PHYSICIANS REFERENCE MANUAL

Please note
This manual is not intended for the purpose of preventing, diagnosing, or treating any illness or disease. It is intended solely as a source of information about Herbalifes nutritional programs. The products and programs mentioned in this manual are represented as foods or food supplements and not being represented by Herbalife International or its scientific and nutrition advisors as being medical treatments or cures, nor are they considered to be substitutes for proper medical diagnosis or treatments. This manual is intended for physicians and health professionals as a guide to the science of nutrition behind Herbalifes products and programs. The information contained in this manual does not cover all possible uses, actions, precautions, side effects, and interactions. It is not intended as medical advice for individual problems. Liability for individual actions or omissions based upon the contents of this manual is expressly disclaimed.

3rd Edition, 2007, Herbalife International, Inc. Copyright: David Heber, M.D., Ph.D. Chairman, Herbalife Scientific and Nutrition Advisory Boards

A Letter to Doctors from Herbalife

Dear Colleague, Obesity is the number one nutritional problem in the world today, yet our medical offices are not set up to deal with this epidemic that costs the health care system over $130 billion a year. Many of your patients with diabetes, hypertension and heart disease could benefit from a program to achieve and maintain a healthy body weight. Despite all the drugs and surgical options for weight management available today, the most cost-effective method of fighting this epidemic in your office is to engage your patients using a method that works and that works for your practice. Herbalife Internationala publicly traded company listed on the New York Stock Exchange and a leader in nutrition and weight loss for over 27 years, with $3 billion in revenues yearlyinvites you to become an Independent Distributor. You have a built-in referral base in the patients coming into your practice every day, and Herbalife will provide you with a business system that will enable you to help your patients, engage your office staff and improve the economics of your practice in three ways. First, your patients with common co-morbidities of obesityincluding diabetes, hypertension and heart diseasemay require less costly medications at their ideal weight. In todays capitated care environment, that can make your practice much more profitable while increasing patient satisfaction. Second, your patients will pay your office staff for the use of supplements that are customized to their needs based on their metabolism, and your practice will make a reasonable profit on these products. Finally, some of your most dedicated and successful patients will want to share their success with their friends and family, leading to more referrals to your practice, which will now have a reputation for expertise in weight management and nutrition. A recent survey done in the UCLA Primary Care Network found that 50 percent of patients in typical practices were obese with a body mass index over 30. Among these patients, almost 60 percent had low back pain, 20 percent had high cholesterol, 20 percent had diabetes, and 5 percent had sleep apnea. Yet the average primary care practitioner finds the busy practice environment unable to accommodate a weightmanagement and nutrition program. Doctors in Herbalife was developed by Herbalife International to meet the need for a program that works both medically and financially for busy primary care practitioners. Doctors in Herbalife is based on concepts developed by David Heber, M.D., Ph.D., professor of medicine and public health at UCLA* and director of the Center for Human Nutrition at the David Geffen School of Medicine at UCLA*. Dr. Heber is chairman of both the Scientific and Nutrition Advisory Boards at Herbalife International and directs an international group of scientific and nutrition advisors. Setting up a weight-management center in your office is fast, easy and profitable. Your patients will see results and live healthier lives. You will be increasing your practice revenue with many possibilities for international travel as you grow your business at home.

*Dr. Hebers name and title are for identification purposes only. The University of California does not endorse specific products or services as a matter of policy.

PHYSICIANS REFERENCE MANUAL

Doctors who currently use the Herbalife program design a quick and easy weightmanagement program for their patients. Patients lose weight under medical supervision while using some of the best foods and food supplement products on the market. As patients achieve success, practice revenue grows. Your local involvement builds your practice, and there are many international opportunities to grow and expand as Herbalife is sold in 65 different countries worldwide. This state-of-the-art program, offered to you by an industry leader with a history of over 27 years in weight management and based on the best science available in weight management and nutrition, will help you to provide a comprehensive program to support your patients health while you improve the financial health of your practice. Please feel free to email us with any further questions at medadvbrd@herbalife.com. Sincerely,

.. Luigi Gratton, M.D., M.P.H. Vice President, Medical Affairs and Education

David Heber, M.D., Ph.D., F.A.C.P., F.A.C.N. Chairman, Scientific and Nutrition Advisory Boards

Contents
SECTION I INTRODUCTION A. B. C. D. Philosophy and History of Herbalife International What Is the Rationale Behind Doctors in Herbalife? Cellular Nutrition Herbalife ShapeWorks Program 8 9 10 11

Section II BACKGROUND

A. B. B.1 B.2 B.3 B.4 B.4.1 B.4.2 B.4.3 B.4.4

History and Future of Nutritional Science and Medicine Fundamentals of Nutrition Fundamentals of Cellular Nutrition Quality of the Diet: Good vs. Bad Energetics and Obesity Protein and Its Role in Cellular Nutrition Protein Quality Protein Requirements Optimum Protein Intake Proteins Role in Satiety

13 16 16 16 17 17 17 19 19 20 21 21 22 23 23 24 28 28 28 32 38 38 38 39 39 40 41 42 44 44 44 45 45 46 46 48 49 49 50 50 52 55 55 56 56

B.5 Fats in Cellular Nutrition B.5.1 Fatty Acid Structure and Classification B.5.2 Fatty Acids as Cellular Signals B.6 Carbohydrates in Cellular Nutrition B.6.1 Sugars and Starches B.6.2 Glycemic Index and Glycemic Load B.7 B.7.1 B.7.2 B.7.3 C. C.1 C.2 C.3 C.4 C.5 C.6 C.7 D. D.1 D.2 D.3 D.3.1 D.3.2 D.3.3 D.3.4 D.4 D.4.1 D.4.2 Functional Foods Soy Protein Phytochemical-Rich Fruits, Vegetables and Grains Beyond the Four Food Groups Vitamins and Minerals Introduction Pregnancy and Birth Defects Immune Function Cardiovascular Disease Cancer Obesity and Diabetes Safety of Vitamins

Weight Management and Meal Replacement Definition of Obesity Causes of Obesity Body-Fat Regulation and Function as an Endocrine Organ Female Fat Abdominal Fat Brain Centers and Body Fat Genes and Obesity Meal Replacements History of Meal Replacements Nutrient Composition of Herbalife Formula 1 and High-Protein/ Low-Carb Drink Mix D.4.3 Clinical Research on Meal Replacements D.4.4 Recent Research on ShapeWorks (Abstract) E. E.1 E.2 E.3 Body Composition Classification According to Lean-Body Mass RMR and Predicted Weight Loss from Lean Body Mass Basic Science Behind Bioimpedance

PHYSICIANS REFERENCE MANUAL

E.4 E.5 F. F.1 F.2 F.3 F.4 F.5 F.6 F.7 F.8 G. G.1 G.2 G.3 G.3.1 G.3.2 G.4 G.5

Challenges in the Clinical Use of Bioelectrical Impedance Future Research and Other Methods The Safety of Caffeine and Its Effects in Weight Management What is Caffeine? Coffee Consumption Caffeine Safety Fibrocystic Breast Disease and Caffeine Consumption Osteoporosis and Caffeine Consumption Caffeine and Blood Cholesterol Caffeine and Blood Pressure Caffeine and Heart Disease Metabolic Syndrome and the Co-morbidities of Overweight and Obesity Diabesity Heart Disease and Hypertension Fatty Liver Disease and Cirrhosis Diagnosing Fatty Liver Disease Other Causes of Fatty Liver and Liver Failure Cancer Changes with Aging in Body Fat and Chronic Disease Risk

58 58 60 60 61 61 62 62 63 63 63 64 65 65 66 66 66 67 68

SECTION I: INTRODUCTION

Section l Introduction

A.

PHILOSOPHY AND HISTORY OF HERBALIFE INTERNATIONAL

Herbalife International is a unique company that has a worldwide mission of changing peoples lives through improved lifestyles, nutritional health and weight management. This company, now traded on the New York Stock Exchange (symbol HLF), is the largest manufacturer of meal replacements in the world, with over 1.6 million Distributors in 65 countries. How did Herbalife grow to this position as an international leader in nutrition? Herbalife was founded in 1980 by Mark Hughes. At the time, this remarkable individual was only in his 20s, but he had the passion to bring healthy weight-loss solutions to the world after his mother died of complications from taking diet pills. In his first year of business, he was able to sell $1 million of meal replacements from the trunk of his car by offering people the opportunity to both lose weight and make money by helping others. However, the company did more than give people a chance to make money. Mark Hughes inspired people to change for the better in many ways. He taught them to speak in front of groups as they received recognition. He taught them to train others to do the same job and learn business and leadership skills in the process. The critical issue in weight management is adherence to diet and lifestyle change. In our best universities, the average weight loss achieved in any trial is on the order of 5 percent of initial body weight on average, with dropout rates from clinical trials of between 20 percent and 40 percent after one year. However, in these trials there are always individuals who do much better than the average and some who gain weight despite being given all of the nutritional and lifestyle tools to be successful. The key difference between those who succeed and those who fail is found in their personal motivation and ability to change themselves. Through hard work and person-to-person contact, Herbalife Independent Distributors from every walk of life move up through the ranks, at first helping their family and friends and then developing the skills to run a small business. Through training they can reach leadership positions in the company as Presidents Team and Chairmans Club members. These individuals with innate business skills often have little or no formal education, or have been unsuccessful in other businesses before coming to Herbalife. However, by combining product results, recognition and a sense of community, Herbalife has helped countless individuals change their health status through long-lasting weight loss and maintenance. In the process, Herbalife has developed an army of over 1.6 million agents of change throughout the world, and one of the most powerful weapons in the war against the international epidemic of obesity. Herbalife International was acquired from the estate of Mark Hughes in 2003 by the investment banking firms of Whitney and Golden Gate, and is led by Chairman and CEO Michael O. Johnson, former head of Disney International, and President and COO Gregory Probert. Chief Scientific Officer Steven Henig, Ph.D., has an over 20-year history in the food business, which included positions with Con-Agra, Ocean Spray* and POM Wonderful, and was a member of the Board of Directors of the International
*

Ocean Spray is a registered trademark of Ocean Spray Cranberries, Inc. POM Wonderful is a registered trademark of POM Wonderful, LLC.

PHYSICIANS REFERENCE MANUAL Life Sciences Institute (ILSI). A prestigious Scientific Advisory Board is led by David Heber, M.D., Ph.D., F.A.C.P., F.A.C.N., professor of medicine and public health and director of the prestigious UCLA Center for Human Nutrition. Louis Ignarro, Ph.D., winner of the 1998 Nobel Prize for Physiology or Medicine, is a member of the board. Under the leadership of Dr. Heber, Luigi Gratton, M.D., M.P.H., a clinical physician at the University of California, Los Angeles (UCLA), administers a worldwide Nutrition Advisory Board made up of highly qualified physicians, often with current or former prestigious university affiliations, who work in the training of Herbalife Independent Distributors in science-based approaches to nutrition and weight management.

B.

WHAT IS THE RATIONALE BEHIND DOCTORS IN HERBALIFE?

Over the past 27 years, several hundred physicians in the United States alone, and many others throughout the world, have discovered that they can help far more individuals to attain and maintain a healthy lifestyle through their activities as Herbalife Distributors than through their routine medical practice. It is very difficult to motivate patients to achieve and maintain a healthy body weight even when you are able to take the time to do this important job. Too often, prescriptions for drugs to lower cholesterol, blood pressure or blood sugar take the place of lifestyle change precisely because longterm adherence to diet and lifestyle is so problematic. The Doctors in Herbalife initiative is meant to accelerate the Herbalife mission of changing peoples lives by recruiting practicing doctors to be Herbalife Distributors. As physicians, you have a constant stream of patients coming to your office who could benefit from diet and lifestyle change. However, your education, your facilities, reimbursement mechanisms and time constraints all make it impossible for you to deliver this service within a traditional practice. What is rewarded is the prescription of medications for lowering cholesterol, blood pressure and blood sugar, or referring patients for expensive cardiovascular or bariatric surgery. Surveys done within the UCLA Primary Care Network have shown that over 50 percent of patients are obese with BMIs of greater than 30. Among these, 58 percent have musculoskeletal pain, such as knee or back pain. Subgroups of patients amounting to 20 percent to 40 percent each of the total population have metabolic syndrome, hyperlipidemia, hypertension or abnormal glucose tolerance. About 5 percent have sleep apnea, which can be fatal. Many of these problems respond to lifestyle change, improved nutrition and weight loss. The Diabetes Prevention Program funded by the National Institutes of Health (NIH), demonstrated that a modest 5 percent weight loss among individuals with impaired glucose tolerance led to a 58 percent reduction in new cases of type 2 diabetes over a five-year period. Meal replacements work. The scientific data is presented in this manual in detail and has appeared in the peer-reviewed medical literature. The NIH LookAHEAD trial, examining the impact of weight loss on cardiovascular mortality in patients with type 2 diabetes, is successfully utilizing this strategy. The Herbalife ShapeWorks program described in this manual applies the latest nutritional science on weight management to provide a personalized approach based on individualizing protein recommendations and on lean body mass. When this science-based approach is combined with the motivational tools developed by Herbalife, successful individuals achieve remarkable results. Herbalife has committed to a worldwide program of outreach to the medical and scientific communities through medical meetings and presentations at key medical

SECTION I: INTRODUCTION conferences. Through the Scientific and Nutrition Advisory Board and Doctors in Herbalife, it will be possible to build an international medical alliance dedicated to providing healthy nutrition solutions. The power of the Internet and high tech is being coupled with the high touch of Herbalife Distributors worldwide to create unprecedented efforts to prevent the spread of the international epidemics of obesity and obesity-associated chronic diseases.

C.

CELLULAR NUTRITION

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Good nutrition begins at the cellular level. Not only must the nutrients be delivered, but they must get to the appropriate cells of the body. These principles are the basis for Cellular Nutrition. Cellular Nutrition is the overriding nutritional philosophy of Herbalife International. A fully referenced section on Cellular Nutrition and the Fundamentals of Human Nutrition is included in Section II of this manual. Today, throughout the world, people are facing a lack of vital nutrients that their cells need for good health. This occurs even in countries where overweight and obesity are common. In the past 100 years, the human diet has changed drastically in ways that do not fit well with our genes. Our cells are adapted to a calorie-poor environment rich in bioactive substances from colorful fruits and vegetables, and high in dietary fiber and healthy plant-based proteins. Our genes cannot change rapidly enough through evolution to enable us to adjust in only the past few hundred years to a diet missing key cellular nutrients. For example, humans and fruit-eating bats have given up the cellular machinery to make Vitamin C, since both our diets and those of fruit-eating bats were originally rich in Vitamin C from plant foods. Unfortunately many individuals in the United States go all day without eating a single piece of fruit, and so do not get enough Vitamin C for optimum health. They often can get the tiny amount (20 milligrams) needed to prevent scurvy from fortified foods, but not enough to get the antioxidant benefits of this essential vitamin. Similarly, many different pathways promote retaining calories when excess food is eaten. The key element in reaching a successful body composition is not simply eating less but eating more of the right foods. Significant scientific evidence supports a highprotein/low-fat diet, including meal replacements such as Herbalifes ShapeWorks Formula 1, fortified (when necessary) with Performance Protein Powder, which provides additional protein to help control hunger and support increasing muscle mass with exercise. ShapeWorks meal replacements taken twice a day with a healthy meal and exercise leads to weight loss, while one meal replacement per day with two meals and exercise can help keep weight off for life. Meal replacements work by structuring the diet so that the healthy shake is providing better control of hunger and more protein to support the lean body mass than do the foods normally eaten at meal time. However, these shakes are taken in addition to at least one healthy meal per day, and Herbalife includes a healthy, colorful meal plan recommending seven servings of fruits and vegetables each day. While it was generally taught in medical schools for some 20 years that the so-called four basic food groups provided all the nutrition the body needed, this was not true. Significant research, which will be reviewed in this manual, demonstrates that most Americans are not getting what they need from their diet, and that nutritional supplements are a useful prevention strategy for the general population. Of course, nutritional supplements work best when combined with a healthy diet and lifestyle. Nutritional supplements help you obtain vitamins, minerals, proteins and

PHYSICIANS REFERENCE MANUAL other nutrients frequently missing from modern diets. Multivitamin supplements, protein supplements, individual mineral and vitamin supplements (provided alone or in combination), as well as botanicals, amino acids, and other forms of supplementation, are being used by millions of consumers around the world. Herbalife International has been providing nutritional supplements to over 1.6 million Distributors in 65 countries and is making a positive contribution to the lives of millions around the world. With over 27 years of experience in providing the finest nutritional supplements available, Herbalife is changing the health of the world, one person at a time.

D.

