Chapter 2
Weight and Physical Health

If we could give every individual the right amount of nourishment and exercise, not too little and not too much, we would have found the safest way to health

—Hippocrates c. 460–377 bc

During the twentieth century, advances in public health and medical care helped Americans to lead longer, healthier lives. Two important measures of the health of the population are infant mortality (death) rates and life expectancy at birth rates. Infant mortality rates significantly decreased and life expectancy increased by thirty years. Table 2.1 shows the decline in infant mortality between 1983 and 2001 as well as the slight increase in 2002, which probably represents a leveling off rather than a statistically significant rise in infant mortality. Table 2.2 shows the long-term upward trend in life expectancy as well as recent gains. In 2002 life expectancy at birth for the total population reached a record high of 77.3 years, up from 75.4 years in 1990. The CDC estimated that in 2005 life expectancy at birth had increased to 77.6 years.

As deaths from infectious diseases declined, mortality from chronic diseases, such as heart disease and cancer, increased. Table 2.3 displays the ten leading causes of death in the United States in 1980 and 2002. Overweight and obesity are considered contributing factors to at least four of the ten leading causes of death in 2002—diseases of the heart, malignant neoplasms (tumors), cerebrovascular diseases (diseases affecting the supply of blood to the brain), and diabetes mellitus. (Obesity also may be implicated in some deaths attributable to another leading cause of death—kidney disease or chronic renal failure, which are called nephritis, nephrotic syndrome, and nephrosis in Table 2.3.) Table 2.3 also reveals the rise of diabetes as a cause of death. In 1980 it was the seventh leading cause of death, claiming nearly 35,000 lives. By 2002 it rose to the sixth leading cause of death overall, the fifth leading cause of death among women, and the sixth leading cause of death among men. It was the underlying cause of over 73,000 deaths and was mentioned on the death certificates of more than twice as many additional deaths. Epidemiologists (scientists who study the occurrence and distribution of diseases and the factors that govern their spread) and medical researchers believe that the increasing prevalence of diabetes in the U.S. population and the resultant rise in deaths attributable to diabetes are direct consequences of the obesity epidemic in America.

Figure 2.1 reveals little change in the prevalence of overweight and obesity between the 1960s and 1980, and increasing prevalence of overweight and obesity in the two decades between 1980 and 2000. As Figure 2.1 shows, 65% of American adults were overweight during 1999–2002, including the 31% who were classified as obese. The prevalence of obesity varies somewhat by gender, race, and ethnicity. In 1999–2002 slightly more women (34%) than men (28%), and one-half of non-Hispanic black women, were obese. (See Figure 2.2.)

Overweight and obesity not only increase the risk of morbidity (disease) and mortality (death) but also the severity of diseases such as hypertension (high blood pressure), arthritis, and other musculoskeletal problems. Table 2.4 lists the health consequences that may result from overweight and obesity among adults and children. It also estimates the likelihood of these health consequences. For example, adults who are obese are twice as likely to suffer from high blood pressure as adults who are at a healthy weight

In 2005 S. Jay Olshansky and his colleagues at the University of Illinois suggested that the steady rise in life expectancy the U.S. enjoyed during the past two centuries might soon come to an end. The investigators used obesity prevalence data and previously published estimates of years of life lost from obesity to project life expectancy. Instead of using historical trends to forecast life expectancy, they calculated in reverse, assessing the fall in death rates that would occur if all obese Americans had a normal weight. Their projections revealed that within fifty years, obesity is likely to reduce the average life expectancy in the United States by at least two to five years from its present 77.6 years. The impact of obesity and its health consequences on life expectancy was considered larger than cancer or heart disease (S. Jay Olshansky et al., "A Potential Decline in Life Expectancy in the United States in the 21st Century," New England Journal of Medicine, vol. 352, no. 11, March 17, 2005).

IS OBESITY A DISEASE?

Researchers now recognize that obesity does not simply result from willful overeating and laziness, but from a complex combination of genetic, metabolic, behavioral, and environmental factors. Rather than viewing it as a lifestyle choice or personal failing, many groups favor declaring obesity a disease. Proponents assert that many public health benefits would result from designating obesity as a disease including:

• Reducing the social stigma and prejudice associated with obesity, and promoting attitudinal changes to reduce weight-based discrimination.
• Enabling more people to seek treatment for obesity by providing health insurance coverage for treatment.
• Increasing public awareness of the severity of obesity as a threat to health and longevity.
• Stimulating scientific and medical research about prevention and treatment of the condition and speeding approval of new antiobesity drugs.

Advocates of classifying obesity as a disease, including the World Health Organization, National Institutes of Health, National Academy of Sciences' Institute of Medicine, Federal Trade Commission, Maternal and Child Health Bureau, American Heart Association, American Academy of Family Physicians, American Society for Bariatric Surgery, American Society of Bariatric Physicians, and the American Obesity Association (AOA), observe that not long ago in American history alcoholism was viewed as a personal choice or moral weakness, whereas today it is considered a disease. They also observe that such eating disorders as anorexia and bulimia are termed diseases. In view of the size and scope of the obesity epidemic, proponents argue that the social and financial costs of allowing it to go unchecked will far exceed the costs associated with extending health-care coverage for weight-reduction programs.

The AOA argues that obesity meets the criteria for disease because according to Stedman's Medical Dictionary a disease should have at least two of the following three features:

1. Recognized etiologic (causes) agents
2. Identifiable signs and symptoms
3. Consistent anatomical alterations

The AOA describes causative agents for obesity as social, behavioral, cultural, physiological, metabolic, and genetic factors. The identifiable signs and symptoms of obesity include an excess accumulation of adipose tissue (fat), an increase in the size or number of fat cells, insulin resistance, decreased levels of high-density lipoprotein (HDL) and norepinephrine, and alterations in the activity of the sympathetic and parasympathetic nervous system as well as elevated blood pressure and blood glucose, cholesterol and triglyceride levels. The consistent anatomic alteration of obesity is the increase in body mass.

Opponents contend that while obesity increases the risk of developing many diseases, it is not an ailment in itself but an unhealthy consequence of poor lifestyle choices. They liken it to cigarette smoking, a risk factor that predisposes people to disease, and they dispute the notion that labeling obesity as a disease will have a beneficial effect on the ability of public health organizations to alter the course of the obesity epidemic. They maintain that the public tends to view diseases as conditions that are contracted or contagious, and that with disease comes a victim mentality, rather than assumption of personal responsibility. Since many health professionals consider assumption of personal responsibility as

crucial for the long-term success of obesity treatment, any action that releases people from assuming personal responsibility is counterproductive.

In July 2004 Rick Berman, executive director of the Center for Consumer Freedom, a food-industry-funded advocacy group, decried the move to designate obesity as a disease. "This is truly a dumbing-down of the term 'disease.' This is the only disease that I'm familiar with that you can solve by regularly taking long walks and keeping your mouth shut. It's terrible to start using taxpayer money like this when there are other legitimate diseases that need to be addressed" (Rob Stein and Ceci Connolly, "Medicare Changes Policy on Obesity: Some Treatments May Be Covered," Washington Post, July 16, 2004).

In addition to Berman's concern that dollars spent to pay for weight-loss therapies would be diverted from other serious ailments, some observers fear that the nation's health-care system could collapse under the weight of a far-reaching official policy that declares obesity a disease. Opponents to granting disease status to obesity predict that the financial ramifications would be devastating for taxpayers and the health insurance industry. Health-care costs, already escalating every year, would skyrocket. Antiobesity programs would drive insurance premiums even higher and place unreasonable burdens on the already overburdened Medicare and Medicaid programs. Employers, especially small businesses, might be forced by high health-care costs to drop employee coverage altogether.

A related concern is the lack of universally accepted, effective treatment for obesity. If obesity is classified as a disease, which treatment or therapies should be covered? For example, if exercise is deemed beneficial, then health insurers might be required to pay for gym memberships. Further, some opponents believe that it is not necessary to designate obesity as a disease in order to encourage Americans to seek treatment. They cite the more than $50 billion spent annually on weight-loss programs and services as evidence that Americans are not reluctant to seek treatment.

