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Thursday, May 23, 2013
Cardiovascular Risk Factors
Clustering of Cardiovascular Risk Factors: Metabolic Syndrome
Body Fat Distribution and Insulin Resistance
The Connection between Insulin Resistance and Diabetes
Prevention and Treatment of the Metabolic Syndrome
Glossary of Terms
Obesity is a major public health problem that is becoming more common among adults and increasing rapidly in children and adolescents. Obesity has been linked to a broad range of physical, emotional and socioeconomic problems. Importantly, in some people excess body fat causes an increased risk for vascular disease, including heart disease and stroke. Increased fat stored in intra-abdominal deposits is associated with, and may cause, an increase in risk factors for atherosclerotic cardiovascular disease (ASCVD).
There are a number of well established factors that when present increase an individual's risk for atherosclerosis involving the blood vessels to the heart and other vital organs. These risk factors include: Hypertension, elevated levels of cholesterol, particularly LDL-cholesterol, in the blood, diabetes and hyperglycemia, and cigarette smoking. Another important risk factor is a family history of heart disease. To these 5 first order risk factors have been added a number of newer measures that may explain a tendency to get heart disease. High levels of triglyceride and low levels of HDL-cholesterol are a combination that can have as bad an effect on blood vessels as elevated cholesterol. Markers of inflammation such as C-reactive protein and tumor necrosis factor also seem to be linked with increased occurrence of ASCVD. Finally, increased levels of proteins involved in blood clotting such as fibrinogen and PAI may play a role in promoting atherosclerosis.
It has long been known that cardiovascular risk factors are not distributed randomly among members in a population but seem to cluster together in the same individuals. That is to say, people at risk to get diabetes are also more likely to have problems with high blood pressure and abnormalities in their blood triglyceride and cholesterol levels. Similarly, individuals with hypertension are more likely to develop impaired glucose tolerance, a type of pre-diabetes. This clustering, or development of several risk factors at once, leads to a greatly increased risk for ASCVD. At the other end of the spectrum, there are many individuals who never develop any risk factors for ASCVD. The designation of Metabolic Syndrome recognizes the fact that risk factors cluster and the diagnosis is based on the presence of specific abnormalities predisposing to cardiovascular disease. There are currently two sets of criteria for Metabolic Syndrome, one put forth by the World Health Organization (WHO) and the other by the National Institutes of Health (NIH). These working definitions are similar and include some element of abnormalities in glucose/insulin, blood pressure and lipids, and obesity. In general a person who is classified with Metabolic Syndrome by the WHO criteria is also diagnosed using the NIH criteria. The fact that two sets of standards exist indicates that the understanding and use of the term Metabolic Syndrome is new and evolving.
|Table 1- Definitions of the Metabolic Syndrome
1. Waist hip ratio > 0.85 in women and > 0.9 in men or Body mass index of > 30 kg/m2
1. Abdominal obesity: waist circumference > 35 inches in women or 40 inches in men
The clustering of risk factors in some individuals and complete sparing in others suggests that a common abnormality is involved in causing these problems. In fact, it is generally agreed on that increased body weight and particularly central obesity is at the core of Metabolic Syndrome. It has been known for many years that body fat tends to be distributed in different patterns. That is, some people tend to store a larger amount of fat in their hips and buttocks, while others have more of their body fat in their abdomen. These patterns have in the past been termed gynoid and android obesity because of the general tendency of women to have more fat in peripheral sites (hips and buttocks) and men to store fat centrally (in their abdomen). Interestingly, some of the distribution of body fat seems to be driven by sex hormones since men who make low levels of testosterone often have a gynoid distribution of body fat, and women tend to shift to a more android pattern after menopause when their estrogen levels decline. However, it is clear that the distribution of body fat is much more complex than the rules of gender since the patterns of body fat distribution overlap considerably among men and women.
Central, or abdominal, fat is more metabolically active than peripheral fat. This is to say that rates of fat storage and fat release are greater in central fat deposits than fat collections in the hips. On the one hand central fat is the site that decreases first when people embark on physical training sufficient to lose weight. On the other hand, in societies where food consumption is high and people are sedentary, central obesity seems to be a prominent problem. Interestingly, the weight gain or change in body composition that is commonly seen as people age often involves a relative increase in central fat stores.