HERBALIFE ShapeWorks PROGRAM

Over the past 27 years, Herbalife International has become the leading global manufacturer of meal replacements for healthy nutrition and weight management. The goal of weight management is to achieve and maintain not only a healthy weight, but also a healthy shape. Shape is critical to achieving the health goals of weight management, since shape includes the concept of body-fat distribution, optimizing lean body mass and getting into a proper level of fitness. Shape means both body shape and getting into shape, and so provides a valuable tool for communicating the benefits of a healthy diet and lifestyle, regardless of body weight. It is not simply the weight of the body that determines health, but the quality of the body tissues in terms of lean versus fat. Simply because an individual is overweight, normal weight, or underweight is not neccessarily a gauge of his or her nutritional balance. Weight loss can lead to loss of lean body mass, which occurs during unsupplemented starvation and with hypocaloric diets that are deficient in protein. A body of scientific research is demonstrating that increased protein provided at about one gram per pound of lean body mass (29 percent of resting metabolic rate) provides better control of hunger and maintains lean body mass better than the usually recommended amount of protein, which is about 15 percent of total calorie intake. In addition to research at UCLA which forms the basis for the ShapeWorks program, recent studies in Australia and in Colorado demonstrate that increased protein may be especially useful for promoting weight loss in the pre-diabetic, insulin-resistant, obese individual. Many Americans take in too little protein and lead a sedentary lifestyle, resulting in loss of muscle and increase in fat or sarcopenic obesity. Attempts at rapid weight loss by eating less of their favorite foods results in deficiencies of multiple nutrients, which usually includes protein. In this common condition, lean tissue is deficient and the percentage of body fat is high (>30 percent), despite a normal Body Mass Index (BMI). Similarly, weight lifters can be overweight with a high BMI but have a normal body-fat percentage. Their increased weight is due to increased muscle tissue, and they require increased protein based on their lean mass, both to control hunger and maintain muscle. The rate at which weight is lost is a function of how much of a calorie deficit is created from the calories required to maintain current weight. For every 500 cal/day deficit created through calorie restriction, increased physical activity or some combination of the two, there will be a one-pound weight loss per week. Increased protein intake does not make weight loss more rapid, but it does result in better maintenance of lean body mass at the same rate of weight loss when compared to a lower protein intake. Starvation is the extreme, in which about one pound of body

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SECTION I: INTRODUCTION protein is lost for every four pounds of weight lost. With exercise and increased protein intake during weight loss, it is possible to minimize the loss of lean body mass. Some thin women will gain weight when given adequate protein, due to an increase in muscle mass. They may not be happy with this, and it is their choice to remain at a lower muscle mass. However, in order to keep their body-fat percentage in a healthy range, these women will need to burn calories daily with aerobic exercise and carefully watch their food intake to minimize total calorie intake. Their lower muscle mass means that they will need fewer calories to maintain their tiny shape. The ultimate secret ingredient in this program is the care that each Herbalife Distributor provides to their customers. Herbalife International provides many resources in the form of pamphlets, DVDs and educational materials, as well as downloadable Web-based information, to help Distributors provide the best care for their customers. It is our hope that this manual will help you in your efforts as a Doctor in Herbalife Distributor.

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Section II Background Material

A.

HISTORY AND FUTURE OF NUTRITIONAL SCIENCE AND MEDICINE

The understanding of human nutrition has evolved throughout history in parallel to the development of key sciences, including chemistry, biochemistry and physiology. During the Naturalistic Era (400 BC1750 AD), Hippocrates hypothesized about the bodys innate heat and coined his famous phrase, Let food be your medicine and medicine be your food. During the next 500 years, little happened in either the development of scientific knowledge or nutritional science. However, the level of knowledge that could be gleaned from careful clinical observation of the effects of foods on physiological function was remarkable, as typified in the writings of Maimonides in the 11th century. The late 1700s ushered in the Chemical-Analytical Era (17501900), highlighted by Lavoisiers calorimetry studies (McCollum, 1957). He discovered how food is metabolized by oxidation to carbon dioxide, water and heat. He also invented the calorimeter, crucial to further understanding heat energy. In the 19th century, Liebig recognized that carbohydrates, proteins and fats are oxidized by the body, and he calculated energy values for each. While chemists were examining the composition of foods and metabolism, physicians were studying the mechanisms and process of digestionthe means by which food is converted to useful, oxidizable components. The Biological Era (1900present) was founded on advances in chemistry, biochemistry and the understanding of the metabolic pathways. In the early 20th century, considerable research had been done on energy exchange and on the nature of foodstuffs. Nutritional science took a leap forward, as evidenced by publication of the laws of nutrition by Langworthy. Once understanding of macronutrients was developed and better tools were developed, nutritional scientists turned their attention to the understanding of micronutrientsvitamin and mineral nutrition (Pike and Brown, 1975). The Cellular Era of the late 20th century (after 1955) focused on understanding the functions of essential nutrients and the roles of micronutrients (vitamins and minerals) as cofactors for enzymes and hormones, and their subsequent roles in metabolic pathways. The roles of carbohydrates and fats in diseases such as diabetes and atherosclerosis were discovered, and actual and potential mechanisms have been uncovered (University of Vermont). Today we are still in the era of Cellular Nutrition, but the coming era of Molecular and Cellular is developing in the 21st century. It has been spurred on by the sequencing of the human genome, but is not yet ready for application. Here is a glimpse of the future as Herbalife International uses its high-tech and international reach to change lives around the world. Observations of health and disease in the 20th century raised some new questions. Why can some individuals consume high-fat diets and yet show no evidence of atherosclerotic disease? Genetic differences certainly were suspected, but elucidating and proving cellular, molecular and ultimately genetic-level mechanisms in both healthy and unhealthy individuals proved to be a challenge. With the continuing developments in tools that enable molecular-level exploration of cause-effect phenomena, scientists have begun to develop hypotheses and conduct experiments to lay the foundation for a deeper level of understanding of gene-nutrient interactions. 13

S E C T I O N I I : BACKGROUND Today, an emerging field of nutritional research focuses on identifying and understanding molecular-level interaction between nutrients and other dietary bioactives with the human genome during transcription, translation and expressionthe processes during which proteins encoded by the genome are produced and expressed. The UCLA Center for Human Nutrition and the Mark Hughes Cellular and Molecular Nutrition Laboratory are at the cutting edge of this new science. Continuing and accelerating discoveries in genomics present possibilities for an ever more dynamic era of scientific investigation based on understanding the effects of nutrients in molecular-level processes in the body, as well as the variable effects nutrients and nonnutritive dietary phytochemicals have on each of us as individuals. We call this new era in nutritional science the Genetic Era, or nutrigenomics. There is a coming revolution in the way nutrition and diet are viewed. Enabling science and technology platforms and techniques are essential for development of knowledge and advancements in science. However, the ultimate result will require both high tech and high touch. The latter involves behavior and lifestyle changes best performed on an individualized basis. What do we know about behavior that makes Herbalife such a powerful approach? The National Weight Control Registry includes a group of more than 3,000 men and women who have been classified as successful losers. Wing and colleagues and Klem studied these individuals and found that their long-term success was due to a combination of a healthy, low-fat diet and regular, moderate exercise. The ShapeWorks program is based on sound science and the latest advances in formulating a low-fat/highprotein diet and incorporating fitness into future messaging and image. Second, we know that our success as physicians in a clinical setting is typically poor, with up to 50 percent dropouts at one year. We know what the signposts of success are. They include readiness to change, and a step-wise approach to lifestyle change. These principles were built into the successful Herbalife programs over the last 27 years. Moreover, they have always been based on a proven way to enhance compliance. Meal-replacement shakes organize the diet and simplify long-term adherence. As discussed in this background section, there is significant evidence that higher protein levels than recommended for the general population are particularly useful in weight management, both to control hunger and maintain lean body mass. However, these physiological principles would be useless without the proper behavioral approach.

A Glimpse at the Future of Nutritional Medicine Individual genetic differences in response to dietary components have been evident for years: lactose intolerance, alcohol dehydrogenase deficiency, individual and population differences in blood lipid profiles and health outcomes after consumption of high-fat diets. Genomic informationincluding proteomics and SNPswill be used to understand the basis of individual differences in response to dietary patterns. The resulting nutrigenomic data also will provide a sound basis for development of safe and effective diet therapies for individuals or subgroups of the population. Refined models of disease mechanism based on understanding the genome may provide new lines of research and possibly new diets. The elaboration of physical and genetic linkage maps combined with techniques to catalog massive databases of genetic information will uncover genes that may interact with diet to influence disease.

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PHYSICIANS REFERENCE MANUAL Personalized medicine developed through growing knowledge of genomics has generated a lot of well-deserved enthusiasm as an important tool for the future, but it will require a personalized behavioral approach as well. Who will do this? Public health officials will continue to issue vague one size fits all solutions and will necessarily need to run these through the funnel of special interests that distort nutritional advice given to the public. The drug industry, while recognizing that nutrition may play a role, minimizes this and uses the general government guidelines in patients given drugs to ameliorate conditions driven by diet and lifestyle, such as hypertension, hypercholesterolemia and diabetes. Food processors marketing mainstream products will wait a long time for the products to be created and the demand to be established. At the present time, Herbalife International can provide you with a unique opportunity to impact your patients and your practice using a high-tech and high-touch approach. With the resources of a $3 billion company in 65 countries and with over 1.6 million agents of change, what a unique opportunity for you as a Doctor in Herbalife to ride the wave of the coming advances in nutrition that will change the way you practice medicine. You will begin to appreciate the power of the personal touch in lifestyle change, and you can enlist the help of successful staff and patients to help you in the mission of changing peoples lives one at a time and hundreds at a time. You will learn how you can duplicate your expertise and spread a message of health. If you take on this challenge, you will gain satisfaction and enhance your clinical practice. At the same time, you will be acting within the highest ethical standards of physicians who have an obligation, not simply to prescribe drugs and surgery for the treatment of disease, but to use the resources available to motivate and follow their patients as they prevent disease through changes in diet and lifestyle.

REFERENCES
A History of Nutrition, E.V. McCollum 1957 QU 145 McCol. Nutrition; An Integrated Approach, Ruth Pike and Myrtle Brown, John Wiley & Sons, 1975, pp 4-8. Fundamentals of Nutrition, Course Syllabus, University of Vermont. Biospace.com Pharmacogenomic Medicine: Technology Outpacing the Health Care System. AAAS symposium on Gene-diet Interactions in Coronary Heart Disease, AHA press release 2/14/98. Attenuated hypercholesterol response to a high-cholesterol diet in subjects heterozygous for the apolipoprotein A-IV-2 allele, Weiberg et al, N Engl J Med, Vol. 331, No.11, pp 706-710. Attacking Heart Disease at Its Genetic Base, Agricultural Research, 7/99. Autism and Schizophrenia: Intestinal Disorders, Cade R et al. Nutritional Neuroscience, in press 1999. Symposium: Interactions of diet and Nutrition with Genetic Susceptibility in Cancer, Journal of Nutrition, Vol. 129, 2/99, pp 550S-551S.

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B - B.2

S E C T I O N I I : BACKGROUND

B. B.1

FUNDAMENTALS OF NUTRITION

FUNDAMENTALS OF CELLULAR NUTRITION

Diets are made up of numerous foods in varied proportions that are prepared in many different ways, but ultimately the purpose of foods is to contribute energy to the body to support basic cellular energy needs. How that energy is provided as foods which are made up of the basic macronutrientsprotein, carbohydrate and fatplays a major role in determining the impact of dietary patterns on health and disease. Within each category of macronutrient, there are marked differences in how different food sources are digested, absorbed and metabolized. It is critical to understand the impact of the specific food sources of these macronutrients. Foods can be grouped according to their content of macronutrients combined with their traditional use in an ethnic or societal geographic cuisine. Food groupings such as the basic four food groups [1) Grains and Cereals, 2) Fruits and Vegetables, 3) Meat, Beans, Nuts and Cheese and 4) Dairy Products] classify foods of very different compositions together (such as red meat and ocean-caught fish, or muffins and wholegrain bread). However, considerations of chemical structure, digestibility, metabolism and functionality contribute to what is called the quality of the diet overall, as well as for individual macronutrients.

B.2

QUALITY OF THE DIET: GOOD VS. BAD

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The quality of dietary macronutrients, such as the ratio of n-3 fatty acids to n-6 fatty acids or of whole grains to refined grains, complicates the basic considerations of the effects of diet on the incidence of chronic diseases and efforts to organize dietary interventions designed to reduce risk. An additional and important consideration is the presence of phytochemicals in fruits, vegetables and whole grains leading to their designation in some cases as functional foods. The term functional food indicates the presence of bioactive substances that affect physiology or cellular and molecular biology. The term quality implies that a value judgment is being leveled against a particular food. While there is a hierarchical ranking of fats, carbohydrates and proteins common to the disease-prevention literature, the mechanisms underlying the differences among foods that provide protein, fat and carbohydrate to the diet are simply analyzed in light of fundamental principles of nutrition. Taken together, these aspects of foods contribute to the assessment of the quality of the diet. The lowest quality foods are called junk foods, since they are high in energy density but low in nutrient density (e.g., French fries). It has been said that there are no junk foods but simply junk diets. Obviously, if one combines enough junk foods, it results in a junk diet.

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B.3 - B.4.1

B.3

ENERGETICS AND OBESITY

Among species, smaller surface area animals such as mice burn more energy at rest per unit body mass than large mammals such as elephants. Children have higher metabolic rates than adults per unit body mass. Within the same species there can be significant variations in metabolic rates. For example, the sedentary and overfed laboratory rat has a higher metabolic rate than does the desert rat, which is better adapted to starvation (Kalman et al., 1993). Energy efficiency may vary as well among humans. There is evidence that the post-obese adult may have a lower metabolism than a never-obese individual of the same size. However, the impact of excess energy is modulated by the location of excess body fat and its effects on hormones and inflammatory cytokines. Therefore, while energy balance is critical, it is not sufficient for an understanding of the effects of nutrition on disease risk. Since obesity results from an imbalance of energy intake and expenditure, certain dietary factors have been identified as contributing to obesity. These include hidden processed fats in foods, added refined sugars in foods and a high-glycemic-load diet rich in refined carbohydrates. Therefore, the quality of the diet, in terms of nutrient density, can contribute to the tendency of a dietary pattern to promote the development of obesity in genetically susceptible individuals. Low-energy density foods include all fruits and vegetables, generally due to their high-water content. High-energy density foods include red meats, fats, cheeses, pastries, cookies, cakes, ice cream, snack chips, some fruit juices and refined grains.

B.4

PROTEIN AND ITS ROLE IN CELLULAR NUTRITION

Proteins are involved in the growth, repair and replacement of tissue, and serve numerous functions in the body as enzymes, antibodies, hormones, regulators of fluid and acid-base balance, and as integral parts of most body structures, including skin, muscle and bone. Within each cell, there is a continuous process of synthesis and breakdown of proteins in the body, referred to as protein turnover. The rate of protein turnover affects organ-protein mass, body size and ultimately, the bodys protein and amino acid requirements (Matthews, 1999; Fuller, 2000). The amino acids are the basic units in protein metabolism, and all have the same basic structure of a central carbon atom with a hydrogen, an amino group and an acid group attached to it. Attached to the fourth site on the carbon atom is a distinct side chain, which defines the amino acid. Cells link these amino acids in an infinite variety to create proteins which become metabolically essential compounds.

B.4.1

PROTEIN QUALITY

There are 21 amino acids in human proteins, and 12 of these are synthesized by the body and are, therefore, known as non-essential amino acids. The nine remaining amino acids (histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine) are either not made by the body or not made in sufficient quantities to meet needs, and are, thus, termed essential amino acids.

17

B.4.1

S E C T I O N I I : BACKGROUND The proper balance and sufficient intake of essential amino acids, along with an adequate amount of nitrogen for the production of non-essential amino acids, is required for proper protein nutriture (Berdanier, 2000). In order to manufacture proteins, cells require all the needed amino acids simultaneously with adequate nitrogen-containing amino groups for the manufacture of the non-essential amino acids. The amino acid composition of a food can vary widely, and determines the nutritional quality of the dietary protein. Foods that contain essential amino acids at levels that facilitate tissue growth and repair are known as complete proteins and are supplied in the diet from animal sources and soy protein. There are several ways of measuring protein quality. Most commonly, the term biological value is used, which is a measure of the efficiency of a given protein in supporting the bodys needs. Complete proteins have a high biological value, which is an expression of the amount of nitrogen absorbed relative to the amount of nitrogen retained by the body. All protein sources are compared with egg white, which provides the most complete protein and has the highest biological value of 100, indicating that 100 percent of the nitrogen absorbed is retained. A low concentration of one or more essential amino acids in a food lowers its biological value. With the exception of soy, most plant proteins are deficient in one or more essential amino acids and are, therefore, regarded as incomplete. However, the biological value of incomplete proteins can be improved by combining two proteins that are complementary so that those essential amino acids lacking or deficient in one protein are provided by the other when they are combined. In this way, the two complementary proteins together provide all the essential amino acids in ratios ideal for human protein utilization (Kreutler and CzajkaNarins, 1987; Lappe, 1971; Matthews, 1999). For example, the combination of corn (limited in lysine) with beans (limited in methionine) results in a high-quality protein food combination. Thus, the requirement for adequate essential amino acids can be met in a vegetarian diet by mixing foods of complementary amino acid composition (Berdanier, 2000; Committee on Diet and Health, 1989; Lappe, 1971).