Although the debate has not been fully resolved, obesity is rapidly acquiring recognition as a disease. In 2002 the Internal Revenue Service ruled that for tax purposes, obesity is a disease, allowing Americans for the first time to claim a deduction for some health-care expenses related to obesity, just as they can for expenditures related to heart disease, cancer, diabetes, and other illnesses.

In July 2004 the federal Medicare program discarded its long-standing position that obesity is not a disease, which effectively removed a major roadblock for people seeking coverage for treatment of obesity. After years of review, the Centers for Medicare & Medicaid Services, which administers the health program for older adults and people who are disabled, announced that it had eliminated language—that "obesity itself cannot be considered an illness"—from its policy that had been used to deny coverage for weight-loss treatment. Although the decision stopped short of declaring obesity a disease and does not automatically imply coverage for any specific treatment, it enables individuals, physicians, and companies to apply to Medicare for reimbursement for a variety of weight-loss therapies. Since private insurance companies often use Medicare as a model for their coverage and benefits, the Medicare decision has pressured them to expand coverage for weight-loss treatments. Ironically, the Medicare decision was announced at the same time many private insurers intended to eliminate or sharply curtail coverage of weight-loss surgery.

TABLE 2.4

Health consequences of overweight and obesity

Premature death

• An estimated 300,000 deaths per year may be attributable to obesity.
• The risk of death rises with increasing weight.
• Even moderate weight excess (10 to 20 pounds for a person of average height) increases the risk of death, particularly among adults aged 30 to 64 years.
• Individuals who are obese (body mass index (BMI) > 30) have a 50 to 100% increased risk of premature death from all causes, compared to individuals with a healthy weight.

Heart disease

• The incidence of heart disease (heart attack, congestive heart failure, sudden cardiac death, angina or chest pain, and abnormal heart rhythm) is increased in persons who are overweight or obese (BMI >25).
• High blood pressure is twice as common in adults who are obese than in those who are at a healthy weight.
• Obesity is associated with elevated triglycerides (blood fat) and decreased high density lipoprotein (HDL) cholesterol ("good cholesterol").

Diabetes

• A weight gain of 11 to 18 pounds increases a person's risk of developing type 2 diabetes to twice that of individuals who have not gained weight.
• Over 80% of people with diabetes are overweight or obese.

Cancer

• Overweight and obesity are associated with an increased risk for some types of cancer including endometrial (cancer of the lining of the uterus), colon, gall bladder, prostate, kidney, and postmenopausal breast cancer.
• Women gaining more than 20 pounds from age 18 to midlife double their risk of postmenopausal breast cancer, compared to women whose weight remains stable.

Breathing problems

• Sleep apnea (interrupted breathing while sleeping) is more common in obese persons.
• Obesity is associated with a higher prevalence of asthma.

Arthritis

• For every 2-pound increase in weight, the risk of developing arthritis is increased by 9 to 13%.
• Symptoms of arthritis can improve with weight loss.

Reproductive complications

Complications of pregnancy

• Obesity during pregnancy is associated with increased risk of death in both the baby and the mother and increases the risk of maternal high blood pressure by 10 times.
• In addition to many other complications, women who are obese during pregnancy are more likely to have gestational diabetes and problems with labor and delivery.
• Infants born to women who are obese during pregnancy are more likely to be high birthweight and, therefore, may face a higher rate of Cesarean section delivery and low blood sugar (which can be associated with brain damage and seizures).
• Obesity during pregnancy is associated with an increased risk of birth defects, particularly neural tube defects, such as spina bifida.
• Obesity in premenopausal women is associated with irregular menstrual cycles and infertility.

Additional health consequences

• Overweight and obesity are associated with increased risks of gall bladder disease, incontinence, increased surgical risk, and depression.
• Obesity can affect the quality of life through limited mobility and decreased physical endurance as well as through social, academic, and job discrimination.

Children and adolescents

• Risk factors for heart disease, such as high cholesterol and high blood pressure, occur with increased frequency in overweight children and adolescents compared to those with a healthy weight.
• Type 2 diabetes, previously considered an adult disease, has increased dramatically in children and adolescents. Overweight and obesity are closely linked to type 2 diabetes.
• Overweight adolescents have a 70% chance of becoming overweight or obese adults. This increases to 80% if one or more parent is overweight or obese.
• The most immediate consequence of overweight, as perceived by children themselves, is social discrimination.

source: "Overweight and Obesity: Health Consequences," in The Surgeon General's Call to Action to Prevent and Decrease Overweight and Obesity, U.S. Department of Health & Human Services, Office of the U.S. Surgeon General, 2001, http://www.surgeongeneral.gov/topics/obesity/calltoaction/fact_consequences.htm (accessed January 9, 2006)

Inspired by the change in Medicare policy, Blue Cross and Blue Shield of North Carolina, the state's largest health insurance company announced in October 2004 that it would offer more than one million of its members comprehensive coverage and benefits to prevent and treat overweight and obesity. The insurance company began paying for four visits to a physician per year specifically to evaluate body weight and provide a range of treatment options including nutritional counseling, prescription diet drugs, and weight-loss surgery.

In 2005 the American Medical Association (AMA) adopted directives that suggest that this powerful professional organization will soon enter into this debate. Specifically, the AMA "Will work with the Centers for Disease Control and Prevention to convene relevant stakeholders to evaluate the issue of obesity as a disease, using a systematic, evidence-based approach." The AMA also resolved to continue to "actively pursue measures to treat obesity as an urgent chronic condition, raise the public's awareness of the significance of obesity and its related disorders, and encourage health industries to make appropriate care available for the prevention and treatment of obese patients."

THE GENETICS OF BODY WEIGHT AND OBESITY

Genetics, the study of single genes and their effects, explains how and why such traits as hair color and blood types run in families. In the early twenty-first century the scientific community agrees that body shape and body weight also are regulated traits, that genes govern much of this regulation, and that altering genetically predetermined set points for body weight is often difficult. "Geno-mics," a discipline that emerged during the 1980s, is the study of more than single genes; it considers the functions and interactions of all the genes in the genome. In terms of understanding genetics as a risk factor for obesity, genomics has broader applicability than does genetics because it is likely that humans carry dozens of genes that are directly related to body size, and most obesity is multi-factorial—resulting from the complex interactions of multiple genes and environmental factors.

Since genomics is a relatively new discipline, many questions are still unanswered about how genes influence the ability to balance energy input and energy expenditure, and why individuals vary in their abilities to perform this critical body function. Table 2.5 summarizes what is known and what remains to be learned about variations in body weight, energy metabolism, and inherited obesity syndromes.

Single Mutant Genes Cause Obesity

While the majority of obesity in humans is not due to mutations (alterations or changes) in single genes, there are obesity syndromes caused by variations in single genes, and these account for approximately 5% of all obesity. In rare cases of severe obesity that begin during childhood, a single gene has a major effect in determining the occurrence of obesity, with environmental factors playing a lesser role. The mutations occur in genes that encode proteins related to the regulation of food intake. One example is mutations of the leptin gene (on chromosome 7) and its receptor. The circulating hormone leptin (leptos means thin) sends the brain a satiety signal to decrease appetite. Obese mice of the ob/ob strain produce no leptin and tend to overeat; when given leptin, the mice stop eating and lose weight. Unfortunately, experiments have failed to replicate these findings in humans. Blood concentrations of leptin are usually elevated in obese humans, suggesting that they may be insensitive or resistant to leptin, rather than leptin deficient. The majority of obese individuals appear to have normal genetic sequences for leptin and its receptor, although humans with a demonstrable genetic leptin deficiency suffer from extreme obesity.

