlled clinical trials have never been performed that document the benefit of vitamin C. The current RDA for vitamin C is 75 mg per day for women and 90 mg per day for men. This is somewhat higher than earlier RDAs. However, it is not nearly as high as the 500-1000 mg per day that are suggested by those who believe that vitamin C will protect against heart disease, cancer, and aging. Although the scientific evidence for a long-term beneficial effect of high doses of vitamin C is not strong, the side effects are few. This leads many people to opt for higher intake on theoretical grounds, in the absence of definitive controlled clinical trials.
Treatment: Pharmaceuticals (Drugs)
Since LDL cholesterol is the primary risk factor for coronary heart disease, the first priority in drug treatment of the metabolic syndrome is to lower the LDL-cholesterol level. Fortunately, powerful LDL-lowering drugs are now available. Drugs call statins head the list of LDL-lowering drugs. Another drug category includes the bile acid sequestrants. A new bile acid sequestrant, called WelChol, is particularly attractive for LDL lowering. Most patients who already have coronary heart disease should receive an LDL-reducing agent. In addition, in patients without coronary heart disease who have elevated LDL cholesterol will be candidates for drug therapy if they have the metabolic syndrome. The demonstration of the efficacy of LDL-lowering drugs in high-risk patients points to the need to make LDL lowering a critical component of treatment of the metabolic syndrome.
Many persons with the metabolic syndrome also have elevations of serum triglycerides. A critical question is whether they also should receive drugs to lower triglycerides. The first priority is LDL lowering. Once this priority is attained, consideration can be turned to reducing triglycerides. Two kinds of drugs are available for treatment of elevated triglycerides. They are nicotinic acid and fibric acids. Between these two, nicotinic acid is the most powerful. Not only does it effectively lower triglycerides, but it also strongly raises HDL. On the other hand, it has more side effects than do the fibric acids. For this reason, in clinical practice, fibric acids usually are the preferred drugs. Available fibric acids are gemfibrozil and fenofibrate. If a patient has an elevated triglyceride and a low LDL, a triglyceride-lowering drug can be used as a single agent. But if LDL is elevated, the usual practice is to lower LDL with a cholesterol-lowering drug and then decide whether to add a second drug — a nicotinic acid or a fibric acid. These drug combinations are highly effective. Of course, combined therapy increases the costs of treatment; and the frequency of side effects increases by drug combination.
Blood pressure regulating drugs
Over the past four decades enormous advances have been made in the development of drugs for the treatment of high blood pressure. Four classes of drugs have emerged at the top of the list: diuretics, beta-adrenergic blocking agents (beta-blockers), angiotensinogen converting enzyme inhibitors (ACE inhibitors), and calcium channel blockers. With these drugs, either alone or in combination, high blood pressure can be corrected in the vast majority of persons. They have made it possible to effectively treat the high-blood pressure component of the metabolic syndrome. There is little excuse for allowing patients to remain hypertensive. The first step is detection of high blood pressure. Any person with clinical evidence of the metabolic syndrome should have regular checks for elevated blood pressure. When it is found, it should be treated. Although changes in eating habits and other life habits will eliminate hypertension in some patients with the metabolic syndrome, many will require the use of blood-pressure lowering medications.
Drugs against insulin resistance
Since insulin resistance appears to be intimately associated with the metabolic syndrome, the development of drugs that will reduce insulin resistance is an attractive concept. No such drug has been perfected. Nonetheless the search for drugs acting against insulin resistance is intense. One group of drugs will in fact reduce insulin resistance. These drugs act to stimulate a nuclear receptor called PPAR gamma. Two agents that currently are available for clinical practice are rosiglitazone and pioglitazone. Their use at present is restricted to patients with type 2 diabetes. Their long-term safety of persons with the metabolic syndrome, who do not have type 2 diabetes, has not been proven. Nonetheless, they represent a first step toward the develop of a new category of drugs that may attack the basic mechanism of the metabolic syndrome. It is to be expected that more drugs against insulin resistance will be developed in the future.
Another risk factor of the metabolic syndrome is a prothrombotic state. Two types of drugs could potentially reduce a tendency for thrombosis. One of these is an anti-platelet drug like aspirin. Even more powerful anti-platelet drugs have been developed and are in clinical practice for patients with some forms of cardiovascular disease. Another drug category acts against the protein clotting factors. Warfarin is the best known drug of this type. Both antiplatelet drugs and warfarin have been demonstrated to reduce risk for myocardial infarction. Between the two, the anti-platelet drugs are safer and are much more widely used. In the future, new pharmaceutical approaches to reduce the prothrombotic state likely will become available.
A final type of drug that might reduce risk for coronary heart disease in patients with the metabolic syndrome is one that acts to reduce inflammation. As mentioned, chronic inflammation is at the heart of atherogenesis; and it also seems to play a vital role in the causation of coronary plaque rupture, the immediate cause of myocardial infarction. In fact, three agents in use even now appear to dampen the inflammatory process. LDL-lowering drugs almost certainly reduce the chronic inflammation that occurs within the arterial wall; this is because LDL itself is a proinflammatory agent.
Aspirin also has anti-inflammatory properties, and some investigators believe that part of the action of aspirin to reduce risk for myocardial infarction lies in its ability to suppress inflammation. Finally Vitamin E is anti-inflammatory. It reduces the inflammatory properties of macrophages. These agents must be considered to be "first-generation" anti-inflammatory drugs to be used to slow down development of atherosclerosis. A large commitment has been made to understand the atherogenesis at the level of the arterial wall; this understanding will reside largely in the area of chronic inflammation. When new drugs are developed that prevent atherosclerosis at the arterial-wall level, they probably will act as anti-inflammatory drugs.