TABLE 1

A Few Facts on Amino Acids

There are 21 common (non-essential) amino acids and nine essential amino acids. Essential amino acids are those that cannot be synthesized from other amino acids, but must be consumed in the diet. The usual way that non-essential amino acids are formed is by metabolism of other amino acids. All amino acids have a basic structure of an alpha-amino nitrogen and carboxylic acid. What defines their identity is the side chain denoted as R in the diagram below: R-CCOOH NH2 Some amino acids are called conditionally essential, because they must be consumed in the diet during growth to provide adequate growth rates, but become non-essential in adults who are not growing. One such amino acid is histidine, which is essential for rats that are still growing but not for adult rats. Much of the data on essentiality of amino acids is obtained from rats, where single amino acid elimination is a way of determining whether a given amino acid is essential. For example, lysine and threonine cannot be

18

PHYSICIANS REFERENCE MANUAL TABLE 1 (Continued) made from other amino acids by transamination and must be included in the diet. Essential Amino Acids Histidine Isoleucine Leucine Lysine Methionine Phenylalanine Threonine Tryptophan Valine Non-essential Amino Acids Alanine Arginine Asparagine Aspartic Acid Cysteine Glutamic Acid Glutamine Glycine Proline Serine Taurine Tyrosine

B.4.2 - B.4.3

B.4.2

PROTEIN REQUIREMENTS

The U.S. food supply can provide an average of 102 grams of protein per person per day (Nationwide Food Consumption Survey, 1984). Actual daily protein consumption ranges from 88 grams to 92 grams for men and from 63 grams to 66 grams for women (McDowell et al., 1994). Animal products provide 75 percent of the essential amino acids in the food supply, followed by dairy products, cereal products, eggs, legumes, fruits and vegetables (McDowell et al., 1994). The recommended daily allowance (RDA) for protein of high biological value for adults, based on body weight, is 0.8 grams/kilograms (National Research Council, 1989) or 0.36 grams/lb. However, the RDA is set to meet the needs of a defined population group as a whole, rather than indicating individual requirements. In a recent report concerning Dietary Reference Intakes (DRI) the Acceptable Macronutrient Distribution Range (AMDR) was set at 10 percent to 35 percent of total calories from protein. The AMDR is defined as the acceptable range of intakes for protein associated with reduced risk of chronic disease while providing intakes of essential nutrients (Barr et al., 2003). This range was largely set so that the intake of other macronutrients in the diet would be in an acceptable range. There are many conditions in which extra protein is needed, including periods of growth, pregnancy, lactation, intensive strength and endurance training, and other forms of physical activity, and possibly in the elderly (Campbell et al., 1994). Additionally, there is recent research into the role of protein in the regulation of longterm energy balance, maintenance of body weight and satiety (see B.4.4: Proteins Role in Satiety on page 20).

B.4.3

OPTIMUM PROTEIN INTAKE

19

Given the variation in the needs for protein throughout the life cycle, there is an individual optimum intake that exists based on lean body mass and activity levels.

B.4.3 - B.4.4

S E C T I O N I I : BACKGROUND However, optimal intakes are difficult to determine based on the existing science base in nutrition. In 1977, Garza et al. studied a small number of healthy volunteers and found that 0.8 (grams per kilograms per day) resulted in positive nitrogen balance. Subsequent studies in endurance athletes found that more than 1 g/kg/day was required for positive nitrogen balance (Tarnopolsky, 2004) and studies of weight lifters indicated that more than 2 g/kg/day was needed to achieve positive nitrogen balance (Tarnopolsky et al., 1992). Therefore, while the DRI (which is the same as the RDA) is set at 56 grams per day for men consistent with the 1977 study, the allowable range of macronutrient intake is broad (10 to 35 percent of total calories), enabling some individual adjustment for optimal intakes both to control hunger and to provide support to lean tissues.

B.4.4

PROTEINS ROLE IN SATIETY

20

In comparison with carbohydrate or fat, protein provides a stronger signal to the brain to satisfy hunger. While the mechanism of action is unknown, it has been suggested that either single amino acids or small peptides enter the brain to elicit their effects, and several amino acids, including tryptophan, phenylalanine and tyrosine, have been theorized to affect the hunger control mechanisms once they cross the blood-brain barrier. Small differences in the rates at which proteins release their amino acids into the bloodstream may also affect satiety. In subjects consuming high-protein meals, compared with high-carbohydrate meals fed ad libitum, a voluntary reduction in energy consumption has been observed. Researchers in the Netherlands (Westerterp-Plantenga et al., 1999) have studied the effects of protein on hunger perceptions by studying two groups of subjects in a whole-body energy chamber under controlled conditions for over 24 hours. Subjects were fed isocaloric diets that were either high-protein/high-carbohydrate (protein/carbohydrate/fat, percentage of calories 30/60/10) or high-fat (protein/carbohydrate/fat, percentage of calories 10/30/60). Significantly more satiety was reported by subjects on the high-protein/high-carbohydrate diet. At the same time, hunger, appetite, desire to eat and estimated quantity of food eaten were significantly lower in this group, with less hunger both during and after the high-protein meals. The level of protein in the diet may also impact maintenance of body weight after weight loss. After following a very low-energy diet for four weeks, subjects who consumed a 20 percent higher intake of protein than did control subjects (15 percent versus 18 percent of energy) showed a 50 percent lower body-weight regain, only consisting of fat-free mass, with increased satiety and decreased energy efficiency during a three-month maintenance period (Westerterp-Plantenga et al., 2004). Similar studies have reported improved weight loss and fat loss in subjects consuming a high-protein diet versus a control diet (25 percent versus 12 percent energy from protein) ad libitum, due to a reduction in daily calorie intake of approximately 16 percent (Skov et al., 1999) and improved utilization of body fat with maintenance of lean body mass in subjects consuming 32 percent of energy from protein compared with control subjects who consumed 15 percent of calories as protein (Layman et al., 2003). A similar study comparing diets with 15 percent versus 30 percent of calories from protein found that while weight loss in the two groups was similar over the six-week trial, diet satisfaction was significantly greater in those consuming the higher-protein diet (Johnston et al., 2004). A meta-analysis of studies (Eisenstein et al., 2002) concluded that, on average, highprotein diets were associated with a 9 percent decrease in total calorie intake. While the role of protein (in comparison to fat and carbohydrate) in affecting overall calorie intake and in body-weight regulation needs further investigation, the evidence is strong that protein affects hunger-signaling mechanisms in the brain, induces thermogenesis and contributes to the building and maintenance of lean body mass.

PHYSICIANS REFERENCE MANUAL

B.5 - B.5.1

B.5

FATS IN CELLULAR NUTRITION

Fats are a subset of the lipid family, which includes triglycerides (fats and oils), phospholipids and sterols. Fats play an extremely important role in energy balance by enabling efficient storage of calories in adipose tissue. It is possible for the mythical 70-kilogram man to carry 130,000 calories in 13.5 kilograms of fat tissue, compared to only 54,000 calories stored as protein in an equivalent weight of lean tissue. This efficient storage is accomplished both largely by excluding water from adipose tissues and by storing energy in the chemical bonds of very long chain fatty acids. The typical fatty acids found in digested and stored fat range between 16 and 22 carbons in length. Triglycerides, the chief form of fat in the diet and the major storage form of fat in the body, are composed of a molecule of glycerol with three fatty acids attached. The principal dietary sources of fat are meats, dairy products, poultry, fish, nuts, and vegetable oils and fats used in processed foods. Vegetables and fruits contain only small amounts of fat, so that vegetable oils are only sources of fat due to processing of vegetables. The most commonly used oils and fats for salad oil, cooking oils, shortenings and margarines in the United States include soybean, corn, cottonseed, palm, peanut, olive, canola (low-erucic-acid rapeseed oil), safflower, sunflower, coconut, palm kernel, tallow and lard. These oils contain varying compositions of fatty acids which have particular physiological properties. The fats stored in tissues reflect, to a certain extent, the fats in the diet. Humans synthesize saturated fats (e.g., palmitic acid) from carbohydrates, but the polyunsaturated essential fats (linoleic and linolenic acids) must be taken in from the diet. The balance of these fats and the metabolic products of these fats reflect short-term and long-term dietary intake. There is a statistically significant but poor correlation between adipose tissue fatty acid profiles and dietary fatty acid intake as measured on a food frequency questionnaire (London et al., 1991). Red blood cell membranes change their composition in about three weeks. However, it is clearly possible to change the amount of fatty acids in tissues (Bagga et al., 1997) and total quantitative fatty acids can be altered by dietary intervention. The quality of fats in the diet is defined as that ratio of fatty acids that can be measured in plasma and tissues.

B.5.1

FATTY ACID STRUCTURE AND CLASSIFICATION

Fatty acids are organic compounds composed of a carbon chain with hydrogens attached at one end and an acid group at the other. Most naturally occurring fatty acids have an even number of carbons in their chain, up to 24 carbons in length, with 18-carbon chains the most abundant fatty acids in the food supply. Saturated fatty acids are completely saturated with hydrogens. Those fatty acids lacking two hydrogen atoms and containing one double bond are monounsaturated fatty acids, and polyunsaturated fatty acids contain two or more double bonds in the carbon chain. The degree of saturation influences the texture of fats so that, in general, polyunsaturated vegetable oils are liquid at room temperature and the more saturated fats, most of which are animal fats, are solid. Some vegetable oils such as palm and coconut oils are highly saturated, and liquid oils can be hydrogenated in the presence of a nickel catalyst to produce a firmer fat. The nomenclature of fatty acids is based on location of the double bonds: an omega-3 fatty acid has its first double bond three carbons from the methyl end of the carbon chain. Similarly, an omega-6 fatty acid has its double bond six carbons from the

21

B.5.1 - B.5.2

S E C T I O N I I : BACKGROUND methyl end. Fatty acids are also denoted by the length of the carbon chain and the number of double bonds they contain, such that linoleic acid is an 18:2 fatty acid which contains 18 carbons and two double bonds. The human body requires fatty acids and can manufacture all but two essential fatty acids: linoleic acid and linolenic acid (18:3) (see Figure 1 below). Omega-3 fatty acids possess anti-inflammatory, antiarrhythmic and antithrombotic properties and have been shown to reduce the risk for sudden death caused by cardiac arrhythmias and decrease mortality from all causes in patients with coronary heart disease. Conversely, the omega-6 fatty acids, obtained in the diet primarily from vegetable oils such as corn, safflower, sunflower and cottonseed, are proinflammatory and prothrombotic. Fish and fish oils are the richest sources of the omega-3 fatty acids Figure 1

eicosapentaenoic acid (EPA) and docosshexaenoic acid (DHA) and are also present in algae. Green leafy vegetables, nuts, seeds and soybeans contain the omega-3 fatty acid alpha-linolenic acid (AHA). The increased consumption in the United States of omega-6 fats from vegetable oils and grain-fed animals has led to a drastic increase in the ratio of omega-6 to omega-3 fatty acids in the diet from an estimated ratio of 1:1 in early human diets to a ratio exceeding 10:1 today (Simopoulos, 2001).

B.5.2

FATTY ACIDS AS CELLULAR SIGNALS

Increasing evidence from animal and in vitro studies indicates that omega-3 fatty acids, especially the long-chain polyunsaturated fatty acids EPA and DHA, present in fatty fish and fish oils inhibit carcinogenesis (Karmali et al., 1984; Lindner, 1991; Rose et al., 1991; Tsai et al., 1998; Boudreau et al., 2001; Narayanan et al., 2001). Several molecular mechanisms have been proposed for the influences on the process, including suppression of arachidonic acid-derived eicosanoid biosynthesis (Rose, 1999; Okuyama, 1996) and influences on transcription factor activity, gene expression and signal transduction pathways (Bartsch et al., 1999). The peroxisome proliferator-activated nuclear receptors (PPARa, d, g ) are activated by polyunsaturated fatty acids, eicosanoids, and various synthetic ligands (Willson et al., 22

PHYSICIANS REFERENCE MANUAL 2000). Consistent with their distinct expression patterns, gene-knockout experiments have revealed that each PPAR subtype performs a specific function in fatty acid homeostasis. Over a decade ago, PPARa was found to respond to hypolipidemic drugs, such as fibrates. Subsequently, it was discovered that fatty acids serve as their natural ligands. Together with the analyses of PPARa null mice, these studies established PPARa as a global regulator of fatty acid catabolism. PPARa target genes function together to coordinate the complex metabolic changes necessary to conserve energy during fasting and feeding. In the fatty acid metabolic cascade, PPARa activation up-regulates the transcription of liver fatty acid-binding protein, which buffers intracellular fatty acids and delivers PPARa ligands to the nucleus (Wolfrum et al., 2001). In addition, expression of two members of the adrenoleukodystrophy subfamily of ABC transporters, ABCD2 and ABCD3, is similarly up-regulated to promote transport of fatty acids into peroxisomes (Fourcade et al., 2001) where catabolic enzymes promote beta-oxidation. The hepatocyte CYP4A enzymes complete the metabolic cascade by catalyzing gamma-oxidation, the final catabolic step in the clearance of PPARa ligands (Lee et al., 1995). PPARg was identified initially as a key regulator of adipogenesis, but it also plays an important role in cellular differentiation, insulin sensitization, atherosclerosis and cancer (Rosen and Spiegelman, 2001). Ligands for PPARg include fatty acids and other arachidonic acid metabolites, antidiabetic drugs (e.g., thiazolidinediones) and triterpenoids. In contrast to PPARa, PPARg promotes fat storage by increasing adipocyte differentiation and transcription of a number of important lipogenic proteins. Ligand homeostasis is regulated by governing expression of the adipocyte fatty acid-binding protein (A-FABP/aP2) and CYP4B1(Way et al., 2001). In macrophages, PPARg induces the lipid transporter ABCA1 through an indirect mechanism involving the LXR pathway, which in turn promotes cellular efflux of phospholipids and cholesterol into high-density lipoproteins (Chawla et al., 2001; Chinetti et al., 2001).

B.5.2 - B.6.1

B.6

CARBOHYDRATES IN CELLULAR NUTRITION

As with proteins and fats, one can consider the quality of carbohydrates based on the source of the carbohydrates (fruits, vegetables, or whole grains versus refined grains and simple sugars) and their digestibility (soluble versus insoluble fiber). A quantitative approach to the analysis of dietary carbohydrate has been developed based on glycemic index and glycemic load, as will be discussed.

B.6.1

SUGARS AND STARCHES

Simple carbohydrates are present in foods as mono- or di-saccharides, and are naturally present in such foods as fruit and milk. Glucose, fructose and galactose are the most common monosaccharides in the human diet and combine to form the disaccharides sucrose (glucose + fructose), lactose (glucose + galactose) and maltose (glucose + glucose). Oligosaccharides are short chains of 3-10 sugar molecules, and the most common ones, raffinose and stachyose, are found in beans, peas and lentils. Polysaccharides are starches which contain more than 10 sugar molecules, found in wheat, rice, corn, oats, legumes and tubers. Starches form long chains that are either

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B.6.1 - B.6.2

S E C T I O N I I : BACKGROUND straight (amylose) or branched (amylopectin). Amylose and amylopectin occur in a ratio of about 1:4 in plant foods. While there are several dietary factors that contribute to obesity, a dietary pattern that is rich in sugars and starches is considered a risk factor for obesity, whereas a high intake of nonstarch polysaccharides in the form of dietary fiber is considered protective (Swinburn et al., 2004). The typical Western diet is high in refined starches and sugars which are digested and absorbed rapidly, resulting in a high glycemic load and increased demand for insulin secretion. This, in turn, promotes postprandial carbohydrate oxidation at the expense of fat oxidation. Both acute (Ludwig et al., 1999; Febbraio et al., 2000) and short-term studies (Agus et al., 2000; Howe et al., 1996) indicate that a dietary pattern that produces a high-glycemic response affects appetite and promotes body-fat storage. However, diets based on high-fiber foods that produce a low glycemic response can enhance weight control because they promote satiety, minimize postprandial insulin secretion, and maintain insulin sensitivity (Brand-Miller et al., 2002). This is supported by several intervention studies in humans in which energy-restricted diets based on low glycemic index foods produced greater weight loss than did equivalent diets based on high glycemic index foods. Long-term studies in animal models have also shown that diets based on high glycemic index starches promote weight gain, visceral adiposity and higher concentrations of lipogenic enzymes than do isoenergetic diets with a low glycemic index, which are macronutrient-controlled.

B.6.2

GLYCEMIC INDEX AND GLYCEMIC LOAD

24

Conventional approaches to weight loss have focused on decreasing dietary fat, due to its high-calorie density. However, the relationship between dietary fat and obesity has been brought into question for several reasons. Low-fat diets have been shown to produce only modest weight loss, and prospective epidemiological studies have not been able to consistently correlate dietary fat intake with weight. Despite a decrease in fat consumption as a percentage of total calories and widespread availability of low-fat and fat-free foods, obesity prevalence in the United States has risen dramatically since the 1970s (Putnam and Allshouse, 1999). At the same time, carbohydrate consumption has increased, and most of this increase has been in the form of refined starches and concentrated sweets with a high glycemic index (GI) and/or glycemic load (GL). In 1981, Jenkins et al. introduced the glycemic index as a system for classifying carbohydrate-containing foods based upon their effect on post-prandial glycemia (Jenkins et al., 1981). The glycemic response to the ingestion of 50 grams of available carbohydrate from the test food is compared to the response from the ingestion of 50 grams of the reference food (glucose or white bread), and the glycemic index is expressed as the area under the glucose response curve for the test food divided by the area under the curve for the standard, multiplied by 100. However, the amount of carbohydrate in 50 grams of a given food will vary depending upon the food, and this observation led to the introduction of the concept of glycemic load. This is an expression of the glycemic index of the food multiplied by the carbohydrate content of the food, and takes into account the differences in carbohydrate content among foods (Liu, 1998). Foods with a high index but relatively low total carbohydrate content, such as carrots, have a low glycemic load. In general, fruits, non-starchy vegetables, nuts and legumes have a low GI (see Table 2 on the following pages). One problem with the GI

PHYSICIANS REFERENCE MANUAL is that it only detects carbohydrate quality, not quantity. A GI value tells you only how rapidly a particular carbohydrate turns into sugar; it doesnt tell you how much of that carbohydrate is in a serving of a particular food. Both should be known to understand a foods effect on blood sugar. The most famous example of this is the carrot. The form of sugar in the carrot has a high glycemic index, but the total carbohydrated content of the carrot is low, so it doesnt add a lot of calories. A low glycemic load (GL) is less than 16, and this has been found to be the most important variable in studies of populations and their risk of chronic disease. You are not going to be able to eat all low GL foods, but it is important to know both the GL and the calories that the food provides. The problem with GL is that fatty foods which carry lots of calories have a lower glycemic index. Fatty foods can still add calories to the diet even though they have a low glycemic index.