Melanocortin 4 receptor (MC4R) deficiency is the most commonly occurring monogenic (single gene) form of obesity. Nearly 6% of people with severe obesity commencing in childhood have this mutation. Inheriting one copy of certain variants of the gene causes obesity in some families. Researcher I. Sadaf Farooqi and his colleagues screened 500 subjects with severe, early-onset obesity for mutations in MC4R and conducted clinical studies of those with mutations. The investigators conducted body composition studies, measured subjects' resting metabolic rates (calories expended at rest), performed metabolic and endocrine testing, and assessed eating behaviors. In "Clinical Spectrum of Obesity and Mutations in the Melanocortin 4 Receptor Gene" (New England Journal of Medicine, vol. 348, no. 12, March 2003), the investigators reported that mutations in MC4R produced a distinct obesity syndrome that is inherited. They also concluded that these mutant receptors played a pivotal role in the control of eating behavior—that regulation of body weight in humans is sensitive to variations in the amount of functional MC4R.

Multiple Gene Variants Involved in Body Weight and Obesity

It has long been known that heredity affects health. Heritability studies, which seek to determine the proportion of variance of a particular trait that is attributable to genetic factors and the proportion that is attributable to environmental factors, indicate that genetic factors may account for as much as 75% of the variability in human body weight and approximately one-third of the variation in the overall body mass index (BMI; body weight in kilograms divided by the height in meters squared). Genetic factors affect the variations in resting metabolic rate, body fat distribution, and weight gain related to overfeeding, which explains in part why some individuals are more susceptible than others are to weight gain or weight loss. To ensure survival in times of scarce food supplies, the human body has evolved to resist any loss of body fat. This biological drive to maintain weight is coordinated through central nervous system pathways, with the involvement of many neuropeptides. (Peptides released by neurons as intercellular messengers. Many neuropeptides are also hormones outside of the nervous system.) Evidence from twin, adoption, and family studies reveals that biological relatives exhibit similarities in maintenance of body weight. First-degree relatives of moderately obese people are at three to four times the risk of obesity relative to the general population. First-degree relatives of severely obese people are at five times greater risk. Genetic predisposition to obesity does not mean that developing the condition is inevitable; however, research indicates that inherited genetic variation is an important risk factor for obesity.

Genetic factors have been implicated in the development of such eating disorders as anorexia and bulimia and appear to be involved in the extent to which diet and exercise are effective strategies for weight reduction. Further, genetic variations among individuals may promote different food preferences and eating patterns that interact with environmental conditions to maintain healthy body weight or promote obesity.

These genetic risk factors tend to be familial but are not inherited in a simple manner; they may reflect many genetic variations, and each variation may contribute a small amount of risk and may interact with environmental elements to produce obesity. By 2005 the eleventh update of the human obesity gene map contained more than 600 genes, markers, and chromosomal regions had been associated or linked with human obesity. In addition to offering direction for future efforts to prevent and treat obesity, mounting genetic evidence offers a compelling argument that obesity is not a personal failing, and that in the majority of cases, obesity involves multiple genetic and environmental components that affect endocrine, metabolic, and regulatory mechanisms.

Genetic Susceptibility and Environmental Influences

Although genetics may largely predetermine adult body weight absent specific environmental triggers or influences, genetic destiny in terms of body weight may not necessarily be realized. For example, an individual with a strong genetic predisposition for obesity will not become obese in the absence of sufficient food (caloric) intake. Similarly, when people genetically predisposed to normal body weight consume a largely high-fat diet, they may become overweight or obese because they may be more inclined to overeat. This is in part because the brain has difficulty conveying the satiety signal—the message to stop eating—when fatty foods are being consumed.

In addition to caloric intake and physical activity, both of which are able to modify body weight, environmental influences before birth also significantly influence adult health and body weight. Research has demonstrated that the pregnant mother's nutritional status affects the metabolism of her unborn child. Women who are severely malnourished during pregnancy stimulate the fetus to modify its metabolism to conserve and store energy, a survival practice that can promote overweight when the food supply is ample.

Societal and cultural norms also can cause such environmental influences as lifestyle and behavior to override genetic programming. For example, in the United States many young women with genetic predisposition to normal body weight or even overweight sharply limit their caloric intake and exercise vigorously in order to achieve "model thin" bodies. Similarly, in cultures where overweight is perceived as an indication of prosperity and is admired and coveted, people may override genetic tendencies to be normal weight by increasing caloric intake in an effort to achieve the culturally established ideal.

HEALTH RISKS AND CONSEQUENCES OF OVERWEIGHT AND OBESITY

In February 2002 former U.S. Surgeon General David Satcher predicted that "Overweight and obesity may soon cause as much preventable disease and death as cigarette smoking," and that failure to address these conditions "could wipe out some of the gains we've made in areas such as heart disease, several forms of cancer, and other chronic health problems." By 2005 the scientific community acknowledged that the health consequences of overweight and obesity threatened to erode Americans' life spans.

People who are overweight or obese are at higher risk of developing one or more serious medical conditions, and obesity is associated with increases in deaths from all causes. Overweight and obesity significantly increase the risk for Type 2 diabetes; hypercholesterolemia (high cholesterol), hypertension, heart disease, and stroke; gallbladder disease; osteoarthritis, chronic joint pain, and back injury; sleep apnea and other respiratory problems; and several cancers. According to the American Obesity Association, obesity is a contributing cause in at least 400,000 deaths per year. Approximately sixty-two million visits to the physician's office are usually due to obesity-related problems.

Hypercholesterolemia, Hypertension, Heart Disease, and Stroke

Overweight, obesity, and excess abdominal fat are directly related to cardiovascular risk factors, including high levels of total serum cholesterol, LDL-cholesterol (a fat-like substance often termed "bad cholesterol" because high levels increase risk for heart disease), triglycerides, blood pressure, fibrinogen, and insulin, and low levels of HDL-cholesterol (often termed "good cholesterol" because high levels appear to protect against heart disease). The association between total serum cholesterol and coronary heart disease is largely due to low-density lipoprotein (LDL). A high-risk LDL-cholesterol is greater than or equal to 160 mg/dL with a 10 mg/dL rise in LDL-cholesterol corresponding to approximately a 10% increase in risk. The relationship of the age-adjusted prevalence of high total cholesterol (defined as greater than or equal to 240 mg/dL) to BMI is shown Figure 2.3. The age-adjusted prevalence of low HDL-cholesterol (defined as less than 35 mg/dL in men and less than 45 mg/dL in women) is shown in Figure 2.4. The percent of the population suffering from high serum cholesterol levels fell from 19.7% between 1988 to 1994 to 17% during the years 1999 to 2002. (See Table 2.6.) The overall decline in high serum cholesterol occurred in response to the increasing use of effective cholesterol-lowering statin drugs. Figure 2.5 shows the steady rise in medical office visits to obtain cholesterol-lowering statin drugs from 1995 through 2002—a 200% increase among adults age forty-five-sixty-four—and the even sharper increase among men age sixty-five and older (250%) and women age sixty-five and older (180%) from 1999 to 2002.

The percent of the population suffering from hypertension increased between the periods 1988 to 1994 and 1999 to 2002, from 21.7% of the population to 25.5%. The highest rates for those aged twenty to seventy-four during the 1999–2002 period were reported among African-American females (39.4%). Both men and women were increasingly likely to have hypertension as they aged. (See Table 2.7.) The American Heart Association estimates that more than 75% of hypertension is directly attributable to obesity. Hypertension is approximately three times more common in obese than in normal-weight people, and the relationship between weight and blood pressure is clearly one of cause and effect because when weight increases, so does blood pressure, and when weight decreases, blood pressure falls. Data from the National Health and Nutrition Examination Surveys (NHANES III 1988–1994) revealed that the age-adjusted prevalence of high blood pressure increases progressively with higher levels of BMI in men and women. (See Figure 2.6.) The prevalence of high blood pressure (defined as mean systolic blood pressure greater than or equal to 140 mm Hg, or mean diastolic blood pressure greater than or equal to 90 mm Hg, or currently taking anti-hypertensive medication) in adults with BMI greater than or equal to 30 is 38.4% for men and 32.2% for women, respectively, compared with 18.2% for men and 16.5% for women with BMI less than 25.