It is now established that obesity is associated with the various components of Metabolic Syndrome and that central obesity is even more predictive than total body weight of a predisposition to ASCVD. Obesity, especially central obesity, causes insulin resistance, a decrease of the typical responses of tissues to the hormone insulin. Insulin resistance is primarily measured as the ability of insulin to decrease blood glucose levels because this is one of the primary actions of insulin. Since the normal response to decreased insulin action is to secrete more insulin, people with insulin resistance often times have higher than normal insulin levels; this is termed hyperinsulinemia. Insulin resistance is probably the most common feature of Metabolic Syndrome and may be the link that causes the other factors to cluster together. For example, it has been proposed that hyperinsulinemia causes increased triglyceride production by the liver and salt retention by the kidney, effects that could lead to increases in circulating lipids and blood pressure.
There are two points about hyperinsulinemia that are important for understanding the diagnosis and treatment of Metabolic Syndrome. First, insulin levels in the blood vary considerably between different people and within a given individual throughout the day. Thus, there are no clear standards to use in clinical practice that absolutely define a high from an appropriate insulin level in a given person. Second, insulin resistance and hyperinsulinemia are intermediary features of Metabolic Syndrome- more markers than root cause. Central obesity causes insulin resistance, and while hyperinsulinemia may bring out other features of Metabolic Syndrome, lowering blood insulin levels alone is not a useful treatment approach (and in fact would cause high blood glucose levels or diabetes).
The causative link between central body fat and insulin resistance has not been proven. However, a number of possibilities to explain this connection are now under study including: increased levels of fatty acids in the blood, fat derived hormones and cytokines, and abnormalities in the brain's interpretation and coordination of metabolic cues.
One of the most important consequences of insulin resistance is the development of diabetes. Normally blood glucose is controlled in a tight range through a balance of insulin secretion and insulin sensitivity. In persons who are very sensitive to insulin (generally lean, young and physically fit people) the amount of insulin that must be secreted to keep blood glucose controlled is low. Conversely in persons who are relatively insensitive to the action of insulin (generally heavy, older, inactive people) more insulin must be secreted to overcome resistance and maintain normal blood glucose. As long as the pancreas can produce sufficient insulin even very insulin resistant individuals will maintain normal blood glucose levels. However, defects in insulin secretion are fairly common in the population and tend to develop as people age. The combination of suboptimal insulin release with insulin resistance is the major cause of impaired glucose intolerance or type 2 diabetes. Diabetic patients also very frequently fit the classification of Metabolic Syndrome, a fact best explained by the key role of insulin resistance in both diagnoses. The clustering of risk factors in persons with diabetes accounts for why they have 2-4 times the risk of ASCVD as most nondiabetic persons. However, many persons without diabetes also fit the criteria for Metabolic Syndrome, and the clustered risk factors in these people identifies them as high risk for heart disease and related problems. This is the primary value of defining Metabolic Syndrome as a clinical entity.
Heart disease and other components of ASCVD like stroke, remain the major cause of death in the United States. In the last 10-20 years advances in treatment of cardiac risk factors have been shown to prevent clinical events. For example, effective treatment of hypertension or elevations in blood cholesterol or triglycerides decreases the incidence of myocardial infarction (heart attacks) and death. Furthermore rigorous treatment of diabetes also decreases vascular complications. These findings have coalesced into the clinical practice of preventive cardiology, which is the strategy of trying to prevent heart disease by minimizing or correcting risk factors.
Current estimates are that approximately 25% of American adults, and an increasing percentage of children and adolescents, can be classified as having Metabolic Syndrome. The wide prevalence of Metabolic Syndrome makes this condition a major contributor to cardiovascular risk. First and foremost these individuals are best served by identifying and trying to minimize risk factors. Thus, elevations in blood pressure should be detected, treated and monitored. Blood levels of cholesterol and triglyceride should be determined and diet and medications instituted if they are high. Blood glucose should be measured after a 10-12 hour fast (usually overnight) to detect diabetes or suggestions of glucose intolerance. These patients should receive special encouragement to stop smoking if they do so, and a clear warning not to start if they do not smoke.
Probably the single most effective approach to the abnormalities comprising Metabolic Syndrome is weight loss. A decrease of about 10% of body weight is often sufficient to have a major impact on blood pressure, plasma lipids and glucose, insulin resistance and the other abnormalities of Metabolic Syndrome. However, losing weight is very challenging for most people in our society and none of the currently available approaches- diet, exercise, or medications- are effective for the long term maintenance of weight loss. Some combination of caloric restriction and exercise should be suggested for most patients with Metabolic Syndrome, but given the limited response in most patients, should not replace treatment of specific risk factors.