B.6.2

TABLE 2 GLYCEMIC INDEX, GLYCEMIC LOAD AND CALORIES The GI, GL, and total calories of foods are listed here. The GI is of foods based on the glucose indexwhere glucose is set to equal 100. The other is the glycemic load, which is the glycemic index divided by 100 multiplied by its available carbohydrate content (i.e., carbohydrates minus fiber) in grams. Each of these foods is equivalent to one serving size. Except as noted, each of the GI values shown below is based on the 120 studies in the professional literature referenced in The American Journal of Clinical Nutrition, July 2002. LOW GI (<55) and LOW GL (<16) FOODS Lowest Calorie (110 calories per serving or less) GI 40 52 22 25 53 51 48 42 39 40 38 <20 32 GL 6 12 3 5 6 14 5 7 5 1 4 <5 4 CALORIES 75 90 85 75 45 110 65 70 70 50 40 40 90

APPLE BANANA CHERRIES GRAPEFRUIT KIWI MANGO ORANGE PEACH PLUM STRAWBERRIES TOMATO JUICE Most Other Vegetables NONFAT MILK

Moderate Calorie (110 to 135 calories per serving or less) GI 40 48 33 48 GL 12 9 10 3 CALORIES 135 115 125 135

APPLE JUICE GRAPEFRUIT JUICE PEAR PEAS

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B.6.2

S E C T I O N I I : BACKGROUND TABLE 2 (Continued) GI GL PINEAPPLE JUICE 46 15 WHOLE-GRAIN BREAD 51 14 SOY MILK 44 8 Higher Calorie (160 to 300 calories per serving) GI 25 20 28 46 23 29 18 37 GL 11 8 13 13 10 7 1 13 CALORIES 190 235 285 160 210 230 300 160

CALORIES 130 120 130

BARLEY BLACK BEANS GARBANZO BEANS GRAPES KIDNEY BEANS LENTILS SOYBEANS YAM

HIGH GI (>55) BUT LOW GL (<16) FOODS All Low Calorie (110 calories per serving or less) GI 57 57 60 59 75 75 74 72 GL 6 15 9 7 3 15 15 7 CALORIES 70 110 55 75 85 110 110 50

APRICOT ORANGE JUICE PAPAYA PINEAPPLE PUMPKIN SHREDDED WHEAT TOASTED OATS WATERMELON

Low GI and Low Gl - But High Fat and High Calorie GI 22 38 37-50 14 72 54 27 44 31 50 GL 4 10 13 1 16 15 3 16 9 13 CALORIES 395 360 220 330 110 345 150 250 200+ 200+

CASHEWS PREMIUM ICE CREAM LOW-FAT ICE CREAM PEANUTS POPCORN (FULL-FAT) POTATO CHIPS WHOLE MILK VANILLA PUDDING FRUIT YOGURT SOY YOGURT 26

PHYSICIANS REFERENCE MANUAL TABLE 2 (Continued) HIGH GI >55 HIGH GL >16 Includes Typical Trigger Foods, Many Higher Calorie GI 85 50 63 60 63 92 68 74 67 75 64 75 60 83 61 66 74 76 73 64 GL 34 16 33 20 21 24 24 22 17 25 46 17 20 33 29 42 18 18 20 23 CALORIES 220 215 200 130 350 100 145 130 275 515 285 140 300 115 185 250 155 150 160 210

B.6.2

BAKED POTATO BROWN RICE COLA CORN CORN CHIPS CORN FLAKES CRANBERRY JUICE CREAM OF WHEAT CROISSANT FRENCH FRIES MAC N CHEESE OATMEAL PIZZA PRETZELS RAISIN BRAN RAISINS SODA CRACKERS WAFFLES WHITE BREAD WHITE RICE

The intake of high GI/GL meals induces a sequence of hormonal changes, including an increased ratio of insulin to glucagon, that limit the availability of metabolic fuels in the post-prandial period and promote nutrient storage (Ludwig, 2002) and would be expected to stimulate hunger and promote food intake. Short-term feeding studies have demonstrated less satiety and greater voluntary food intake after consumption of high GI meals as compared to low GI meals (Ludwig et al., 1999), for example, the demonstration of prolonged satiety after consumption of a low GI bean puree vs. a high GI potato puree (Leathwood and Pollett, 1998). Weight loss on a low-calorie, reduced-fat diet may be enhanced if the diet also has a low GI (Slabber et al., 1994), and even when energy intake is not restricted, low GI and/or low GL diets have been shown to produce greater weight loss than conventional low-fat diets (Ebbeling et al., 2003). Additionally, subjects consuming a low GI diet ad libitum have been reported to experience a spontaneous 25 percent reduction in energy intake, with significant reductions in body weight and waist and hip circumference when compared with control subjects (Dumesnil et al., 2001). Other data suggest that low GI/GL diets may confer protection against certain forms of cancer, cardiovascular disease and the metabolic syndrome and type 2 diabetes. In the Womens Health Study, a high GL dietary pattern was associated with an increased risk for colon cancer (Higginbotham et al., 2004), and data from the Iowa Womens study indicated that a higher GL pattern may be a risk factor for endometrial cancer incidence in nondiabetic women (Folsom et al., 2003). In a study of 244 healthy women, a strong and statistically significant positive association was found between 27

B.6.2 - B.7.2

S E C T I O N I I : BACKGROUND dietary GL and plasma C-reactive protein, a plasma marker for chronic inflammation associated with an increased risk for heart disease (Liu et al., 2002). In large prospective epidemiologic studies, both the GI and the GL of the overall diet have been associated with a greater risk of type 2 diabetes in both men and women (Salmeron et al., 1997a; Salmeron et al., 1997b).

B.7

FUNCTIONAL FOODS

Functional foods contain bioactive substances and have effects on health and physiological function beyond simply providing calories. While many of the foods reviewed above fit this definition (e.g., n-3 fatty acids), the foods reviewed in this section have received attention as foods and food ingredients for health. They are contained in Herbalife products. For example, soy protein is a major ingredient in the ShapeWorks Formula 1 Protein Drink Mix; Performance Protein Powder also consists of soy protein, as well as whey protein.

B.7.1

SOY PROTEIN

Soy protein is the highest-quality protein found in the plant kingdom, and it is consumed by two-thirds of the worlds population. Soy protein naturally contains isoflavones (primarily genistein and daidzein), which are called phytoestrogens. They are usually found in foods linked to sugars called glycosides, and these phytoestrogens act like very weak estrogens or anti-estrogens similar to raloxifene. When primates have a surgical menopause induced and are given estradiol alone or estradiol in combination with soy isoflavones, the isoflavones antagonize the actions of estradiol in the breast and the uterus but demonstrate estrogen-like beneficial activities in the bone, on serum lipids and in the brain. These observations are explained by the existence of two estrogen receptors called alpha and beta. Soy isoflavones bind with very low affinity (1/50,000 to 1/100,000 the affinity of estradiol) to the alpha-estradiol receptor, but bind equally well to the beta-estradiol receptor (Clarkson et al., 2001). Soy protein isoflavones have been shown to influence not only sex hormone metabolism and biological activity but also intracellular enzymes, protein synthesis, growth-factor action, malignant cell proliferation, differentiation and angiogenesis, providing strong evidence that these substances may have a protective role in cancer (Kim et al., 2002).

B.7.2

PHYTOCHEMICAL-RICH FRUITS, VEGETABLES AND GRAINS

28

Because fruits and vegetables are high in water and fiber, incorporating them into the diet can reduce energy density, promote satiety and decrease energy intake, while at the same time provide phytonutrients. Few interventions have specifically addressed fruit and vegetable consumption and weight loss, but evidence suggests that the recommendation to increase these foods while decreasing total energy intake is an effective strategy for weight management. Obesity, while often considered synonymous

PHYSICIANS REFERENCE MANUAL with overnutrition, is more accurately depicted as overnutrition of calories but undernutrition of many essential vitamins, minerals and phytonutrients. This increased incidence of obesity has been associated with an increased incidence of heart disease, breast cancer, prostate cancer and colon cancer in comparison with populations eating a dietary pattern consisting of less meat and more fruits, vegetables, cereals and whole grains. The intake of 400 to 600 grams/day of fruits and vegetables is associated with a reduced incidence of many common forms of cancer, heart disease and many chronic diseases of aging (Temple, 2000; Willett, 1994; Willett, 1995). The common forms of cancer, including breast, colon and prostate cancer, are the result of genetic-environmental interactions. Most cancers have genetic changes at the somatic cell level, which lead to unregulated growth through activation of oncogenes or inactivation of tumor suppressor genes. Reactive oxygen radicals are thought to damage biologic structures and molecules, including lipids, protein and DNA, and there is evidence that antioxidants can prevent this damage. Fruits and vegetables provide thousands of phytochemicals to the human diet and many of these are absorbed into the body. While these are commonly antioxidants, based on their ability to trap singlet oxygen, they have been demonstrated scientifically to have many functions beyond antioxidation. These phytochemicals can interact with the host to confer a preventive benefit by regulating enzymes important in metabolizing xenobiotics and carcinogens; modulating nuclear receptors and cellular signaling of proliferation and apoptosis; and acting indirectly through antioxidant actions that reduce proliferation and protect DNA from damage (Blot et al., 1993). Phytochemicals found in fruits and vegetables demonstrate synergistic and additive interactions through their effects on gene expression, antioxidation and cytokine action. Fruits and vegetables are 10- to 20-fold less calorie dense than grains; Figure 2

B.7.2

Adapted from What Color Is Your Diet?, Harper-Collins/Regan Books 2001

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B.7.2

S E C T I O N I I : BACKGROUND provide increased amounts of dietary fiber compared to refined grains; and provide a balance of omega-3 and omega-6 fatty acids and a rich supply of micronutrients. Several studies have sought to characterize dietary patterns and relate these patterns to body weight and other nutritional parameters. A prospective study of 737 non-overweight women in the Framingham Offspring/Spouse cohort explored the relationship between dietary patterns and the development of overweight over a 12-year period. Participants were grouped into one of five dietary patterns at baseline, which included a heart-healthy pattern (low-fat, nutritionally varied); a light-eating pattern (lower calories, but proportionately more fat and fewer micronutrients); a wine and moderate-eating pattern; a high-fat pattern; and an empty-calorie pattern (rich in sweets and fat, and low in fruits and vegetables). Women in the heart-healthy cluster consumed more servings of vegetables and fruits than women in each of the other four clusters. Over the 12-year period, 214 cases of overweight developed in this cohort. Compared with women in the heart-healthy group, women in the empty-calorie group were at a significantly higher risk for developing overweight (RR1.4, 95 percent CI) (Quatromoni et al., 2002). In another analysis of dietary patterns among 179 older rural adults, those in the high-nutrient-dense cluster (higher intake of dark-green/yellow vegetables, citrus/melons/berries, and other fruits and vegetables) had lower energy intakes and lower waist circumferences than those in the low-nutrient-dense cluster (higher intake of breads, sweets, desserts, processed meats, eggs, fats and oil). Those with a lownutrient-dense pattern were twice as likely to be obese (Ledikewe et al., 2004). Similar observations were reported utilizing data from the Canadian Community Health Survey from the years 2000 to 2001. The frequency of eating fruits and vegetables was positively related to being physically active and not being overweight (Perez, 2002). In a controlled clinical trial, families with obese parents and non-obese children were randomized into a comprehensive behavioral weight-management program, which featured encouragement either to increase fruit and vegetable consumption or to decrease intake of high-fat, high-sugar foods. Over a one-year period, parents in the increased fruit and vegetable group showed significantly greater decreases in percentage of overweight than in the group attempting to reduce fat and sugar (Epstein et al., 2001). Current NCI dietary recommendations emphasize increasing the daily consumption of fruits and vegetables from diverse sources such as citrus fruits, cruciferous vegetables, and green and yellow vegetables (Steinmetz and Potter, 1991).

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B.7.2

THE SEVEN COLORS OF HEALTH AND GARDEN 7 In addition to well-known vitamins and minerals present in fruits and vegetables, scientists are now focusing on other bioactive substances found in fruits and vegetables called phytonutrients (also referred to as phytochemicals). An important property of these phytonutrients is that they appear to work together synergistically in some studies (Erdman, 2004) suggesting that by including a variety of different colors of fruits and vegetables in the diet daily (including those which provide such compounds as carotenoids, bioflavonoids and glucosinolates) may contribute to the health benefits associated with consuming five to nine servings of fruits and vegetables a day. The benefits of consuming diverse classes of phytonutrients are reviewed in the popular book What Color is Your Diet? by Dr. David Heber (Harper-Collins/Regan Books, 2001). Garden7 is based on the philosophy of Dr. Hebers book. In it, he recommends the consumption of at least one serving per day from each of the color groups discussed below (also see Figure 2 on page 29). An interesting property of these antioxidant compounds is their localization in specific tissues. They are transported to major organs (e.g., lycopene to the prostate, lutein to the macular area of the retina). It is this localization in specific tissues that makes the phytonutrients in Garden 7 different from general antioxidants such as Vitamin E. It is in this regard that these phytonutrients provide a special benefit to tissues in several vital body organs, such as the heart, brain, eyes, colon, prostate/breast, liver and skin. Furthermore, it should be noted that these phytonutrients do not occur as isolated compounds but as mixtures with other vitamins such as Vitamin C and Vitamin E, and where possible, Garden 7 tablets and capsules are not only derived from extracts of the corresponding fruit (e.g., tomato) or vegetable (e.g., broccoli), but are standardized to the key phytonutrient provided (e.g., lycopene or glucosinolates). Therefore, Garden7 provides standardized extract capsules and tablets of different key phytonutrients as a supplement to the diet. Thus Garden7 contains selected beneficial phytonutrients; these specific phytonutrients are present in quantities equivalent to those found in approximately one-half cup of broccoli, one-half cup of spinach, one cup of red grapes, three ounces of cranberries, one orange, one carrot, one tomato and a clove of garlic. The supportive and protective effects of these phytonutrients localized in tissues where they have antioxidant and other protective effects are based on the current knowledge base in the nutritional literature for each of the colors. They are as follows: Red: Lycopene and related phytonutrients from tomatoes are localized in the prostate tissues and help support healthy prostate by protecting the cells of the prostate. Some evidence suggests that similar protection is provided to breast cells. Green: Glucosinolates from broccoli support healthy liver function and the capacity of liver cells to produce enzymes which can clear certain poisons and drugs from the body. Good evidence is available for glucosinolates affecting detox enzymes in gut, liver, prostate, colon and breast (benefit of indole-carbinols). There is some evidence for 31

B.7.2 - B.7.3

S E C T I O N I I : BACKGROUND

THE SEVEN COLORS OF HEALTH AND GARDEN 7 (Continued) sulforaphane and colon health. There is also evidence for broccoli glucosinolates inducing intestinal detox enzymes. White-Green: Allyl sulfides from garlic support a healthy cardiovascular system and healthy heart. Red-Purple: Polyphenols from berries, plums and cranberries localize in the brain and help support normal memory by protecting the nerve cells in the brain. Yellow-Green: Lutein is concentrated in the area of the retina called the macula, which receives the most ultraviolet light. Lutein supports healthy eyes and vision by protecting the cells of the retina. There is evidence for protection against age-related macular degeneration, a slow process that is the leading cause of blindness in individuals over 65 years of age. Orange-Yellow: Flavonoids, normally found in citrus fruits, are localized in the cells of the colon where they provide local antioxidant protection. There is some evidence in cells for protection of DNA by stimulation of repair enzymes. Orange: Alpha- and beta-carotene from carrots localize in the skin where they act as a local antioxidant to help protect the skin cells from ultraviolet light. There is significant evidence for carotenoid accumulation in skin (alpha- and beta-carotenes) to provide UVA/UVB protection.