The physiological processes that produce the hypertension associated with obesity include sodium retention and increases in vascular resistance, blood volume, and cardiac output (the volume of blood pumped, measured in liters per minute). While it is not known precisely how weight loss results in a decrease in blood pressure, it is known that weight loss is associated with a reduction in vascular resistance and total blood volume and cardiac output. Weight loss also results in improvement in insulin resistance, a reduction in sympathetic nervous system activity, and suppression of the rennin-angiotensin-aldosterone system. (The rennin-angiotensin-aldosterone system is a group of hormones that are responsible for the opening and narrowing of blood vessels and retention of fluids.)

Obesity increases risk for coronary artery disease, which in turn increases risk for future heart failure. Congestive heart failure is not a disease but a condition that occurs when the heart is unable to pump enough blood to meet the needs of the body's tissues. When the heart fails, it is unable to pump out all the blood that enters its chambers. Congestive heart failure is a frequent complication of severe obesity and a major cause of death. The duration of the obesity is a strong predictor of congestive heart failure because over time elevated total blood volume and high cardiac output cause the left ventricle of the heart to increase in size (known as left ventricular hypertrophy) beyond that expected from normal growth. Although left ventricular hypertrophy is frequently identified in cardiac patients with obesity and in part results from hypertension, abnormalities in left ventricular mass and function also occur in the absence of hypertension and may be related to the severity of obesity.

Inflammation in blood vessels and throughout the body is thought to increase risk for heart disease and stroke. People with more body fat have higher blood levels of substances such as plasminogen activator inhibitor-1—an enzyme produced in the kidneys that inhibits conversion of plasminogen to plasmin and initiates fibrinolysis. Fibrinolysis leads to the breakdown of fibrin, which is responsible for the semisolid character of a blood clot that can occlude (block) blood vessels. This is the mechanism believed to account for the finding that obesity is associated with an increased risk of blood clot formation. Occluded arteries may produce myocardial infarction (heart attack) or stroke (sudden injury to the brain due to compromised blood and oxygen supply). Overweight increases risk for ischemic stroke—resulting from a clot or blockage—but does not appear to increase risk for hemorrhagic stroke (bleeding inside the brain), which, in general, is associated with more fatality. According to the National Heart, Lung, and Blood Institute in Guidelines on Overweight and Obesity: Electronic Textbook (http://www.nhlbi.nih.gov/guidelines/obesity/e_txtbk/ index.htm), the risk of stroke increases as BMI rises. For example, ischemic stroke risk is 75% higher in women with BMI greater than 27, and 137% higher in women with a BMI greater than 32, compared with women having a BMI less than 21.

Even when there are no other risk factors present, such as smoking or elevated cholesterol levels, obesity by itself increases the risk of heart disease. Modest elevations in BMI are associated with increased risk for nonfatal myocardial infarction and coronary heart disease. Data from the Framingham Heart Study (a landmark study of fifty years of data from residents of Framingham, Massachusetts, that significantly contributed to understanding the development and progression of heart disease and its risk factors) indicated that being overweight might contribute to the risk of stroke, independent of the known association of hypertension and diabetes with stroke.

Figure 2.7 shows the process, known as a treatment algorithm, used to assess and treat overweight individuals, based on their body weight, abdominal fat, and the risk factors for cardiovascular morbidity and mortality.

Type 2 Diabetes

Diabetes is a disease that affects the body's use of food, causing blood glucose (sugar levels in the blood) to become too high. Normally, the body converts sugars, starches, and proteins into a form of sugar called glucose. The blood then carries glucose to all cells throughout the body. In the cells, with the help of the hormone insulin, the glucose is either converted into energy for use immediately or stored for the future. Beta cells of the pancreas, a small organ located behind the stomach, manufacture the insulin. The process of turning food into energy via glucose (blood sugar) is important because the body depends on glucose for every function.

In diabetes, the body can convert food to glucose, but there is a problem with insulin. In one type of diabetes (insulin-dependent diabetes or Type 1), the pancreas does not manufacture enough insulin, and in another type (non-insulin dependent or Type 2), the body has insulin but cannot use the insulin effectively (this latter condition is called insulin resistance). When insulin is either absent or ineffective, glucose cannot get into the cells to be used for energy. Instead, the unused glucose builds up in the bloodstream and circulates through the kidneys. If a person's blood-glucose level rises high enough, the excess glucose "spills" over into the urine, causing frequent urination. This, in turn, leads to an increased feeling of thirst as the body tries to compensate for the fluid lost through urination.

Non-insulin-dependent diabetes (also known as Type 2) is most often seen in adults and is the most common type of diabetes in the United States. In this type, the pancreas produces insulin, but it is not used effectively, and the body resists responding to it. Heredity may be a predisposing factor in the genesis of Type 2 diabetes, but since the pancreas continues to produce insulin, the disease is considered more of a problem of insulin-resistance, in which the body is not using the hormone efficiently.

Because diabetes deprives body cells of the glucose needed to function properly, several complications can develop to threaten the lives of diabetics further. The healing process of the body is slowed or impaired, and the risk of infection increases. Complications of diabetes include: higher risk and rates of heart disease; circulatory problems, especially in the legs, are often severe enough to require surgery or even amputation; diabetic retinopathy, a condition that can cause blindness; kidney disease that may require dialysis; dental problems; and problems with pregnancy. Close attention to preventive health care such as regular eye, dental, and foot examinations and tight control of blood sugar levels have been shown to prevent some of the consequences of diabetes.

More than 80% of people with Type 2 diabetes are overweight, and in people prone to Type 2 diabetes becoming overweight can trigger onset of the disease. It is not known precisely how overweight contributes to causation of this disease. One hypothesis is that being overweight causes cells to change, making them less effective at using sugar from the blood. This then stresses the cells that produce insulin, causing them gradually to fail. Maintaining a healthy weight and keeping physically fit can usually prevent diabetes.

The relatively recent rise in Type 2 diabetes in the United States is in part attributed to rising obesity among adults, and overweight among children and adolescents. A CDC study found that 54.8% of diabetics over age nineteen were obese between 1999 and 2002 compared with 45.7% in the same age group between 1988 and 1994. When the category was expanded to include diabetics who were obese or overweight, the percentage escalated to 85.2% in 1999–2002 compared with 78.5% in the earlier period.

In 2002, 18.2 million people, more than 6% of the adult population suffered from diabetes. Among people age twenty and older, 8.7% have diabetes and among those age 60 or older 18.3% suffer from the disease. (See Figure 2.8.) Between 1997 and 2002 the percent of adults diagnosed with diabetes increased for all age groups. Worse still, these numbers may significantly underestimate the true prevalence of diabetes in the United States in view of National Health and Nutrition Surveys findings that showed sizeable numbers of adults have undiagnosed diabetes.

"DIABESITY" AND "DOUBLE DIABETES"

Recognition of obesity-dependent diabetes prompted scientists and physicians to coin a new term to describe this condition—diabesity. The term was first used in the 1990s and has gained widespread acceptance. Although diabesity is attributed to the same causes as Type 2 diabetes—insulin resistance and pancreatic cell dysfunction, researchers are beginning to link the inflammation associated with obesity to the development of diabetes and cardiovascular disease.

Pediatric endocrinologist Francine R. Kaufman, who served as president of the American Diabetes Association, contends that the diabesity epidemic "imperils human existence as we now know it" in Diabesity: The Obesity-Diabetes Epidemic That Threatens America—And What We Must Do to Stop It (New York: Bantam, 2005) and observes that more than one-third of American children born in 2000 will develop diabetes in their lifetime. Kaufman warns that unless drastic measures are taken, by 2020 there will be a 72% increase in the number of diabetics in America.

Another recent phenomenon is patients diagnosed with both Type 1 and type 2 diabetes simultaneously. Dubbed "double diabetes," it has been reported in children and adults. Among children it often results when children with Type 1 diabetes who rely on insulin injections to control their diabetes gain weight and develop the insulin resistance that characterizes Type 2 diabetes. Adults who have been diagnosed with Type 2 diabetes, but fail to respond to treatment have been found to also suffer from the Type 1, insulin-dependent form of the disease.