Metabolic Syndrome is a clinical designation that is useful for identifying persons at high risk for ASCVD. The definition of Metabolic Syndrome recognizes the clustering of important risk factors for cardiac and vascular disease. The core abnormality of Metabolic Syndrome is an increase in body fat, most commonly some form of central obesity. Having increased amounts of abdominal fat causes insulin resistance which may then lead to other abnormalities such as hypertension, elevated triglycerides and impaired glucose tolerance. Persons diagnosed with Metabolic Syndrome benefit from treatment of risk factors to prevent ASCVD.
Atherosclerosis - the process of disease in blood vessels leading to narrowing and diminished blood flow. Atherosclerosis occurs when cholesterol and other lipids are deposited in the artery wall, and inflammation and other degenerative processes cause the vessel to become obstructed. Atherosclerosis involves primarily arteries and reduced blood flow leads to damage of the tissues that do not receive enough oxygen and nutrients. Also called hardening of the arteries.
Atherosclerotic cardiovascular disease (ASCVD) - the clinical result of atherosclerosis. Myocardial infarction (heart attack), and stroke are the most common and significant forms of ASCVD. Disease of the legs and kidneys can also occur from atherosclerosis.
Body composition - the relative proportions of fat, muscle and bone making up a given human. Body composition can be measured experimentally using several techniques such as underwater weighing, DEXA and CT scan. The total percentage of body fat in a lean individual is about 20%. Obesity results from increased fat mass so that the percent body fat is typically higher than 30%.
C-reactive protein - a small molecule secreted from the liver and other tissues in response to inflammation. The function of C-reactive protein is not clear, but it can be used as a marker of the amount of inflammation occurring in a person. Inflammation is now known to contribute to atherosclerosis and C-reactive protein can be used as a risk factor for this.
Central obesity - increased amounts of fat stored in the abdominal cavity. Central obesity is frequently detected by measuring the circumference of the abdomen and comparing it to the circumference of the hips. A waist to hip ratio of > 0.85 in overweight women and > 0.9 in overweight men is indicative of central obesity. Also called intra-abdominal or visceral obesity.
Cytokines - signaling molecules released from immune cells (like lymphocytes) or fat cells (adipocytes) that are typically part of the inflammation response. Cytokines such as tumor necrosis factor have also been implicated in insulin resistance.
Glucose intolerance - increased blood glucose levels following a meal (or glucose tolerance test). The degree of glucose elevation can be severe, for example in diabetes, or relatively modest in persons with impaired glucose tolerance, a state of abnormal glucose metabolism between normal and diabetic.
HDL cholesterol - high density lipoprotein cholesterol. These are specific particles that are important in carrying cholesterol from peripheral sites, like the blood vessels, to the liver for processing or breakdown. High levels of HDL particles promote removal of lipid from blood vessels and decrease the risk for ASCVD. Low levels of HDL are a risk factor for heart disease.
Hyperglycemia - elevated blood glucose levels. Hyperglycemia occurs in normal people after they eat, but the level is modest and restored to the fasting level within 60-90 minutes. Persons with impaired glucose intolerance have normal glucose levels after an overnight fast but more pronounced hyperglycemia after eating. Diabetic individuals have hyperglycemia in the fasting state and this worsens after meals.
Hyperinsulinemia- elevated levels of plasma insulin. Insulin levels increase normally after eating. Fasting levels of insulin are generally proportional to the degree of insulin resistance- higher levels suggest worse insulin resistance.
Triglyceride - The major storage form of fat as three fatty acids attached to a glycerol backbone. Triglycerides are the major form of lipid in the diet and are an excellent source of energy and the most efficient form of stored fuel.
Type 2 diabetes - the most common form of diabetes accounting for approximately 90% of cases in America. Persons with type 2 diabetes have a combination of decreased insulin secretion and insulin resistance that combine to cause hyperglycemia. Most persons with type 2 diabetes have Metabolic Syndrome.
The information in this article is based on "METABOLIC SYNDROME: The Dark Side of the Obesity Epidemic" presented on October 7, 2003 at the University of Cincinnati Mini Medical College, and was adapted for use on NetWellness with permission, 2004.
Last Reviewed: Apr 26, 2004
David D´Alessio, MD
Professor of Clinical Medicine
College of Medicine
University of Cincinnati