B.7.3
Figure 3

BEYOND THE FOUR FOOD GROUPS

The USDA Pyramid is the result of deliberations within the USDA which must take into consideration economic factors related to food production and stabilization of the food supply as well as health. The food groups are 1) Cereals and Grains; 2) Fruits and

THE USDA PYRAMID

Sweets, Fats and Oils Meats, Beans, Nuts and Cheese Dairy Products

Fruits and Vegetables

1
Cereals and Grains

3 4

Vegetables; 3) Meat, Beans, Nuts and Cheese; and 4) Dairy Products. There is also a fifth group called Sweets, Fats and Oils which sits atop the USDA pyramid developed in 1992 (see Figure 3 above). 32

PHYSICIANS REFERENCE MANUAL In the current USDA Pyramid developed in 2005, the largest band to the left 1, which is orange in color, is still Cereals and Grains (again, see Figure 3). It remains the major recommended food group, but now the advice is to eat at least three ounces per day of whole grain bread, cereals, rice, crackers, or pasta. The next group 2, which is the green band, is Vegetables. Vegetables are divided into dark-green colored, orange colored, dry beans and peas, and others. The next band 3, which is red in color, is the Fruit Group. Depending on the number of calories you burn each day, between nine and 13 servings of fruits and vegetables are recommended. However, since these are divided into two groups, the orange band for Grains remains the predominant food group recommended. In this sense, there was no change from the old pyramid, despite a strong push from many scientists to put the Fruits and Vegetables together as one group to form the base of the diet. The next group 4 is a thin yellow band for Oils, even though the recommendations indicate most Americans get enough. They get too much of the wrong oils and fats. The next band 5 is the blue band for Milk. One change here is that milk itself is advised at three servings per day on average. This group does not include cheeses, cream cheese or other products made from milk. It also recommends low-fat or nonfat milk be used. Meats, beans, nuts, seeds, peas and eggs are members of the last group to the right 6, which is purple in color. Lean meats are advised. As you can see, the width of each band varies, suggesting you eat more of the good foods within each category. Also, the figure running up the side of the pyramid indicates for the first time the importance of exercise. The pyramid is fully described and individualized by age, gender and calorie requirements at the Web site www.mypyramid.gov. However, this is hardly personalized and the number of calories recommended will promote obesity and overweight. The new pyramid leaves in place traditional therapeutic diets which provide suggested servings of foods in the food groups defined by the USDA, since it is impractical to calculate specific food values for every diet plan that is individually administered. For example, exchange diets are based on the idea that all human diets can be simplified into protein, carbohydrate or fat exchanges. So a serving of iceberg lettuce and a serving of spinach are equivalent, as would be a serving of grain-fed prime rib and a serving of ocean-caught tuna. Also, the pyramid makes fruit juices equivalent to whole fruits, although it takes over two oranges to make a small glass of orange juice, which does not have the fiber of a whole orange. However, there is a large Florida orange juice industry depending on sales of the juice that provides 160 calories per serving as simple carbohydrate. Ultimately, this simplification leads to the misconception that food is simply an energy source for the body and that there are certain minimum requirements for avoiding deficiency and promoting health. To some extent, according to these notions, a calorie is a calorie. The body can interconvert from one source to another, and this is a key part of our adaptation to starvation. However, there is no genetic pressure for eating a healthful diet that avoids the chronic diseases of aging, since these arise after the age of reproduction has passed. Therefore, the preventive properties of the diet are dissociated from its provision of nutritional energy or calories alone. The California Cuisine Pyramid developed at UCLA in 1997 by Dr. David Heber and his colleagues puts fruits and vegetables at the base and then whole grains. This was the first pyramid to do so and was followed by the Mayo Clinic Pyramid in 2001, which did the same thing. However, this idea was never accepted by the USDA. It should be noted that fruits and vegetables in 2000 received only 4.5 percent of the nearly $80 billion in total subsidies largely given by the USDA to grain producers. As our society is solving the problem of malnutrition throughout the world, we are left with chronic diseases of aging related to too many calories relative to physical

B.7.3

33

B.7.3

S E C T I O N I I : BACKGROUND activity. These diseases are also related to poor-quality diets consisting of too few servings of fruits, vegetables and whole grains and too many servings of high-fat, highsugar processed foods. The latter lack naturally occurring vitamins, minerals and the thousands of secondary plant substances (phytonutrients, or phytochemicals). The Herbalife-recommended Pyramid is based on seven or more colorful fruits and vegetables per day (see Figure 4 on this page). These whole fruits and vegetables provide less than 100 calories per serving compared to an average of over 200 calories per serving of grains and cereals. Protein on the next level is provided by high-protein, lowfat shakes which can be made with fresh or frozen fruits to help meet the fruit and vegetable requirements. In addition, lean meats and fish round out this level. Getting your protein from beans and rice, or beans and corn, can result in too many calories. Soy protein found in Herbalife shakes can provide the protein at about half the calories. While grains are not mandatory (since there is carbohydrate included in Herbalife shakes), it is possible to have one to three servings per day of whole-grain bread. A serving is reduced on our pyramid to one-half cup of rice, pasta or potato so that you are getting 125 calories per serving, which is more comparable to the 100 calories or less found in fruits and vegetables. The top of the Herbalife-recommended Pyramid has herbs and spices rather than sweets, fats and oils. The vertical organization of this pyramid is clearer and less confusing than the vertical bands of the current USDA Pyramid. Back in 1992, the food industry fought the original pyramid and recommended a bowl with bands because it did not like the idea of a hierarchy of foods. The current USDA Pyramid with vertical bands gave the food industry what it wanted more confusion for the consumer. Herbalife teaches consumers how to build a healthy diet, and recognizes that supplements and exercise are also needed daily for good health. Figure 4

HERBALIFE-RECOMMENDED PYRAMID

Herbs and Spices

Grains

Protein

Colorful Fruits and Vegetables

Why worry about the composition of the diet? The premise is simple: Diet is a major etiologic factor in chronic disease. Dietary chemicals change the expression of ones genes and even the genome itself. Genetic variation may explain the reason two people can eat exactly the same diet and respond very differently. Nutritional genomics emphasize the interactions at a cellular and molecular level studied through systems biology. Herbalife products provide not only a balance of macronutrients, but also vitamins and minerals critical to health, as will be reviewed in the next section. 34

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Rosen ED, Spiegelman BM. (2001). PPARgamma : a nuclear regulator of metabolism, differentiation, and cell growth. J Biol Chem 276, 37731-37734. Salmeron J, Ascherio A, Rimm EB, Colditz GA, Spiegelman D, Jenkins DJ, Stampfer MJ, Wing AL, Willett WC. (1997a). Dietary fiber, glycemic load, and risk of NIDDM in men. Diabetes Care 20, 545550 Salmeron J, Manson JE, Stampfer MJ, Colditz GA, Wing AL, Willett WC. (1997b) Dietary fiber, glycemic load, and risk of non-insulin-dependent diabetes mellitus in women. JAMA 277, 472477. Schatzkin A, Lanza . Polyp Prevention Trial Study Group. (2002). Polyps and vegetables (and fat, fibre): the polyp prevention trial. IARC Sci Publ 156, 463-466. Simopoulos AP. (2001). N-3 fatty acids and human health: Defining strategies for public policy. Lipids 36:S83-89. Skov AR, Toubro S, Ronn B, Holm L, Astrup A. (1999). Randomized trial on protein vs carbohydrate in ad libitum fat reduced diet for the treatment of obesity. Int J Obes Related Metab Disord 23, 528-536. Slabber M, Barnard HC, Kuyl JM, Dannhauser A, Schall R. (1994). Effects of a low-insulin-response, energy-restricted diet on weight loss and plasma insulin concentrations in hyperinsulinemic obese females. Am J Clin Nutr 60, 48-53. Steinmetz KA, Potter JD. (1991). Vegetables, fruits, and cancer. I. Epidemiology. Cancer Causes and Control 2:325-337. Steinmetz KA, Potter JD. (1996). Vegetables, fruits and cancer prevention: a review. J Am Diet Assn. 10, 1027-1039. Swinburn BA, Caterson I, Seidell JC, James WP. (2004). Diet, nutrition and the prevention of excess weight gain and obesity. Public Health Nutr 7, 123-146. Tarnopolsky MA, Atkinson SA, MacDougall JD, Chesley A, Phillips S, Schwarcz HP. (1992). Evaluation of protein requirements for trained strength athletes. J Appl Physiol. 73, 1986-1995. Tarnopolsky M. (2004). Protein requirements for endurance athletes. Nutrition. 20, 662-668. Temple NJ. (2000). Antioxidants and disease: more questions than answers. Nutr Res 20, 449-559. Tohill BC, Seymour J, Serdula M, Kettel-Khan L, Rolls BJ. (2004). What epidemiologic studies tell us about the relationship between fruit and vegetable consumption and body weight. Nutr Rev. 62, 365-374. Tsai WS, Nagawa H, Kaizaki S, Tsuruo T, Muto T. (1998). Inhibitory effects of n3 polyunsaturated fatty acids on sigmoid colon cancer transformants. J Gastroenterol 33, 206212. Verhoeven DT, Assen N, Goldbohm RA, Dorant E, van t Veer P, Sturmans F, Hermus RJ, van den Brandt PA. (1997). Vitamins C and E, retinol, beta-carotene and dietary fiber in relation to breast cancer risk: a prospective cohort study. Br J Cancer 75, 149-155. Way JM, Harrington WW, Brown KK, Gottschalk WK, Sundseth SS, Mansfield TA, Ramachandran RK, Willson TM, Kliewer SA. (2001). Comprehensive messenger ribonucleic acid profiling reveals that peroxisome proliferator-activated receptor gamma activation has coordinate effects on gene expression in multiple insulinsensitive tissues. Endocrinology 142, 1269-1277. Westerterp-Plantega MS, Rolland V, Wilson SAJ, Westerterp KR. (1999). Satiety related to 24 h diet-induced thermogenesis during high protein/carbohydrate vs. high fat diets measured in a respiration chamber. Eur J Clin Nutr 53, 495-502. Westerterp-Plantenga MS, Lejeune MP, Nihs I, van Ooijen M, Kovacs EM. (2004). High protein intake sustains weight maintenance after body weight loss in humans.Int J Obes Relat Metab Disord 28, 57-64. Willett WC. (1994). Diet and health: what should we eat? Science 254, 532537. Willett WC. (1995). Diet, nutrition and avoidable cancer. Environ Health Perspect 103, 165-171. Willett WC, Hunter DJ, Stampfer MJ, Colditz G, Manson JE, Spiegelman D, Rosner B, Hennekens CH, Speizer FE. (1992). Dietary fat and fiber in relation to risk of breast cancer: an 8-year follow-up. J Am Med Assoc 268, 20372044. Willson TM, Brown PJ, Sternbach DD, Henke BR. (2000). The PPARs: From Orphan Receptors to Drug Discovery. J Med Chem 43, 527-550. Wolfrum C, Borrmann, CM, Borchers T, Spener F. (2001). Fatty acids and hypolipidemic drugs regulate receptors alpha - and gamma-mediated gene expression via liver fatty acid binding protein: a signaling path to the nucleus. Proc. Natl. Acad. Sci. U.S.A. 98, 2323. World Cancer Research Fund. (1997). Food, Nutrition and the Prevention of Cancer: A Global Perspective. American Institute for Cancer Research, Washington, DC. Yamamoto S, Sobue T, Kobayashi M, Sasaki S, Tsugane S. S(2003). Soy, isoflavones, and breast cancer risk in Japan. Japan Public Health CenterBased Prospective Study on Cancer Cardiovascular Diseases Group. Cancer Information and Epidemiology Division, National Cancer Center Research Institute, Tokyo, Japan, J Natl Cancer Inst 95, 906-913.

Zhang X, Shu XO, Gao YT, Yang G, Li Q, Li H, Jin F, Zheng W. (2003). Soy food consumption is associated with a lower risk of coronary heart disease in Chinese women. J Nutr 133, 2874-2878.

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C - C.2

S E C T I O N I I : BACKGROUND

C. C.1

VITAMINS AND MINERALS INTRODUCTION

There is still controversy about vitamins in the newspapers and medical journals in this country, which reflects the poor state of nutrition education in our medical schools. Studies in which vitamins are compared to drugs are publicized as showing that vitamins have no benefit. Additionally, many physicians and other healthcare providers are not familiar with the significant body of scientific studies supporting the use of vitamins and minerals. The majority of Americans do not meet through their diets the recommended daily allowance of many of the vitamins and minerals that are critical to promoting health and preventing disease. Vitamin supplementation has been shown to prevent neural tube defects and improve immune function, and other studies suggest that generous intakes of vitamins and minerals may reduce the risk of coronary heart disease, cancer and osteoporosis. Optimal intakes of vitamins and minerals from a combination of food and supplements are important goals in efforts at heath promotion and disease prevention. There are three scientific arguments supporting the use of vitamins and mineral supplements. First, use of these supplements can help bring consumption of vitamins and minerals up to recommended levels. Second, there may be benefits of vitamins and minerals in maintaining optimal health and preventing disease at levels above the recommended intakes. Finally, adequate micronutrient intake can be beneficial in reducing the risk of birth defects and may help reduce the risk of some chronic diseases. These concepts are grounded in evidence provided by a large number of studies, including laboratory studies, population studies and a small number of clinical trials. Additional research looking at dosing levels, targeted populations and long-term effects is now underway.

C.2

PREGNANCY AND BIRTH DEFECTS

One out of every 30 babies born in the United States has a serious birth defect. Each year, some 3,000 pregnancies are affected by what is called a neural tube defect (NTD), such as spina bifida (in which an opening in the spinal cord does not close) or anencephaly (in which a baby is born without a brain). Since 1980, more than a dozen studies have looked at the role of folic acid in reducing the incidence of neural tube defects. Perhaps the most important, the 1991 United Kingdom Medical Research Council (UKMRC) randomized clinical trial, found that folic acid use could reduce the relative risk of NTD by more than 70 percent (MRC Vitamin Study Research Group). The United States Public Health Service (USPHS) drew on this data to issue recommendations on folic acid the following year. It said that women capable of becoming pregnant should take 400 micrograms (or millionths of a gram) of folic acid daily, which is the amount contained in a daily multivitamin The Food and Drug Administration (FDA) followed this advisory with orders requiring all products made with enriched grain to contain additional folic acid, and approved the 38

PHYSICIANS REFERENCE MANUAL use of health claims for products that contain significant amounts of the vitamin. The Centers for Disease Control and Prevention (CDC) suggest that the consumption of supplemental folic acid could significantly reduce that number even beyond what has been achieved to date with the fortification of enriched grain productsto the extent that about 80 percent of these birth defects could be prevented. Educational programs soon emerged, targeting women of childbearing years, healthcare professionals, womens groups and policy makers. Surveillance studies conducted in China, Canada and the United States have shown that fortification programs have dramatically lowered the prevalence of NTD. More and more women of childbearing age have become familiar with the need for folic acid; the percentage of women between ages 18 and 45 who heard about folic acid grew by more than 50 percent between 1995 and 2000. However, only 10 percent knew the correct dose and only one-third actually consumed the vitamin daily. Thus, although at least part of the folic acid message is reaching targeted women, not all are benefiting from that information.

C.3 - C.4

C.3

IMMUNE FUNCTION

Diet and nutritional status are two of the key factors affecting the bodys immune response. Recent studies show that multivitamin use, in concert with a good diet, is a cost-effective tool to enhance immunity, reduce the incidence of infection, and improve overall quality of life. Immune status is relatively easy to test, because unlike in cardiovascular disease or cancer, established and accepted measures of immune function are available. In randomized clinical trials conducted by Dr. Ranjit Chandra in Newfoundland, Canada, micronutrients have been shown to enhance the response of lymphocytes and natural killer cells; increase production of interleukin-2; and reduce the duration of infection and the time spent on antibiotics. These studies demonstrate that inadequate micronutrient intakes are associated with poorer immune responses and an increased incidence of infection, and that consumption of a multivitamin can help eliminate this deficit.

C.4

CARDIOVASCULAR DISEASE

Elevated levels of homocysteine are a major risk factor for coronary disease and ischemic stroke. Indeed, people with the highest homocysteine levels have a nearly two-fold increase in the risk of coronary heart disease (CHD), compared to those with normal levels. This risk is comparable to that associated with smoking or high cholesterol. Folate is essential to homocysteine metabolism, and a number of studies have established the link between folate intake and CHD. Contributions to lowering homocysteine levels are also made, though to a lesser degree, by Vitamins B6 and B12. Low-serum folate levels were associated with an increased risk of fatal CHD in studies from Canada (Morrison et al., 1996) and Europe (Robinson et al., 1998), while in the United States, higher intake of folate and Vitamin B6 reduced that risk (Rimm et al., 1998). Homocysteine-lowering therapy with folate and B complex was also found to decrease the incidence of death, nonfatal heart attacks and other adverse events following coronary angioplasty (Schnyder et al., 2002). This finding was confirmed in a large, case-control study from Sweden, which showed that use of a multivitamin supplement reduced the risk of a myocardial infarction by 21 percent 39

C.5

S E C T I O N I I : BACKGROUND in men and 34 percent in women, suggesting that consumption of folate and B complex may aid in the primary prevention of heart attacks (Holmquist et al., 2003). Additional studies are now in progress to further clarify the relationship between these vitamins and coronary disease. Vitamins C and E are essential, well-established antioxidants, and researchers have investigated whether these micronutrients have a role to play in heart disease prevention. To date, some studies have found a mild effect for higher-dose Vitamin C users (Osganian et al., 2003), while others have failed to establish a relationship (Kushi et al., 1996). Similarly, the Nurses Health Study found that women taking modest amounts of Vitamin E had a 44 percent reduction in the incidence of heart disease (Stampfe et al., 1993) and that higher doses (400 to 800 IU) reduced the rate of second heart attacks in heart patients (Stephens et al., 1996). However, other wellcontrolled trials found no effect (Rapola et al., 1997; Yusuf et al., 2000). Since these studies were done in individuals who already had heart disease, it is difficult to account for the many different factors which may have caused their heart disease and made them different from one another. Therefore, when these people were assigned by chance to get the placebo or vitamin supplements, the results may have been more related to the individual profiles of those assigned to the two arms of the study rather than to whether the vitamins were having an effect. Researchers assumed that such differences are overcome by large numbers, but this may not be true in the case of a complex disease such as heart disease, with so many different factors involved. While it would be of great interest to conduct a prevention study in otherwise healthy individuals, such a study would require huge numbers and be prohibitively expensive.