Although there are no reliable statistics about the prevalence of double diabetes, in a July 19, 2005 interview, Dr. Dorothy Becker, a pediatric endocrinologist and leading double-diabetes researcher at Children's Hospital of Pittsburgh, estimated that 25% of children with Type 1 diabetes who are overweight also have symptoms of Type 2 diabetes. Dr. Becker theorizes that overweight people require more insulin to process glucose regardless of whether they are insulin-resistant. It may be that obesity overworks the pancreas until it wears out. It also is possible that obesity triggers or hastens the autoimmune destruction, which implies that individuals genetically predisposed to Type 1 diabetes might not develop the disease if they maintained a healthy weight (Lauran Neergaard, "'Double Diabetes' Harder to Detect, Treat," Associated Press, July 19, 2005).

Osteoarthritis and Joint Injury

Being only ten pounds overweight increases the force on the knee by thirty-sixty pounds with each step. Even small amounts of weight loss reduce the risk of developing knee OA. Preliminary studies suggest weight loss decreases pain substantially in those with knee OA.

—Susan Bartlett, "Osteoarthritis and Body Weight," Johns Hopkins University, 2005

The word "arthritis" literally means joint inflammation. The name applies to more than 100 related diseases known as rheumatic diseases. A joint is any point where two bones meet. When a joint becomes inflamed, swelling, redness, pain, and loss of motion occur. In the most serious forms of the disease, the loss of motion can be physically disabling. Arthritis is the leading cause of disability and the leading cause of limitation of activity among working-age adults in the United States. (See Figure 2.9.)

People who are overweight or obese are at increased risk for osteoarthritis, which is not an inflammatory arthritis. Osteoarthritis, sometimes called degenerative arthritis, causes the breakdown of bones and cartilage (connective tissue attached to bones), and usually causes pain and stiffness in the fingers, knees, feet, hips, and back. Extra weight places extra pressure on joints and cartilage, causing them to erode. Further, people with more body fat may have higher blood levels of substances that cause inflammation. Inflammation at the joints may increase the risk for osteoarthritis.

Osteoarthritis affects about twenty million Americans, usually after age forty-five. The association between overweight and the risk for development of knee osteoarthritis is stronger in women than in men, but for both men and women an increase in weight is significantly associated with increased pain in weight-bearing joints. Data from the National Health and Nutrition Examination Survey revealed that obese women had about four times the risk of knee osteoarthritis compared with women of healthy weight and for obese men, the risk was nearly five times greater. People with clinically severe obesity—those in the highest fifth of body weight have a tenfold risk of developing knee osteoarthritis compared with those in the lowest fifth.

Weight loss may decrease the likelihood of developing osteoarthritis in the knees, hips, and lower back and has been shown to relieve the symptoms of osteoarthritis. The National Heart, Lung, and Blood Institute reported research findings that a decrease in BMI of two units or greater during a ten-year period decreased the risk of developing knee osteoarthritis by more than 50%. Another study found that people with osteoarthritis who lost weight had improved range of motion and less joint pain.

Research conducted by Gary M. Ford and his colleagues at the University of Utah's Rocky Mountain Center for Occupational Environmental Health found that overweight also is linked to cartilage tears in the knee. The investigators studied 544 patients who had surgical cartilage tears repaired between 1996 and 2000. The patients were men and women aged fifty-seventy-nine who had surgery to repair the meniscus, the shock-absorbing cartilage in the knee. The study found that people with BMI even slightly over the healthy range were three times more likely to have a cartilage tear. The heaviest men were fifteen times more likely to have torn knee cartilage, and the heaviest women were twenty-five times more likely to have torn cartilage than those in the healthy weight ranges. One possible explanation for this finding may be that obese people have circulation problems that reduce the blood supply to the cartilage. The investigators concluded that overweight probably accounts for more than half of the nation's 850,000 annual operations to repair cartilage tears in the knee (Gregory M. Ford et al., "Associations of Body Mass Index with Meniscal Tears," American Journal of Preventive Medicine, vol. 28, no. 4, May 2005).

Gallbladder Disease

Gallstones are small, hard pellets that can form when bile in the gallbladder—a muscular sac-like organ that lies under the liver in the right side of the abdomen—precipitates (becomes solid out of the bile solution). Bile contains water, cholesterol, fats, bile salts, proteins, and bilirubin. The gallbladder stores and concentrates the bile produced in the liver that is not immediately needed for digestion. Bile is released from the gallbladder into the small intestine in response to food. The pancreatic duct joins the common bile duct at the small intestine, adding enzymes to aid in digestion. (See Figure 2.10.) If the liquid bile contains too much cholesterol, bile salts, or bilirubin, under certain conditions it can harden into stones. Most gallstones are formed primarily from cholesterol.

People who are overweight are at higher risk for developing gallstones because the liver overproduces cholesterol and delivers it into the bile, which then becomes supersaturated. According to the National Heart, Lung, and Blood Institute in Guidelines on Overweight and Obesity: Electronic Textbook http://www.nhlbi.nih. gov/guidelines/obesity/e_txtbk/ratnl/2217.htm, the risk of gallstones is as high as twenty per 1,000 women per year when BMI is above 40, compared with three per 1,000 among women with BMI less than 24.

Analysis of data from the third National Health and Nutrition Examination Survey, conducted between 1988 and 1994 (NHANES III), revealed that the prevalence of gallstone disease among women increased from 9.4% in the first quartile of BMI to 25.5% in the fourth quartile of BMI. Among men, the prevalence of gallstone disease increased from 4.6% in the first quartile of BMI to 10.8% in the fourth quartile of BMI. Rapid weight loss or weight cycling—dieting, losing weight, and regaining weight lost—further increase cholesterol production in the liver, with resulting supersaturation and risk for gallstone formation.

Jarl Torgerson and his colleagues at the Department of Body Composition and Metabolism, Sahlgrenska University Hospital in Göteborg, Sweden, examined the relationship between gallstones and pancreatitis (inflammation of the pancreas, a large elongated gland located behind the stomach that secretes pancreatic juice and insulin) by analyzing BMI, body fat distribution, and prevalence of gallstones, gallbladder disease, and pancreatitis in 6,328 obese patients and 1,135 randomly selected reference subjects. In "Gallstones, Gallbladder Disease, and Pancreatitis: Cross-Sectional and Two-Year Data from the Swedish Obese Subjects (SOS) and SOS Reference Studies" (American Journal of Gastroenterology, vol. 98, no. 5, May 2003), they reported the results of their research. The researchers found an increased prevalence of gallstones, gallbladder disease, and pancreatitis in the obese subjects. Biliary disease (blockage of any duct that carries bile from the liver to the gallbladder or from the gallbladder to the small intestine) was related to BMI and waist-to-hip ratio in women, but only to BMI in men. Weight loss, but not change in waist-to-hip ratio, increased the risk of biliary disease in both genders.

Fatty Liver Disease

Fatty liver is defined as an excess accumulation of fat in the liver, usually exceeding 5% of the total liver weight. More than 50% of the excess fat deposit in the liver is triglyceride. The enlargement of the liver is caused by the reduction of fatty acid oxidation in the liver, resulting in excess accumulation of fat. It causes injury and inflammation in the liver and may lead to severe liver damage, cirrhosis (build-up of scar tissue that blocks proper blood flow in the liver), or liver failure. An estimated nine million individuals in the United States suffer from nonalcoholic fatty liver disease.

People with diabetes or with higher than normal blood sugar levels (but not yet in the diabetic range) are more likely to have fatty liver disease than those with normal blood sugar levels. It is not known why some people who are overweight or diabetic get fatty liver and others do not. Losing weight reduces the buildup of fat in the liver and prevents further injury; however, weight loss should not exceed 1 kg (2.2 pounds) per week because more rapid weight loss may exacerbate the disease.

Cancer

Cancer is a large group of diseases characterized by the uncontrolled growth and spread of abnormal cells. These cells may grow into masses of tissue called tumors. Tumors consisting of cancer cells are called malignant tumors. The dangerous aspect of cancer is that cancer cells invade and destroy normal tissue.

The spread of cancer cells occurs either by local growth of the tumor or by some of the cells becoming detached and traveling through the blood and lymph systems to start additional tumors in other parts of the body. Metastasis (the spread of cancer cells) may be confined to a region of the body, but left untreated (and often despite treatment), the cancer cells can spread throughout the entire body, causing death. It is perhaps the rapid, invasive, and destructive nature of cancer that makes it, arguably, the most feared of all diseases, even though it is second to heart disease as the leading cause of death in the United States.

Overweight increases the risk of developing several types of cancer, including cancers of the colon, esophagus, gallbladder, kidney, liver and prostate, as well as uterine (specifically cancer of the lining of the uterus) and postmenopausal breast cancer. Excessive weight gain during adult life increases the risk for several of these cancers. For example, according to the National Heart, Lung, and Blood Institute, a gain of more than twenty pounds from age eighteen to midlife doubles a woman's risk of breast cancer, and even more modest weight gains are associated with increased risk. In 2005 researchers from International Agency for Research on Cancer (IARC) estimated that 40% of uterine cancers, up to 25% of kidney cancers, and about 10% of breast and colon cancers would not develop if people avoided gaining excess weight. The IARC also asserted that obesity increases the risk of breast cancer in postmenopausal women by as much as 40%.

Investigators at the Albert Einstein College of Medicine in New York found a relationship between obesity and colorectal cancer. In "Obesity and Colorectal Cancer Risk in Women" (Gut: An International Journal of Gastroenterology and Hepatology, vol. 51, no. 2, August 2002), the authors reported that obesity (BMI of 30 or more) was associated with a nearly twofold increased risk of colorectal cancer in premenopausal women. The investigators hypothesized that the biological mechanism underlying their findings was the positive relationship between adiposity (fatness) and blood insulin levels. An increase in blood insulin levels lowers insulin-like growth factor (IGF) binding protein 1 and may lead to increased levels of free IGF-1, which has been linked to increased risk of colorectal cancer in men and women.

Researchers from the American Cancer Society and the Department of Preventive Medicine, University of Southern California School of Medicine found a relationship between obesity and pancreatic cancer. In 1992 the researchers obtained information on current weight and weight at age eighteen, location of weight gain, and recreational physical activity were obtained at baseline using a self-administered questionnaire for 145,627 men and women who were cancer-free at the start of the study. During seven years of follow-up, 242 cases of pancreatic cancer were diagnosed in the research subjects. Analysis of these data revealed an increased risk of pancreatic cancer among obese men and women compared with men and women of normal weight. The risk of pancreatic cancer was also higher among men and women who reported a tendency for central (abdominal) weight gain compared with subjects who reported a tendency for peripheral weight gain (Alpa V. Patel et al., "Obesity, Recreational Physical Activity, and Risk of Pancreatic Cancer in a Large U.S. Cohort," Cancer Epidemiology Biomarkers & Prevention, vol. 14, February 2005).

Another study suggested that about 30% of cases of acute myelogenous leukemia (AML) in older women might be linked to overweight or obesity. An analysis of data from the Iowa Women's Health Study, which gathered data from more than 40,000 Iowa women ages fifty-five to sixty-nine from 1986–2001 found that the risk for AML was 90% higher among women fifty-five and older who were overweight (BMI 25-29). The risk was 140% higher among obese (BMI of 30 or greater) women in this age group (Julie A. Ross et al., "Body Mass Index and Risk of Leukemia in Older Women," Cancer Epidemiology Biomarkers & Prevention, vol. 13, November 2004).

Overweight also may increase the risk of dying from some cancers. In "Weight Loss in Breast Cancer Patient Management" (Journal of Clinical Oncology, vol. 20, no. 4, February 15, 2002), researchers Rowan Chlebowski, Erin Aiello, and Anne McTiernan concluded that "women with breast cancer who are overweight or gain weight after diagnosis are found to be at greater risk for breast cancer recurrence and death compared with lighter women. Obesity is also associated with hormonal profiles likely to stimulate breast cancer growth."

It is not known exactly how being overweight increases cancer risk, recurrence, or mortality. It may be that fat cells make or influence hormones that affect cell growth and lead to cancer. It also is possible that eating habits—such as a high-fat, high-calorie diet—or physical inactivity that promote overweight contribute to cancer risk.

Sleep Apnea and Sleep Disorders

Sleep apnea is a condition in which breathing becomes very shallow or stops completely for short periods during sleep. Each pause lasts about ten to twenty seconds or longer and pauses can occur twenty times or more an hour. Sleep apnea can increase the risk of developing high blood pressure, heart attack, or stroke. Untreated sleep apnea can increase the risk of diabetes and daytime sleepiness and difficulty concentrating can increase the risk for work-related accidents and automobile accidents.

The most common type of sleep apnea, and the type that is linked to overweight and obesity, is obstructive sleep apnea (OSA). During sleep there is insufficient airflow into the lungs through the mouth and nose, and the amount of oxygen in the blood may drop because the airway is transiently occluded (blocked). According to the National Heart, Lung, and Blood Institute, more than twelve million Americans have OSA, and one in twenty-five men over age forty and one in fifty women over age forty have debilitating sleep apnea that causes them to be very sleepy during the day. The condition is more common in men, African-Americans, Hispanics, and Pacific Islanders.

Obesity, particularly upper body obesity, is a risk factor for sleep apnea and is related to its severity. Most people with sleep apnea have a BMI greater than 30. In general, men whose neck circumference is seventeen inches or greater and women with neck circumference of sixteen inches or greater are at higher risk for sleep apnea. Large neck girth in both men and women who snore is highly predictive of sleep apnea because people with large neck girth store more fat around their necks, which may compromise their airways. A smaller airway can make breathing difficult or stop it altogether. In addition, fat stored in the neck and throughout the body can produce substances that cause inflammation, and inflammation in the neck may be a risk factor for sleep apnea. Weight loss usually resolves or significantly improves sleep apnea by decreasing neck size and reducing inflammation.

Anatomic risk factors for obstructive sleep apnea run in families—the volume of upper-airway soft tissue structures, including the lateral pharyngeal walls and tongue, is greater in individuals with OSA than in healthy control subjects. In "Familial Link Seen in Obstructive Sleep Apnea" (Journal of the American Medical Association, vol. 290, no. 22, December 10, 2003), author Lynne Lamberg observes that family history of OSA explains about 30% of the variability of OSA in the general population and that an individual with a first-degree relative with OSA has a 50% to 75% higher risk of having the condition than an individual with no known affected relatives. Lamberg reported that researchers postulate the existence of a syndrome involving obesity, high blood pressure, and diabetes, in which OSA exacerbates the other traits, generating a vicious cycle.

The results of a large, long-term, prospective controlled study of untreated men with severe obstructive sleep apnea were published in The Lancet in March 2005. Investigators at the Hospital Universitatio Miguel Servet in Spain followed 264 healthy men, 377 men who simply snored, 403 with untreated mild-to-moderate severe OSA, 235 with severe OSA, and 372 with treated severe OSA for about ten years. Treated subjects with OSA had fatal and non-fatal cardiovascular event rates that were closer to those seen in healthy subjects than the other subjects with severe OSA. Subjects with untreated severe OSA had two to three times the risk of fatal and non-fatal cardiovascular events compared with healthy subjects. The investigators concluded that there is a relation between the severity of OSA and cardiovascular risk, but effective treatment with continuous positive airway pressure (CPAP) seems to cut this risk and significantly reduce the cardiovascular illness associated with OSA (J. M. Marin et al., "Long-term Cardiovascular Outcomes in Men with Obstructive Sleep Apnea-Hypopnoea with or without Treatment with Continuous Positive Airway Pressure: An Observational Study," Lancet, vol. 365, March 19, 2005).

Too little sleep is also linked to obesity. A study presented at the November 2004 meeting of the North American Association for the Study of Obesity found that people who got less than four hours of sleep a night were 73% more likely to be obese than those who got the recommended seven to nine hours of rest. People who averaged five hours of sleep had 50% greater risk, and those who got six hours had 23% greater risk of obesity ("Lack of Sleep May Lead to Excess Weight," http://www.naaso.org/news/20041116.asp, November 16, 2004).