C.5

CANCER

Folic acid deficiency may contribute to the development of cancer by interfering with normal gene processes. Thus, there has been much recent interest in the effects of folate supplementation on cancer prevention. Both the Nurses Health Study and the Health Professionals Follow-up Study found that long-term (15 years in the former, 10 in the latter) folate consumption significantly reduced the risk of colorectal cancer. Studies done by Dr. Ed Giovannucci and his team at the Harvard School of Public Health found that in women who use alcohol and have low blood folate levels, supplementation helped lower the elevated risk of breast cancer associated with drinking (Zhang et al., 1999). Ongoing trials continue to explore the effects of folate supplementation, especially in users of alcohol, where the interaction appears to be very strong. Vitamin E has been investigated in connection with a number of major cancers, including breast, lung, colon and prostate. Only in the latter does it appear to have a significant effect across several studies. In the ATBC trial, researchers found that 400 mg of Vitamin E reduced the incidence of, as well as mortality from, prostate cancer in male smokers (Albanes et al., 1995). This association has since been confirmed, both in non-smokers and smokers. On the strength of this evidence, the National Cancer Institute (NCI) is conducting a primary prevention trial (called the SELECT trial) of selenium and vitamin E versus a placebo for prostate cancer prevention in 25,000 normal men. An editorial in The New York Times suggested that no cancer patients should take Vitamin C or Vitamin E, but it was based on a misinterpretation of two basic findings. The first is that Vitamin C is concentrated by cancer cells, which the author of the 40

PHYSICIANS REFERENCE MANUAL editorial assumed meant that the cancer cell used this Vitamin C to stimulate tumor cell growth. Dr. David Golde of the Sloan-Kettering Cancer Center in New York discovered that Vitamin C is taken up by the glucose transport proteins in tumor cells. Before the tumor cell can take up Vitamin C through the glucose transport system, it must be oxidized to a form called dehydroascorbate. This form of Vitamin C is taken up and then trapped in the cell when it is converted back to Vitamin C inside the cell by reducing enzymes. But the concentrations required to do this do not occur in humans who take Vitamin C by mouth; to reach these concentrations, Vitamin C would have to be given by vein. This would never happen in someone taking vitamin supplements. The experiments that resulted in the caution on Vitamin E were performed in animals that were made Vitamin E deficient and compared to normal Vitamin E status animals. Because it is not possible to make humans deficient in Vitamin E, this study also has no relevance to supplements of Vitamin E in humans with cancer. The consumption of various carotenoids, such as lycopene, lutein and beta carotene, may reduce the risk of lung cancer by one-third, but pure beta-carotene at high doses of 30 mg may elevate it, particularly in smokers. Calcium supplementation, too, may protect against osteoporosis and the development and recurrence of colon polyps, which are a precancerous change in the colon (Baron et al., 1999; Bonithon-Kopp et al., 2000), but some data suggest that in extremely high doses (greater than 1,500 mg per day total), calcium may increase the risk of prostate cancer (Chan et al., 2000; Giovannucci et al., 1998). Data in the latter study suggested that taking Vitamin D with calcium may reduce any negative effects while maintaining the colon cancer protection. Also, no man should get less than the recommended dietary allowance, which is 1,000 mg per day of calcium. Cancer is a collection of heterogeneous conditions with complex causes and histories, and there is much more research that needs to be done on the use of vitamins and minerals for cancer prevention.

C.6

C.6

OBESITY AND DIABETES

While most of the population fails to consume adequate levels of micronutrients, the problem is particularly severe for the obese. There is evidence that overweight men and women with high cholesterol levels who are on diets do not achieve the RDA of most essential vitamins and minerals, due to lower micronutrient intake, lack of adherence and over-restriction of foods (Gryzbek et al., 2002). This nutritional deficiency clearly compromises their health status. Research conducted on people with type 2 diabetes has shown that those taking a multivitamin supplement had a lower incidence of infections and infection-related absenteeism than did those receiving placebo (Barringer et al., 2003). While a relatively small study, the magnitude of the differences in infection-incidence noted over one year in diabetic patients were remarkable. Those who took a placebo had a 93 percent incidence over one year of infectious episodes while those taking a multivitamin had an incidence of only 17%. These findings deserve further research in larger populations, as the implications are significant. In a study of people at risk for diabetes, investigators reported that males who took beta-carotene supplements improved their glucose metabolism, as did women who consumed Vitamin E (Ylonen et al., 2003). While dieting has important implications for nutritional intake in all populations, it may play an even more essential role in those who are overweight and those with either metabolic syndrome or adult-onset diabetes mellitus. 41

C.7

S E C T I O N I I : BACKGROUND

C.7

SAFETY OF VITAMINS

The consumption of Vitamin A above 25,000 IU per day (daily value = 5,000 IU) can clearly cause skeletal birth defectsand this amount is only five times the RDA. Pregnant women should not consume more than 2,500 IU of Vitamin A per day to avoid any possibility of problems. A few recent studies suggest that long-term consumption in excess of 5,000 IU/day Vitamin A may be associated with decreased bone mineral density and an increased risk of osteoporosis (Promislow et al., 2000). On the other hand, insufficient intake also may accelerate the loss of bone mineral density. Thus, there is a narrow window of optimal Vitamin A intake in adults. It is recommend that a multivitamin that contains about 2,500 IU of preformed Vitamin A, or 5,000 IU of Vitamin A, be used, of which at least 50 percent comes from beta-carotene. As noted previously, high calcium intakes (above 1,500 mg/day) have been associated with an increased risk of prostate cancer (Giovannucci et al., 1998). Also, an antioxidant supplement combining Vitamins C and E, selenium and beta-carotene was found to reduce the protective effects of a lipid-lowering agent and niacin in 160 patients with heart disease and low HDL cholesterol levels (Brown et al., 2001), although a larger trial of 20,000 patients, using a supplement of Vitamin C, Vitamin E and beta-carotene, reported that the antioxidant combination did not inhibit the protective effects of the lipid-lowering drug (Heart Protection Study Collab. Group). It is important to realize that the safety of vitamins and minerals is often decided by government committees reviewing reports of adverse effects to determine an arbitrary tolerable upper limit. In some countries in the world, any vitamins in amounts above the recommended dietary allowance are considered medicines. There are ongoing discussions on the safety of vitamins and strong opinions based on limited data, often from inconclusive meta-analyses, which combine different studies. Herbalife products contain safe levels of vitamins and minerals, and the product line undergoes constant review. Reformulation is done if the science or regulatory interpretation of science changes in local markets throughout the world. This explains the difference in the various formulations of similar products in different countries.

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PHYSICIANS REFERENCE MANUAL

REFERENCES
Albanes D, Heinonen OP, Huttunen JK, Taylor PR, Virtamo J, Edwards BK, Haapakoski J, Rautalahti M, Hartman AM, Palmgren J, et al. Effects of alpha-tocopherol and beta-carotene supplements on cancer incidence in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study. Am J Clin Nutr. 1995;62(6 Suppl):1427S-1430S. Baron JA, Beach M, Mandel JS et al. Calcium supplements for the prevention of colorectal adenomas. N Engl J Med. 1999;340:101-107. Barringer TA, Kirk JK, Santaniello AC, Foley KL, Michielutte R. Effect of a multivitamin and mineral supplement on infection and quality of life. A randomized, double-blind, placebocontrolled trial. Ann Intern Med. 2003;138(5):365-71. Bonithon-Kopp C, Kronborg O, Giacosa A, Rath U, Faivre J. Calcium and fibre supplementation in prevention of colorectal adenoma recurrence: a randomised intervention trial. European Cancer Prevention Organisation Study Group. Lancet. 2000;356(9238):1300-6. Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS, Dowdy AA, Marino EK, Bolson EL, Alaupovic P, Frohlich J, Albers JJ. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001 Nov 29;345(22):1583-92. Chan JM, Pietinen P, Virtanen M, Malila N, Tangrea J, Albanes D, Virtamo J. Diet and prostate cancer risk in a cohort of smokers, with a specific focus on calcium and phosphorus (Finland). Cancer Causes Control. 2000 Oct;11(9):859-67. Chandra RK. Effect of vitamin and trace-element supplementation on immune responses and infection in elderly subjects. Lancet. 1992; 340:1124-1127. Giovannucci E, Stampfer MJ, Colditz GA, Hunter DJ, Fuchs C et al. Multivitamin use, folate, and colon cancer in women in the Nurses Health Study. Ann. Intern Med. 1998; 129(7):517-524. Giovannucci E, Rimm EB, Wolk A, Ascherio A, Stampfer MJ, Colditz GA, Willett WC. Calcium and fructose intake in relation to risk of prostate cancer. Cancer Res. 1998;58(3):442-7. Graham IM, Daly LE, Refsum HM, Robinson K, Brattstrom LE, et al. Plama homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA. 1997; 277(22):1775-1781. Gryzbek A, Klosiewicz-Latoszek L, Targosz U. Changes in the intake of vitamins and minerals by men and women with hyperlipidemia and overweight during dietetic treatment. Eur J Clin Nutr. 2002;56:1162-1168. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebocontrolled trial. Lancet. 2002; 360(9326):23-33. Holmquist C, Larsson S, Wolk A, deFaire U. Multivitamin supplements are inversely associated with risk of myocardial infarction in men and women.Stockholm Heart Epidemiology Program (SHEEP). J Nutr. 2003; 133:2650-2654. Kushi LH, Folsom AR, Prineas RJ, Mink PJ, Wu Y et al. Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women. N Engl J Med. 1996; 334(18_):1156-1162. Michaud DS, Feskanich D, Rimm EB, Colditz GA, Speizer FE, Willett WC, Giovannucci E. Intake of specific carotenoids and risk of lung cancer in 2 prospective US cohorts. Am J Clin Nutr. 2000;72(4):990-7. Morrison HI, Schaubel D, Desmeules M, Wigle DT. Serum folate and risk of fatal coronary heart disease. JAMA. 1996;275(24):1893-1896. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet. 1991; 338(8760):131-7 Osganian SK, Stampfer MJ, Rimm E, Spiegelman D, Hu FB, Manson JE, Willett WC. Vitamin C and risk of coronary heart disease in women. J Am Coll Cardiol. 2003;42(2):246-52. Persad VL, Van den Hof MC, Dube JM, Zimmer P. Incidence of open neural tube defects in Nova Scotia after folic acid fortification. CMAJ. 2002; 167(3):241-5. Promislow JH, Goodman-Gruen D, Slymen DJ, Barrett-Connor E. Retinol intake and bone mineral density in the elderly: the Rancho Bernardo Study. J Bone Miner Res. 2002;17(8):1349-58. Rapola JM, Virtamo J, Ripatti S, Huttunen JK, Albanes D, Taylor PR, Heinonen OP. Randomised trial of alpha-tocopherol and beta-carotene supplements on incidence of major coronary events in men with previous myocardial infarction. Lancet. 1997; 349(9067):1715-20. Rimm EB, Willett WC, Hu FB, Sampson L, Colditz GA et al. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA. 1998;279(5):359-364. Robinson K, Arheart K, Refsum H, Brattstrom L, Boers G et al. Low circulating folate and vitamin B6 concentrations: risk factors for stroke, peripheral vascular disease, and coronary artery disease. European COMAC Group. Circulation. 1998; 97(5):437-443. Schnyder G, Roffi M, Flammer Y, Pin R, Hess O. Effect of homocysteinlowering therapy with folic acid, vitamin B12 and vitamin B6 on clinical outcome after percutaneous coronary intervention. The Swiss Heart Study: A Randomized Controlled Trial. JAMA. 2002;288:973-979. Stampfer M, Hennekens C, Manson J, Colditz G, Rosner B et al. Vitamin E consumption and the risk of coronary artery disease in women. N. Eng J Med. 1993; 328(20):1444-1449. Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K et al. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet. 1996; 347(9004):781-786. Summary of notifiable diseases United States, 2000. MMWR Morb Mortal Wkly Rep. 2002 Jun 14;49(53):ixxii, 1-100 Ylonen K, Alfthan G, Groop L, Saloranta C, Aro A, Virtanen SM. Dietary intakes and plasma concentrations of carotenoids and tocopherols in relation to glucose metabolism in subjects at high risk of type 2 diabetes: the Botnia Dietary Study. Am J Clin Nutr. 2003; 77(6):1434-41. Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342(3):154-60. Zhang S, Hunter DJ, Hankinson SE, Giovannucci EL, Rosner BA, Colditz GA, Speizer FE, Willett WC. A prospective study of folate intake and the risk of breast cancer. JAMA. 1999; 281(17):1632-7.

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D - D.2

S E C T I O N I I : BACKGROUND

D. D.1

WEIGHT MANAGEMENT AND MEAL REPLACEMENT

DEFINITION OF OBESITY

Obesity is the most common nutritional disorder in the United States. In the world atlarge, the number of overnourished people is now equivalent to the number of undernourished individualsboth at 2.1 billion. Obesity is defined as Excess Body Fat minus Not Excess Body Weight (see section E: Body Composition on pages 55 through 59). However, on average, body weight is a useful surrogate, and body-mass index is used to follow the obesity epidemic and its association with diseases since, as a practical matter, it is difficult to measure body composition on tens of thousands of individuals.

D.2

CAUSES OF OBESITY

The most common causes of obesity are overeating and underactivity. There is evidence for differences in metabolism, making some individuals more efficient in hanging onto calories, but the most common reasons for differences in the tendency to gain or lose weight relate to age, height, sex and weight. Therefore, obesity results from common genetic predisposition, but is expressed only when there is excess energy available for storage.

Energy In = Energy Out + Energy Stored

However, energy out is largely related to body composition in terms of lean tissue rather than fat tissue. So a man who is 74 inches tall might burn 2,200 calories per day, while his wife at 62 inches tall burns only 1,200 calories per day due to differences in the amount of lean-body mass they each have. Is it any wonder that the woman in this case will lose weight more slowly than her husband if both are on the same diet of 1,000 calories per day? Despite these individual differences in energy needs and expenditure, it is clear that the modern diet contains too many calories per bite to enable the normal weightregulatory mechanisms in the body to operate properly. This is illustrated by a rat experiment. If pellets with more oil are fed to a rat, the rat will eat fewer pellets and maintain a normal weight. If fat is removed from the pellets, the rat will eat more pellets and still maintain its weight. On the other hand, if the rat is fed what is known as a cafeteria diet (made up of peanut butter, salami and chocolate chip cookies), the rat will lose all control of its homeostatic mechanisms and become as large as genetically obese rodents. Mankind, by analogy, adapted to low-nutrient density diets and is no longer able to maintain normal body fat on the high-fat, high-sugar diets of modern times.

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PHYSICIANS REFERENCE MANUAL

D.3 - D.3.1

D.3

BODY-FAT REGULATION AND FUNCTION AS AN ENDOCRINE ORGAN

Body fat is a vital organ, just like the heart, liver, kidney or skin. It has nerves, blood vessels and fat cells, and this organ secretes hormones and small proteins that affect energy balance, fat storage and metabolism. The function of body-fat organs depends on where they are located in the body. Each of the body-fat organs in the lower body as female fat and in the upper body in both men and women, has special functions with regard to the uptake and release of fatty acids and in terms of the hormones they secrete and to which they respond. There is emerging evidence that leptin comes from both lower- and upper-body fat, whereas adiponectin comes from abdominal fat.

D.3.1

FEMALE FAT

The fat on womens hips and thighs provide the energy mothers need to provide milk to their newborn babies. This fat responds to female hormones, and in every menstrual cycle right after ovulation there is a one-thousand-fold increase in the blood levels of the female hormone, progesterone. So when women believe they are gaining small amounts of weight in addition to being bloatedthey are correct. The body is preparing for pregnancy by developing the fat organ in the hips and thighs, and it grows much more if a woman becomes pregnant due to the large amounts of estrogen and progesterone produced by the placenta. A considerable number of calories must be stored, since breast-milk production normally requires about 500 calories per day. The main factor accounting for female obesity is weight gain after pregnancy. Women typically gain between 30 and 40 pounds during pregnancy. If they do not breast-feed or diet in the six months after delivery, the weight gained during pregnancy is not lost. The next pregnancy starts at a higher weight, and more weight is gained with the second pregnancyand so forth. Understanding how this fat accumulates can help women lose this fat after delivering their children and can lead to prevention of obesity. Just as women are born with different-shaped bodies, women are born with different-sized hip and thigh fat organs. There is nothing wrong with that body of fat, except that our modern society has labeled it as bad. This was never the case prior to the past four decades, women with lower body fat were considered attractive, and biology reflected what was desirable. There is a disconnect between womens genetics and what is considered attractive by many people. However, there has been a backlash. For instance, full-figured women have begun speaking out about the attractiveness of larger women, and full-figured models have been appearing more and more in billboards and in fashion magazines. A key message is that there needs to be more tolerance of different body shapes in our society. Finally, this fat tends to be more resistant to diet and exercise, and there are many women who starve themselves trying to lose this fat. Some even lose too much fat in their faces and chests to look healthy. It is important to be aware of their appropriate target weight and shape if they have more fat in the hips and thighs than in the upper body. 45

D.3.2 - D.3.3

S E C T I O N I I : BACKGROUND

D.3.2

ABDOMINAL FAT

The fat in the middle of the body surrounds the intestines and has special properties both in terms of the substances released into the bloodstream by this fat and in the hormones to which this fat responds. Both men and women can accumulate abdominal fat. There are some women who have only upper-body fat, and never accumulate much lower-body fat. Then there are also women who accumulate both upper- and lower-body fat. Those women with upper-body fat have higher male hormone levels than do women with lower-body fat. They are three times more likely to get breast cancer and about nine times more likely to get diabetes than women with lower-body fat. This fat is designed to store a limited amount of fat for the purpose of surviving short periods of starvation. It secretes a number of substances called cytokines to fight infection. When malnourished, humans are more susceptible to infections. Therefore, it makes sense that abdominal fat should work to protect against such infections. This fat also responds to the stress hormone cortisol. This stress hormone comes from the adrenal gland. In a disease called Cushings syndrome, there is overproduction of cortisol by the adrenal glands with a resulting increase in this fat organ in the middle of the body. There is an enzyme called 11-betahydroxysteroid dehydrogenase which can convert cortisone to cortisol. In mice genetically altered to produce more of this enzyme, they accumulate fat only in the abdomen and not in other fat pads. Abdominal fat is easier to lose with dieting than lower-body fat. It is often the first fat to be lost in those with both upper- and lower-body fat.