Dr. Robert D. Vorona and his colleagues at Eastern Virginia Medical School found that people who were overweight or obese reported that they slept less per week than their normal-weight counterparts. Total sleep time decreased as BMI increased except in the extremely obese group. The difference averaged sixteen minutes per day between normal weight and overweight subjects totaling nearly two hours per week. The researchers speculated that lost sleep might have metabolic and hormonal consequences. For example, sleep restriction may reduce levels of leptin, a hormone involved in appetite regulation, which could account for the relationship between diminished sleep and obesity. They observed that their findings did not establish a cause-and-effect relationship between sleep and obesity; however, they "suggest that an extra twenty minutes of sleep per night seems to be associated with a lower BMI" (Robert D. Vorona et al., "Overweight and Obese Patients in a Primary Care Population Report Less Sleep than Patients with a Normal Body Mass Index" Archives of Internal Medicine, vol. 165, no. 1, January 10, 2005).

Women's Reproductive Health

In addition to increased risk of breast and endometrial cancers (the endometrium is the lining of the uterus), women who are overweight or obese may suffer from infertility (difficulty or inability to conceive a child), and other gynecological or pregnancy-related medical problems. Obesity is associated with such menstrual irregularities as abnormally heavy menstrual periods and amenorrhea (cessation of menstruation), and has been found to affect ovulation, response to fertility treatment, pregnancy rates, and pregnancy outcomes.

Abdominal obesity in women is linked to polycystic ovarian syndrome (PCOS), an endocrine condition that afflicts approximately 6%-10% of premenopausal women. PCOS is characterized by the accumulation of cysts (fluid-filled sacs) on the ovaries, chronic anovulation (absent ovulation), and other metabolic disturbances. Symptoms include excess facial and body hair, acne, obesity, irregular menstrual cycles, insulin resistance, and infertility. A key characteristic of PCOS is hyperan-drogenism—excessive production of male hormones (androgens), particularly testosterone, by the ovaries—that is responsible for the acne, male pattern hair growth, and baldness seen in women with PCOS. Hyperandrogenism has been linked with insulin resistance, the inability of the body to respond to insulin, and hyperinsulinemia (high blood insulin levels), both of which are common in PCOS. Women with PCOS have an increased risk of early-onset heart disease, hypertension, diabetes, reproductive cancers, and a higher incidence of miscarriage and infertility. In overweight women, modest weight loss (as little as 5%) through diet and exercise may correct hyperandrogenism, and restore ovulation and fertility.

Obesity during pregnancy is associated with increased morbidity for both the expectant mother and the unborn child. Obese pregnant women are significantly more likely to suffer from hypertension and gestational diabetes (glucose intolerance of variable severity that starts or is first recognized during pregnancy) than normal-weight expectant mothers. Obesity also is associated with difficulties in managing labor and delivery, leading to higher rates of Caesarean section (delivery of a fetus by surgical incision through the abdominal wall and uterus). Risks associated with anesthesia are higher in obese women, as there is greater tendency toward hypoxemia (abnormal lack of oxygen in the blood) and greater difficulty administering local or general anesthesia.

The children of women who are obese during pregnancy are at increased risk of birth defects—congenital malformations, particularly of neural tube defects. Neural tube defects are abnormalities of the brain and spinal cord resulting from the failure of the neural tube to develop properly during early pregnancy. The neural tube is the embryonic nerve tissue that eventually develops into the brain and the spinal cord. Every year, about 4,000 unborn children are affected with neural tube defects. Of these, approximately 2,500 involve infants born with the two most common neural tube defects—anencephaly (absence of a major part of the brain, skull, and scalp) and spina bifida (failure of the vertebrae (backbones) to completely cover the spinal cord early in fetal development, leaving the spinal cord exposed).

Research indicates that boys born to higher-weight mothers may be more likely to develop testicular cancer. Exposure of unborn males to high levels of estrogen is believed to be involved in the subsequent development of testicular cancer. Boys born to higher-weight mothers are more likely to have been exposed to high estrogen levels than boys born to lower-weight mothers because higher weight results in higher insulin levels and lower levels of the protein that normally binds estrogen. As a result, higher levels of estrogen are able to cross the placenta and affect the male fetus. (Elin L. Aschim et al., "Is There an Association between Maternal Weight and the Risk of Testicular Cancer? An Epidemiologic Study of Norwegian Data with an Emphasis on World War II"-International Journal of Cancer, vol. 116, no. 2, August 20, 2005)

Further, women who are obese before pregnancy appear to have a higher risk of stillbirth and of having an infant die soon after birth. A study of more than 24,000 Danish women found that compared with normal-weight women, those who were obese before pregnancy had twice the risk of stillbirth and newborn deaths. Although earlier researchers have reported comparable risks attributed in part to the higher rates of diabetes and high blood pressure observed in overweight pregnant women, this study found that diabetes and high blood pressure were not responsible for their findings. When women with diabetes or high blood pressure were excluded from their analysis, the risks of stillbirth and newborn death linked to obesity were still significantly higher than the risks for normal weight or overweight women. While it is not yet known how obesity increases the risk of stillbirth and early infant death, the Danish researchers posit that obesity influences the hormonal system and the metabolism of blood fats that in turn may compromise blood flow to the placenta (an organ that forms during pregnancy and functions as a filter between the mother and fetus) (Janni Kristensen, "Pre-pregnancy Weight and the Risk of Stillbirth and Neonatal Death," British Journal of Gynecology, vol. 112, no. 4, April 2005).

WEIGHT GAIN DURING PREGNANCY

Weight gain during pregnancy is expected and beneficial. The fetus, expanded blood volume, the enlarged uterus, breast tissue growth, and other products of conception generate approximately thirteen to seventeen pounds of extra weight. Weight gain beyond this anticipated amount is largely maternal adipose tissue that often is retained after pregnancy. The challenge health professionals face when developing recommendations about weight gain during pregnancy is achieving a balance between gains intended to produce high-birth-weight infants, who may then require delivery by Caesarean section, and low-birth-weight infants with a higher infant mortality rate. Analysis of data from the CDC Pregnancy Nutrition Surveillance System showed that very overweight women benefit from reduced weight gain during pregnancy to help reduce the risk for high-birth-weight infants.

A 1990 report by the Institute of Medicine of the National Academy of Sciences issued recommendations about weight gain in pregnancy. The Institute of Medicine suggested that women with BMI of less than 20 should gain about 0.5 kg (1.1 lb) of weight per week during the second and third trimester. For women with BMI greater than 26, a gain of 0.3 kg (0.7 lb) per week during the last two trimesters is recommended. Women who are overweight or obese at the onset of pregnancy are advised to gain less total weight during pregnancy than women at normal weights pre-pregnancy. (See Table 2.8.)

In 2001 Cornell University professor of nutritional science Christine Olsen and her colleagues at the Research Institute of Bassett Healthcare in New York looked at weight gain in 577 pregnant women and found that more than 40% of the women gained more weight during pregnancy than is recommended by the Institute of Medicine. They also found that one-fourth of all the pregnant women studied were at least ten pounds heavier one year after giving birth. The researchers concluded that women who gain more than the amount recommended during pregnancy are four times more likely to be obese one year after giving birth compared with mothers who gain within the recommended range.

Another study conducted by Cornell University and Bassett Hospital researchers in 2001 found that normal-weight women who gained more than the twenty-four to thirty-five pounds during pregnancy recommended by the Institute of Medicine were 74% more likely to be unsuccessful at breastfeeding than mothers who observed the guidelines. The study confirmed previous findings that obese women are at higher risk for discontinuing breastfeeding than normal-weight mothers. Investigator Kathleen Rasmussen speculated that a combination of biological, mechanical, and psychosocial factors combined to make breastfeeding problematical for obese women.