D.3.3

BRAIN CENTERS AND BODY FAT

46

The fat cells make leptin, a hormone named for the Greek word for thinning. It was first discovered in a mutant line of obese mice who made a defective version of this normal hormone. These mice develop about 60 percent of their body weight as fat tissue. When normal mice had their circulation merged with these obese mice, they corrected the abnormality and the mice lost weight. Leptin is sensed in a part of the brain called the Arcuate nucleus of the hypothalamus, where it is one of many different signals to the brain. Leptin deficiency is extremely rare, but there is a village in Turkey where a family has this deficiency. Dr. Julio Licinio at UCLA, recently treated this family with leptin, and they lost large amounts of weight, going from massively obese to a normal size. Leptin has other effects. It both reduces food intake and increases physical activity. It also inhibits new blood-vessel formation, another way it may inhibit new fat-tissue growth in genetically obese mice. Insulin is the feeding hormone and goes up after eating. It pushes fats into fat cells for storage and amino acids into muscle. It also stores some sugars as starch in the liver and muscle. Insulin comes from cells in the pancreas and goes up together with leptin in response to nutrients such as glucose and amino acids. Insulin is transported into the brain. For the last 30 years, Dr. Daniel Porte at the University of California, San Diego, has championed the theory that obesity is due to a lack of insulin action in the brain. Using primates, he has demonstrated that high levels of insulin in the blood are associated with reduced insulin action in the brain. Leptin levels change in the opposite direction to another peptideneuropeptide Y,

PHYSICIANS REFERENCE MANUAL or NPY. When leptin goes down, NPY increases in the brain. NPY has the opposite effect to leptin, and it increases food intake. New insights into the complex regulation of food intake, metabolism and energy homeostasis have refined the understanding of the pathophysiology of malnutrition. Studies in rodents have demonstrated that the adaptation to starvation is far better developed than the adaptation to overnutrition both in the short term and long term. Long-term signals associated with body-fat stores are provided by leptin and insulin. The concentration of leptin in the blood is highly correlated with total fat mass. Excess body fat results in increased leptin production from fat cells, while decreases in body fat that occur with dieting cause leptin and insulin concentrations to decrease, triggering responses that aim to conserve body fat. These circulating hormones also modulate short-term signals that determine meal initiation and termination. Signals that provide short-term information about hunger and satiety include gut hormones such as cholecystokinin, ghrelin, and peptide YY3-36. Vagal afferent nerves within the gastrointestinal tract also provide short-term signals in response to distension, macronutrients, pH, tonicity and hormones. The neural and hormonal signals are then integrated within specific regions of the hypothalamus and brainstem. Anorexigenic (appetite-suppressing) signals are generated by a-melanocytestimulating hormone, a peptide derived from proopiomelanocortin which derives its name from its actions in skin pigmentation through interaction with the melanocortin 1 receptor. This hormone reduces food intake and increases energy expenditure through the melanocortin 4 receptor in the hypothalamus. Deletion of the melanocortin 4 receptor gene in animals results in obesity, hyperphagia and reduced energy expenditure. Deletion of the related melanocortin 3 receptor gene results in obesity due to reduced energy expenditure without hyperphagia. Antagonism of anorexigenic melanocortin signals is caused by orexigenic (appetite-stimulating) peptides such as agouti-related protein and neuropeptide Y. Agouti-related protein antagonizes the interaction between a-melanocyte-stimulating hormone and the melanocortin 4 receptor. Neuropeptide Y, found in the arcuate nucleus of the hypothalamus, is a member of the pancreatic polypeptide family and increases during food restriction, acting to increase food intake. Neuropeptide Y decreases expression of the gene encoding proopiomelanocortin. Neuropeptide Y also decreases the synthesis of thyrotropin-releasing hormone and increases the synthesis of melanin-concentrating hormone, another orexigenic peptide. Ghrelin is a 28-amino-acid, acetylated peptide secreted by oxyntic cells in the stomach fundus. Ghrelin is named for its ability to stimulate growth hormone secretagogue receptors to increase the release of growth hormone from the pituitary. Circulating levels of ghrelin increase before meals and decrease after eating. Ghrelin increases food intake through the stimulation of ghrelin receptors on hypothalamic neuropeptide Y-expressing neurons and agouti-related protein-expressing neurons. Peptide YY3-36 (PYY) is secreted after meals in proportion to the calories ingested by endocrine L cells lining the distal small bowel and colon. The initial release of PYY after eating occurs through neural mechanisms before ingested nutrients arrive in the distal small intestine and colon. Subsequently, PYY is released in response to direct intestinal stimulation by nutrients, especially lipids and carbohydrates. PYY decreases food intake in both lean and obese individuals through inhibition of gut motility. This function is referred to as the ileal brake and results from the actions of vagal afferent neurons that ascend from the intestinal tract to the hindbrain and interact with humoral receptors in the hypothalamus. PYY inhibits NPY-expressing neurons and AgRP-expressing neurons through inhibitory neuropeptide Y2 receptors. This results in disinhibition of neighboring proopiomelanocortin-expressing neurons, resulting in decreased food intake.

D.3.3

47

D.3.3 - D.3.4

S E C T I O N I I : BACKGROUND Following gastric bypass surgery for obesity, hunger diminishes, circulating concentrations of ghrelin decrease and circulating concentrations of PYY increase. This suppression of hunger may contribute to long-term weight maintenance of reduced body weight in these patients. Since ghrelin signals hunger and PYY signals satiety, some investigators have conducted studies in transgenic mice to examine whether these hormones can be manipulated to affect body composition. Experimental knockouts of the ghrelin gene, AgRP, and NPY gene and a double knockout of the AgRP and NPY genes are not associated with any obvious effects on food intake or energy metabolism. On the other hand, inactivating mutations of the genes encoding leptin or the leptin receptor and the melanocortin 4 receptor result in obese phenotypes. Consistent with the hypothesis that humans and mice are better adapted to starvation than overnutrition, it is evident that the orexigenic peptides are so critical to survival that the absence of one peptide is compensated for by the actions of others. However, the orexins also communicate widely throughout the brain, with such regions as those involved in satiety (brainstem) and sleep/wakefulness. Indeed, the orexin knock-out mouse exhibits typical features of narcolepsy in addition to hypophagia. An important role of the orexins might be to integrate a variety of behaviors related to feeding or fasting, including emotional changes, reward responses and sleep/alertness. Insulin-like growth factor I (IGFI)/somatomedin C stimulates amino acid uptake and protein synthesis while inhibiting lipolysis. IGF peptides in serum are associated with IGF binding proteins (IGFBPs), a family of six polypeptides thought to modulate storage, transport and action of the IGFs. As noted above, IGFI secretion parallels GH secretion with age. During starvation, this linkage is broken. In the presence of elevated GH levels, IGFI levels remain low, and the concentration of IGFI inhibitors in the circulation is increased. As if this were not enough, the fat tissue makes other hormones, including omentin, vasofatin and resistin, that have effects on the breakdown of nutrients by the body. Some of the hormones made in abdominal fat are not secreted into the bloodstream and are presumed to regulate the functions of cells within the abdominal fat. The take-home lesson from all of this is that maintaining body weight in the face of starvation is a very important and basic function maintained by overlapping groups of hormones produced in various parts of the body, but the fat organs have a lot to do with transmitting to the brain the state of nourishment. The fat in the body is regulated. It is clearly possible to change it through diet and lifestyle, but the many attempts to fool Mother Nature by changing one part of the system have not succeeded.

D.3.4

GENES AND OBESITY

48

Obesity is the result of an interaction of genes and environment. Nonetheless, the total number of individuals with rare genetic defects account for only 5 percent of all cases of obesity. Some of these disorders are fascinating and involve multiple problems in mental functioning, reproduction, vision and facial appearance. The majority of the obese population is simply well-adapted to starvation. Research on the genes involved in familial obesity have so far shown up some 70 associations with parts of the human genome. However, it is unlikely that this search will uncover any single unique target that accounts for a significant percentage of

PHYSICIANS REFERENCE MANUAL obesity cases. Rather, most experts suggest any one defect may contribute about 2 percent to the tendency to gain weight. Somehow the cumulative effects of multiple genes are what tip the balance towards gaining weight. On the other hand, it is the sedentary lifestyle of the current age which combines with the high-fat, high-sugar, and high-starch diet to unmask the genes for obesity. It is generally believed that the very obese (those over 100 pounds overweight or with a BMI >40) have the greatest genetic programming for obesity. In the last 10 years, when obesity has doubled, the number of people with severe obesity has increased four-fold according to a recent Rand study. However, beyond obesity in general shape is also genetic. Identical twins reared apart not only have similar body weights but photographs of their fat distribution show almost identical pockets of fat. So, the bodys shape is genetically determined, but it can be altered significantly with diet and lifestyle changes.

D.3.4 - D.4.1

D.4 D.4.1

MEAL REPLACEMENT

HISTORY OF MEAL REPLACEMENTS

The late Dr. Ernst Drenick, a UCLA obesity specialist, was featured in a Life magazine article in the 1960s about starvation as a treatment for severe obesity. The only problem was that an individual would lose muscle at a proportion of one pound for every four pounds of weight lost with this method. Protein-modified fasting (also known as very low calorie dieting) was developed clinically by Dr. Victor Vertes at the Cleveland Clinic in the late 1970s. By this method, which was validated by the scientific studies of Dr. George Blackburn and Dr. Vernon Young at the Massachusetts Institute of Technology (MIT), an individual could take in enough protein to restore what was being lost. It worked to some extent and was safe as long as the individual consumed high-quality proteins and had their blood tested every week. The amount of calories in this diet was extremely lowin the range of 375 to 400 calories per day. Satisfying physical hunger to some extent with a liquid meal was the basis of the Opti-Fast diet, which was provided through hospitals beginning in the late 1970s. In 1977, the late Dr. Morton H. Maxwell brought this method of dieting to Los Angeles at the Risk Factor Obesity Clinic, which is still in operation today at UCLA. This clinic collects data on all the patients enrolled and includes a multidisciplinary team of psychologists, exercise physiologists, nurses and dieticians who meet weekly. The emotional support provided by this center has led to miraculous results, with patients losing large amounts of weight safely, and effectively maintaining their weight loss for years. In the late 1970s, the very low-calorie Cambridge diet was sold to people door-to-door without medical monitoring and caused about 80 deaths around the country, mostly in women with less than 40 pounds to lose. These women lost muscle protein from their hearts because they had small protein reserves. The massively obese patients did better because they could draw down their huge protein reserves. Since the heart is both a muscle and an electrical generator that regulates its own beating, the muscle loss in these women resulted in fatal heart attacks as their hearts stopped beating. Due to this

49

D.4.1 - D.4.3

S E C T I O N I I : BACKGROUND bad publicity, doctors avoided having much to do with diets such as this, leaving it to specialists like Dr. Maxwell, who developed centers like the one at UCLA, to carry on quietly saving thousands of lives over the years. In the 1970s and 1980s, research probed into how these diets worked from a nutritional viewpoint, and this research led ultimately to the development of highcarbohydrate/low-fat/low-protein meal replacement shakes that were sold over the counter. These shakes were different from VLCD shakes in that they did not require medical supervision when incorporated into diets at greater than 1,000 calories per day. At about this time, Mark Hughes founded Herbalife in 1980 and began what would grow into the largest distribution method for meal replacements, in the world over the next 27 years, as the effectiveness of meal replacements were immediately evident to him. It would take the next 20 years after Herbalifes founding for the scientific evidence that meal replacements work to be published in peer-reviewed journals and be accepted by the scientific community.

D.4.2

NUTRIENT COMPOSITION OF HERBALIFE FORMULA 1 AND HIGH-PROTEIN/LOW-CARB DRINK MIX

Not all meal replacements are alike. Some taste better than others. The first meal replacements used a lot of sugar and very little protein to optimize taste. Since highprotein diets came into fashion, some have more protein and less sugar, but much more fat. When a meal replacement is packaged in a can, there is a limit to how much protein can be engineered into the liquid without having it settle out. One of the strategies for getting more protein is to add more fat. However, if the meal replacement has more than 5 grams of fat, under FDA rules, its manufacturer can no longer make any health claims. Some of the high-protein drinks contain 10 grams of fat, which is 90 calories of fat in a 270-calorie high-protein drink. Herbalifes ShapeWorks Formula 1 contains high-quality soy protein, low amounts of fat and a moderate amount of carbohydrate, together with vitamins, minerals and a proprietary herbal blend. Note: To be classified as a meal replacement a shake must provide at least 170 calories. Therefore, a high-protein/low-carb drink mix is classified as a nutritional protein snack in the ShapeWorks program. In order to be easily duplicated by patients helping other patients, VLCD at levels below 1,000 calories per day is not part of the ShapeWorks or Doctors in Herbalife program. This minimizes the amount of medical testing needed to safely administer this plan.

D.4.3

CLINICAL RESEARCH ON MEAL REPLACEMENTS: AN ACCOUNT BY DR. DAVID HEBER

50

Throughout the 1980s, meal replacements were being sold over-the-counter, and advertising raised the awareness of the public about the existence of meal replacements. At about this time, I started my research with meal replacements. I had seen the results in my clinic, but in the late 1980s I started to document the effects on blood pressure,

PHYSICIANS REFERENCE MANUAL cholesterol and blood sugar in diabetics and non-diabetics overweight and obese patients. In 1994, I supervised a study of more than 300 patients at six medical centers in the United States. They were paid $25 a week and given a can of the powdered meal replacement each week. They mixed the powder with milk and drank a shake twice a day for weight loss, together with a reasonable dinner, providing about 1,200 calories per day. The results were amazing. Men lost 24 pounds in 12 weeks on average. Women lost 12 pounds in 12 weeks, but by 24 weeks both men and women had lost an average of 17 pounds. In 1994, I published these results in a paper entitled Clinical Evaluation of a Minimal Intervention Meal Replacement Regimen for Weight Reduction in The Journal of the American College of Nutrition. In the late 1990s a series of studies were done which demonstrated the impact of meal replacements on blood pressure, cholesterol, triglycerides, blood sugar and sleep disorders. Our own unit at UCLA conducted key studies showing that meal replacements were safe and effective when used for type 2 diabetes with obesity (what I call diabesity). In these studies, weight loss with meal replacements led to reduction or elimination of expensive medications used to treat high-blood sugar in these diabetes patients after a relatively modest weight loss of about 5 percent of body weight. This amount of weight loss in a study called the Diabetes Prevention Program prevented 58 percent of new cases of diabetes over five years in people who had high-blood sugars (but had not yet developed diabetes) and was better at prevention of diabetes than a drug approach. However, the most striking study was done by Dr. Herwig Ditschuneit at the University of Ulm in Germany. In most American studies, we lose between 20 percent and 40 percent of participants in research studies by the end of one year. This is not because we lose track of them; studies have shown that volunteers in weight-loss research studies are always looking for the magic bullet and tend to abandon these studies in mid-stream. Given the strict overseeing of Human Subjects Protection Committees at UCLA and elsewhere, it is no longer possible to provide strong monetary incentives linked in any way to continued participation in research. This is now considered unethical as it is viewed as forcing the patient to participate in the research. We do have to pay for parking and provide them with monetary compensation for their participation not linked in any way to attending sessions in the research study. So we can hand out some goodies, such as pedometers and provide theater tickets and lotteries for gifts, and thats about it. I bring this up because Dr. Ditschuneit kept 75 percent of his patients on his study for four years and proved that meal replacements were not just effective for weight loss but also for weight maintenance. He couldnt leave the patients on two meal replacements a day for four years, so the study had an interesting design. For the first twelve weeks, volunteers were randomly assigned to either try to cut down on eating their favorite foods to reach a target of 1,200 calories per day or follow a meal replacement plan at the same number of calories, which involved drinking two meal replacements a day and eating a healthy dinner. At the end of twelve weeks, the group that tried to cut down on their favorite foods lost a pound or two on average, but the meal replacement group lost 14 pounds. At that point both groups were told to have one meal replacement a day. By the end of four years, the group that consumed two meal replacements a day for twelve weeks and then one a day for four years lost 10 percent of their body weight. The group who started the meal replacements after 12 weeks and had one per day for four years lost 5%. There were also significant changes in some of the risk factors for obesity-associated diseases, such as glucose and insulin levels, with larger changes in the group that lost 10 percent of body weight compared to the group that lost 5 percent of body weight (see Figure 5 on page 52). A statistician at UCLA analyzed the data, and the results were published in The American Journal of Clinical Nutrition.

D.4.3

51

D.4.3 - D.4.4

S E C T I O N I I : BACKGROUND

Figure 5

Figure: Weight loss over four years using a meal replacement twice a day for twelve weeks (solid triangles) compared to cutting back on favorite foods (solid squares). Until the end of the study at four years, one meal replacement per day was used by both groups (body weight in solid circles). Weight in pounds on the vertical scale is plotted against time in months on the horizontal scale. Figure adapted from reference 2: Flechtner-Mors M, Ditschuneit HH, Johnson TD, Suchard MA, Adler G. Metabolic and weight loss effects of long-term dietary intervention in obese patients: four-year results. Obes Res. 2000 Aug;8(5):399-402.

As a result of all this research, meal replacements are now an accepted method of weight-loss treatment. The National Institutes of Health is sponsoring a multi-million dollar trial on the effects of weight loss on heart disease in type 2 diabetes patients over five years. Based on some of our research at UCLA and that of others, they have chosen to include meal replacements as a nutritional intervention option in one arm of the study.