Metabolic Syndrome

In 2005 an estimated 44% of Americans over age fifty exhibited a cluster of medical conditions characterized by insulin resistance and the presence of obesity, abdominal fat, high blood sugar and triglycerides, high blood cholesterol, and high blood pressure. This constellation of symptoms, termed "metabolic syndrome" was first defined in the May 15, 2001 Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATPIII). The report concluded that for the majority of affected people, metabolic syndrome results from poor diet and insufficient physical activity.

The diagnosis of metabolic syndrome, which is also known as syndrome X, requires that people meet at least three of the following criteria:

• Waistline measurement (waist circumference) of 40 inches or more for men and 35 inches or more for women
• Blood pressure of 130/85 mm Hg or higher
• Fasting blood glucose level greater than 100 mg/dl
• Serum triglyceride level above 150 mg/dl
• High density lipoprotein level (HDL) less than 40 mg/dl for men or under 50 mg/dl for women.

According to the American Heart Association, three groups of people are most likely to be diagnosed with metabolic syndrome—diabetics, people with hypertension and hyperinsulinemia (secreting larger than normal amounts of insulin to maintain blood glucose levels), and people who have suffered heart attacks and have hyperinsulinemia without glucose intolerance.

While research has shown that the signs of metabolic syndrome are common among family members, until recently a definitive genetic link had not yet been identified. Dr. Claude Bouchard and his colleagues at the Pennington Biomedical Research Center in Baton Rouge, Louisiana, demonstrated the existence of genetic regions that may signal a predisposition to metabolic syndrome. The researchers analyzed 509 genetic markers to scan the whole genome of 456 white participants from ninety-nine families and 217 black participants from 105 families, looking for genomic regions harboring genes that could influence metabolic syndrome. In "Genome-Wide Linkage Scan for the Metabolic Syndrome in the HERITAGE Family Study" (Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 12, December 2003), the researchers reported that they found evidence of genetic linkages to metabolic syndrome in both black and white patients. The researchers asserted that "Our research shows a genetic link, contributing to the clustering in families and individuals, between diabetes, cardiovascular disease, and metabolic syndrome. These findings bring us closer to discovering the actual genes that are responsible for metabolic syndrome, which puts patients at risk for so many serious health problems. This information could someday help doctors assess whether specific patients are at risk for developing the metabolic syndrome based on their genes."

Although the exact origins and mechanism of metabolic syndrome are not fully known, affected individuals experience a series of biochemical changes that, in time, lead to the development of potentially harmful medical conditions. The biochemical changes begin when insulin loses its ability to cause cells to absorb glucose from the blood (insulin resistance). As a result, glucose levels remain high after food is consumed, and the pancreas, sensing a high glucose level in the blood, continues to secrete insulin. Loss of insulin sensitivity may be genetic or may be in response to high fat levels with fatty deposits in the pancreas.

Moderate weight loss, in the range of 5% to 10% of body weight, can help restore the body's sensitivity to insulin and greatly reduce the chance that the syndrome will progress into a more serious illness. Increased activity alone also has been shown to improve insulin sensitivity.

John K. Ninomiya and his colleagues from the University of California, San Diego, investigated how each of the factors associated with metabolic syndrome influences cardiovascular risk and reported the results of their research in "Association of the Metabolic Syndrome with History of Myocardial Infarction and Stroke in the Third National Health and Nutrition Examination Survey" (Circulation, vol. 109, January 2004). Using data from 10,357 NHANES III participants, they found that having the metabolic syndrome doubled the risk. High triglycerides independently increased that risk by 66%, high blood pressure raised it by 44%, low HDL cholesterol raised it by 35%, and insulin resistance raised it by 30%. Obesity by itself did not increase the risk, but the researchers observed that obesity places people at increased risk for the other four conditions.

The researchers concluded that metabolic syndrome was significantly associated with myocardial infarction and stroke in both women and men, and asserted that "These findings re-affirm the clinical importance of the metabolic syndrome as a significant risk factor for cardiovascular disease and the need to develop strategies for controlling this syndrome and its component conditions."

Metabolic syndrome is also a risk factor for cognitive decline—loss of memory, thinking and reasoning skills. Dr. Kristine Yaffe and her colleagues at the University of California, San Francisco analyzed data from 2,632 nondemented (cognitively normal) participants in the Health, Aging and Body Composition (ABC) study. The subjects were ages seventy to seventy-nine, and were followed from 1997 through 2002. Subjects with metabolic syndrome were more likely than those without to exhibit cognitive decline. The researchers hypothesized that metabolic syndrome hastened atherosclerosis or inflammation, which led to cognitive decline (Kristine Yaffe et al., "The Metabolic Syndrome, Inflammation, and Risk of Cognitive Decline, Journal of the American Medical Association, vol. 292, no. 18, November 10, 2004).

REDEFINING THE METABOLIC SYNDROME

In an effort to standardize diagnosis, prevention, screening and treatment, on April 14, 2005, the International Diabetes Federation (IDF) presented a new worldwide definition of the metabolic syndrome. The new diagnostic criteria are central obesity, defined as waist equal to or more than 94 cm (37 inches) for males and 80 cm (31.5 inches) for females of European descent, and ethnic-specific levels in Chinese, Japanese and South Asians; along with two of the following: triglycerides of at least 1.7 mmol/L or 150 mg/dL; low HDL-cholesterol, defined as less than 1.04 mmol/L (40 mg/dL) in males and less than 1.29 mmol/L (50 mg/dL) in females; blood pressure of at least 130/85 mm Hg; and fasting hyperglycemia, defined as glucose equal to or greater than 5.6 mmol/L (100mg/dL) or previous diagnosis of diabetes or impaired glucose tolerance. The new definition of the metabolic syndrome, which includes diabetes or prediabetes, abdominal obesity, unfavorable lipid profile and hypertension, triples the risk of myocardial infarction (heart attack) or stroke and doubles mortality from these conditions. It also increases the risk of developing Type 2 diabetes, if not already present, fivefold. Using this definition, about one-quarter of the U.S. adult population may be diagnosed as having the metabolic syndrome.

SOME QUESTION THE DIAGNOSIS OF METABOLIC SYNDROME

In the fall of 2005 two leading diabetes organizations, the American Diabetes Association and European Association for the Study of Diabetes questioned the utility of the diagnosis of metabolic syndrome. Representatives of these organizations said they felt the syndrome was neither a distinct disease nor well established by scientific research. In "The Metabolic Syndrome: Time for a Critical Appraisal—Joint Statement from the American Diabetes Association and the European Association for the Study of Diabetes" (Diabetes Care, vol. 28, no. 9, September 2005), Richard Kahn of the American Diabetes Association, John Buse, of the Division of Endocrinology and of General Medicine & Clinical Epidemiology, University of North Carolina School of Medicine, and their colleagues wrote, "While there is no question that certain CVD risk factors are prone to cluster, we found that the metabolic syndrome has been imprecisely defined, there is a lack of certainty regarding its pathogenesis, and there is considerable doubt regarding its value as a cardiovascular disease (CVD) risk marker. Our analysis indicates that too much critically important information is missing to warrant its designation as a 'syndrome.'"

The authors advised physicians against diagnosing or treating patients with metabolic syndrome as a disease. Instead, they encouraged them to screen and treat high triglyceride levels, high blood pressure, low levels of HDL cholesterol, and high blood glucose as separate conditions to reduce the risk of heart disease. Their specific recommendations are that:

1. Adults with any major CVD risk factor should be evaluated for the presence of other CVD risk factors.
2. Patients with CVD risk variables above the cut point for normal should receive counseling for lifestyle modification, and at cut points indicative of frank disease (e.g., blood pressure >140/90 mmHg, fasting plasma glucose ≥7.0 mmol/l), treatment should correspond to established guidelines.
3. Providers should avoid labeling patients with the term "metabolic syndrome," as this might create the impression that the metabolic syndrome denotes a greater risk than its components, or that it is more serious than other CVD risk factors, or that the underlying pathophysiology is clear.
4. All CVD risk factors should be individually and aggressively treated.
5. Until randomized controlled trials have been completed, there is no appropriate pharmacological treatment for the metabolic syndrome, nor should it be assumed that pharmacological therapy to reduce insulin resistance will be beneficial to patients with the metabolic syndrome.