D.4.4

RECENT RESEARCH ON SHAPEWORKS (ABSTRACT)

The ShapeWorks plan is simple and is based on the meal replacement strategy described below:

THE PLAN TO LOSE WEIGHT Replace two meals a day with portion-controlled, low-calorie, nutritionally balanced meals Snacks between meals (fruit and vegetables) to reduce severe hunger Physical activity and emotional support THE PLAN TO MAINTAIN WEIGHT LOSS Replace one meal a day with portion-controlled, low-calorie meal and eat two well-balanced meals Physical activity and emotional support If weight gain occurs, restart the weight-loss plan until excess weight is lost 52

PHYSICIANS REFERENCE MANUAL Unlike other meal-replacement plans, ShapeWorks allows patients to personalize their protein intake. They can choose to take adequate protein to prevent nutritional deficiency, which is the U.S. RDA of 56 grams for men and 46 grams for women, or they can choose to take 1 gram of protein per pound of lean body mass as determined by body composition (see section E: Body Composition on pages 55 through 59). To test the safety and effectiveness of this approach, 100 obese patients were recruited for study at the UCLA Center for Human Nutrition. At three months, the amounts of weight lost in each of the two groups was equivalent, but there was more lean-body mass retained by the high-protein group. Clearly, compliance in this research setting was not affected by the higher protein and masked the satiety benefits. That is, psychology trumps physiology in weight management, and the nature of this doubleblind study made it impossible to influence behavior. Since it is known that people overeat even when they are not hungry, the equivalent weight loss is not surprising. The retention of increased lean-body mass is significant. Figure 6

D.4.4

Shown in Figure 6 above is the result of bioelectrical impedance determinations at three months. While weight losses were equivalent, the higher-protein group lost significantly more body fat by three months and hence retained more lean-body mass on average. The amounts of weight lost by both groups were typical of the experience with meal replacements in clinical trials and clearly is much less significant than what is seen in individuals with higher levels of compliance. The study design retains all subjects in both groups regardless of compliance level and this minimizes the average weight losses seen. Recent studies done in Seattle and published in The American Journal of Clinical Nutrition confirm the findings of equivalent weight losses with increased retention of lean-body mass. The higher-protein, low-fat, lower-carbohydrate approach of ShapeWorks is a state-of-the-art, science-based program that provides your patients the finest in nutrition and weight-management support.

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REFERENCES
Flechtner-Mors M, Ditschuneit HH, Johnson TD, Suchard MA, Adler G. Metabolic and weight loss effects of long-term dietary intervention in obese patients: four-year results. Obes Res. 2000 Aug;8(5):399-402. Hensrud DD Dietary treatment and long-term weight loss and maintenance in type 2 diabetes. Obes Res. 2001 Nov;9 Suppl 4:348S-353S. Yip I, Go VL, DeShields S, Saltsman P, Bellman M, Thames G, Murray S, Wang HJ, Elashoff R, Heber D. Liquid meal replacements and glycemic control in obese type 2 diabetes patients. Obes Res. 2001 Nov;9 Suppl 4:341S-347S. Bowerman S, Bellman M, Saltsman P, Garvey D, Pimstone K, Skootsky S, Wang HJ, Elashoff R, Heber D. Implementation of a primary care physician network obesity management program. Obes Res. 2001 Nov;9 Suppl 4:321S-325S. Ashley JM, St Jeor ST, Perumean-Chaney S, Schrage J, Bovee V. Meal replacements in weight intervention. Obes Res. 2001 Nov;9 Suppl 4:312S-320S Heymsfield SB, van Mierlo CA, van der Knaap HC, Heo M, Frier HI. Weight management using a meal replacement strategy: meta and pooling analysis from six studies. Int J Obes Relat Metab Disord. 2003 May;27(5):537-49. Weigle DS, Breen PA, Matthys CC, Callahan HS, Meeuws KE, Burden VR, Purnell JQ. A high-protein diet induces sustained reductions in appetite, ad libitum caloric intake, and body weight despite compensatory changes in diurnal plasma leptin and ghrelin concentrationsAm J Clin Nutr. 2005 Jul;82(1):41-8.

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E - E.1

E. E.1

BODY COMPOSITION

CLASSIFICATION ACCORDING TO LEAN-BODY MASS

Obesity = Excess Body Fat (Body Fat > 20% in men, > 30% in women)

Sarcopenic Obesity (reduced lean mass)

Normal Obesity (proportionate)

Hypermuscular Obesity (increased lean mass)

Increased lean mass as well as fat mass is seen in obese individuals. One study reported that lean tissue in obese children was increased compared to non-obese peers (Forbes, 1964). Another study, using total body potassium, found increased lean tissue in obese adults (Drenick et al., 1966). Yet another study measured the body composition of 104 obese and normal weight women by densitometry (Webster et al., 1984). This reported that the excess body weight of the obese over non-obese women consisted of 22 percent to 30 percent lean and 70 percent to 78 percent fat tissue. Forbes and Welle examined data on lean body mass in obese subjects collected in their laboratory or published in the literature (Forbes and Welle, 1983). Their own data demonstrated that 75 percent of the obese population had a lean-to-height ratio that exceeded 1 standard deviation (SD) and that more than half exceeded 2 SD. A review of the literature supported these observations and determined that the lean body mass could account for approximately 29 percent of excess weight in obese patients. A proportionate increase of lean-body mass of approximately 25 percent is considered normal. Deviations both above and below this amount of lean mass are observed on clinical grounds based on various etiologies listed in Table 3 below. An example of data collected in the UCLA High Risk Breast Cancer Clinic is shown in Table 4 on page 56. TABLE 3 Etiologies of Sarcopenic and Hypermuscular Obesity Sarcopenic Obesity Chronic Use of Corticosteroids Prolonged Inactivity or Bed Rest Hypogonadism Hypopituitarism Neuromuscular Diseases Menopause and Age-Related Hypogonadism Genetic Hypermuscular Obesity Childhood Onset Severe Obesity Use of Anabolic Androgens Hyperandrogenism in Females Athletics (e.g., football, wrestling, weight lifting) Genetic 55

E.1 - E.3

S E C T I O N I I : BACKGROUND

TABLE 4 Body Mass and Percent Body Fat in Women at Increased Risk of Breast Cancer (From Heber et. al., The American Journal of Clinical Nutrition, 1996) n=28 Age (yr) Wt. (lbs) Ht. (in) BMI (wt/ht2) Body Fat (%)

Mean + SD

36.8+6.4

137.8+1.9

65.3+2.7

22.9+3.1 (nl < 27)

34.6+4.8 (nl 22-28%)

E.2

RMR AND PREDICTED WEIGHT LOSS FROM LEAN-BODY MASS

Lean-body mass is clinically important for two reasons. First, lean-body mass predicts energy expenditure and, thereby, the predicted rate of weight loss on a given caloricallyrestricted diet (Lohman et al., 1987). Secondly, lean-body mass can be used to diagnose increased or decreased lean-body mass. In the first instance, the increased lean-body mass can be used to calculate a more appropriate target weight than would be predicted from ideal body-weight tables. In those subjects with reduced lean-body mass, a program of aerobic and heavy resistance training can be initiated to provide for an increase in leanbody mass and energy expenditure. In both markedly obese individuals and individuals with decreased lean-body mass, there is a linear relationship (Sterling-Pasmore Equation) of lean-body mass to energy expenditure (ca. 13.8 Kcal/day/lb lean-body mass). This represents approximately 90 percent of total energy expenditure in a sedentary obese individual, and provides a good clinical estimate of maintenance calories.

E.3

BASIC SCIENCE BEHIND BIOIMPEDENCE

The principle behind bioelectrical impedance analysis is that the fat tissues of the body do not conduct electrical impulses as well as lean tissues, such as muscle, which are 70 percent water. While there are many ways to measure bioimpedance, the most widely accepted method involves the placement of four skin paste electrodes similar to those used to obtain electrocardiograms. These are placed at set points on one arm and one leg. By separating the electrodes a known distance based on the height of the individual which is provided to the computer in the analyzer, it is possible for the bioimpedance analyzer to quantitatively measure the electrical characteristics of the body. This can then be used to calculate lean-body mass and fat mass as described in the following: This type of circuit has a frequency-dependent impedance based on the resistance and capacitance (reactance) of the circuit elements, which are fat and lean tissue in this case. As the frequency is increased the circuit acts more like a simple resistor, and 56

PHYSICIANS REFERENCE MANUAL

E.3

The impedance meter is a simple electrical circuit with the following characteristics:

electricity travels through the circuit easily. At low frequencies it acts more like a capacitor until at 0 Hz (cycles/sec) there is no circuit flow and the impedance approaches infinity. All bioimpedance analyzers use an equation such as the one shown below. The Biodynamics impedance analyzer, in particular, uses four sets of equations to be able to predict lean-body mass with different constants for different body types.

LBM = (A X Ht2) + (B X Wt) + (C X Age) + (D X R) + E Where: LBM = lean-body mass Ht2 = the height squared in units the machine reads either centimeters or inches Wt = weight in pounds or kilograms Age = age in years, since lean-body mass tends to decrease with age R = bioimpedance in ohms The reactance is not used, but by convention the bioimpedance is read at 50 Hz. Some variable frequency machines are available which claim to represent extracellular and intracellular water by measuring impedance at different frequencies. Data Provided By a Manufacturer on Correlation With Underwater Weighing (Bioanalogics, Inc.) Clinical Results Percent Body Fat R correlation SEE (% body fat) Sample Size Men 4.3-37.1 0.98 1.50% 198 Women 12.0-45.5 0.96 1.62% 226

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S E C T I O N I I : BACKGROUND

E.4

CHALLENGES IN THE CLINICAL USE OF BIOELECTRICAL IMPEDANCE

During the first week of caloric restriction, there is a loss of body weight in excess of the loss of lean and fat tissue due to a diuresis. If patients are measured at their first visit and then weekly thereafter, it is possible to find that patients are apparently gaining fat as they lose weight using bioelectrical impedance. Since lean-body mass is assessed based on both body water and muscle, the loss of water leads to an apparent decrease in lean-body mass, which in most cases, exceeds the loss of fat in the first week of dieting leading to an increase in percent body fat (Yang, 1988). The bioelectrical impedance measurement is most useful at the first visit for assessing type of obesity (usual, decreased lean mass, increased lean mass, or fat maldistribution), and not useful for multiple serial determinations. In fact, the machine is not accurate enough to pick up small changes; therefore, it is advised to delay repeating the measurement until the patient has reached a weight close to target weight. A second potential problem is overemphasis on the quantitative accuracy of bodyfat estimation. Small changes cannot be measured using this device. It is important to stress this fact to patients. The changes observed in percent fat often do not impress patients as much as the ratio of the absolute change in fat mass in pounds compared to changes in lean mass.

E.5

FUTURE RESEARCH AND OTHER METHODS

There should be standards set for calibrating machines from different manufacturers. There are a number of laboratories that have multiple methods for measuring body composition, including total body potassium, underwater weighing, TOBEC, DEXA and deuterium dilution. Each of these has drawbacks and strong points, but none is the gold standard. The only perfect method is carcass analysis, and that can be done only once. Table 5 on this and the following page shows the methods and the principles underlying their determination. They correlate with one another but do not give the exact same measurements of body composition.

TABLE 5 TOTAL BODY POTASSIUM Detects natural K 39 decay in body from potassium assumed to be in muscle. Assumes potassium concentration of muscle is constantnot always true in malnutrition. Body fat attenuates signal so poor in obesity. DEXA Scan X-ray absorptiometry of body on scan table. Assumes density of muscle and fat different. 58

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E.5

TABLE 5 (Continued) TOBEC Body passes through magnetic field weakening it proportional to conductivity of the body. Uses magnetic field for bioimpedance. (Similar problems to bioimpedance). UNDERWATER WEIGHING Weight underwater compared to land is a function of body density. Air trapped in lungs affects density. DEUTERIUM DILUTION Exact volume of deuterium diluted into the body water. Water volume not exactly equivalent to lean tissues (similar problems to bioimpedance). BOD POD Air displacement in a closed chamber with scale in the seat (similar problems to underwater weighing).

REFERENCES
Garrow JS, Webster J. Quetelets Index (W/H2) as a measure of fatness. Int J Obes 1985;9:147-153. Forbes GB. Lean body mass and fat in obese children. Pediatrics 1964;34:308-314. Drenick EJ, Blahd WH, Singer FR, et al. Body potassium content in obese subjects and postassium depletion during prolonged fasting. Am J Clin Nutr 1966;18:278-285. Webster JD, Hesp R, Garrow JS. The composition of excess weight in obese women estimated by body density, total body water, and total body potassium. Human Nutrition: Clinical Nutrition 1984;38C:299-306. Forbes GB, Welle SL. Lean body mass in obesity. Int J Obesity 1983;7:99-107. Segal KR, Van Loan M, Fitzgerald PI, Hodgson JA, Van Italie, TB. Lean body mass estimation by bioelectrical impedance analysis: a four-site clinical validation study. Am J Clin Nutr 1988;47:7-14. Durnin JVGA, Womersley J. Body fat assessed from total body density and its estimation from skinfold thicknesses: measurements on 481 men and women aged 16 to 72 years. Br J Nutr 1974;32:77-92. Lukaski HC, Bolonchuk WW, Hall CB, Sider WA. Validation of a tetrapolar bioelectrical impedance method to assess human body composition. J Appl Physiol 1986;60:1327-1332. Lohman TG, Going SB, Golding L et al. Interlaboratory bioelectrical resistance comparison. Med Sci Sports Exerc 1987;19:539-545. Yang M-U. Body composition and resting metabolic rate in obesity.In: Obesity and Weight Control (Frankle RT and Yang M-U, eds.) Aspen Publishers, Rockville , 1988 pp.71-96. Gray DS. Changes in bioelectrical impedance during fasting. Am J Clin Nutr 1988;48:1184-1187.

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F - F.1

S E C T I O N I I : BACKGROUND

F.

SAFETY OF CAFFEINE AND ITS EFFECTS IN WEIGHT MANAGEMENT

The information that follows is taken from the International Food Information Council Publication of January 2003. It clearly states the answers to the most common questions about caffeine in Herbalife products. Caffeine is one of the most comprehensively studied ingredients in the food supply. There is considerable knowledge of this compound, with centuries of safe consumption in foods and beverages. However, some questions and misperceptions about the potential health effects associated with this ingredient still persist. Weight management studies by Dulloo et al. published in The New England Journal of Medicine indicate that coffee, in addition to its effects on stimulating mental alertness, can increase energy expenditure by approximately 2 percent per day, which is about 40 calories in an individual expending 2,000 calories per day. Beyond these physiological effects, taking caffeine can help dieters through the low-energy periods of the day, aiding in compliance. The benefits for weight management were recently described by WesterterpPlantenga and co-workers in a research study.

F.1

WHAT IS CAFFEINE?

Caffeine is a naturally occurring substance found in the leaves, seeds or fruits of at least 63 plant species worldwide. Caffeine, also known as trimethylxanthine, coffeine, theine, mateine, guaranine, methyltheobromine and 1,3,7-trimethylxanthine, is a xanthine alkaloid found naturally in such foods as coffee beans, tea, kola nuts, Yerba mat, guarana berries and (in small amounts) cacao beans. For the plant, caffeine acts as a natural pesticide since it paralyzes and kills insects that attempt to feed on the plant. Caffeines main pharmacological properties are: a stimulant action on the central nervous system with psychotropic effects and stimulation of respiration, a stimulation of the heart rate and a mild diuretic effect.

Chemical Structure of Caffeine The most commonly known sources of caffeine are coffee, tea, some soft drinks and chocolate. The amount of caffeine in food products varies depending on the serving size, the type of product and preparation method. With teas and coffees, the plant variety also affects caffeine content. 60

PHYSICIANS REFERENCE MANUAL Coffee is the chief source of caffeine in the United States. An 8 oz cup of drip-brewed coffee typically has 85 milligrams (mg) of caffeine; an 8 oz serving of brewed tea has 40 mg; soft drinks that contain caffeine have an average of 24 mg per 8 oz serving; and an ounce of milk chocolate has just 6 mg.

F.1 - F.3

F.2

COFFEE CONSUMPTION

Published data shows the per capita consumption level of caffeine for the average adult is approximately 200 mg daily. The average child consumes much less caffeineonly one-quarter of the caffeine consumed by adults. For children and young adults, the primary sources of caffeine are tea and soft drinks, while for adults, caffeine intake is mostly from coffee. Foods and beverages derived from cocoa beans, kola nuts and tea leaves often contain some caffeine. Caffeine is also added to some foods and beverages for flavor. It contributes to the overall flavor profile of those foods in which it is added.

F.3

CAFFEINE SAFETY

In 1958, the U.S. Food and Drug Administration (FDA) classified caffeine as Generally Recognized As Safe (GRAS). In 1987, the FDA reaffirmed its position that normal caffeine intake produced no increased risk to health. In addition, both the American Medical Association and the American Cancer Society have statements confirming the safety of moderate caffeine consumption. What constitutes a normal amount of caffeine depends on the individual. Caffeine sensitivity depends on many factors, including the frequency and amount of regular intake, body weight and physical condition. Numerous studies have shown that moderate amounts of caffeineabout 300 milligrams per dayare safe for most adults. Children consume about 35 to 40 mg daily. Depending on the amount of caffeine ingested, it can be a mild stimulant to the central nervous system. Although caffeine is sometimes characterized as addictive, moderate caffeine consumption is safe and should not be classified with addictive drugs of abuse. Often, people who say they are addicted to caffeine tend to use the term loosely, not unlike saying they are addicted to work or television. When regular caffeine consumption is stopped abruptly, some individuals may experience mild symptoms such as headache, fatigue or drowsiness. These effects are usually only temporary and will end in a day or so. Moderate amounts of caffeine are safe for most people. Some individuals may be sensitive to caffeine and will feel effects at smaller doses than do individuals who are less sensitive. Pregnancy and aging all may affect an individuals sensitivity to caffeine. There is no evidence that the caffeine in beverages is dehydrating. Any diuretic effect is more than likely compensated for by the total amount of fluid provided by the beverage. Research has found no evidence to suggest the use of caffeine at the levels in foods and beverages is harmful. As with all foods and beverages, parents should use common sense in giving their children normal servings of caffeinated foods and beverages. 61

F.3 - F.5

S E C T I O N I I : BACKGROUND There is no evidence to show that caffeine is associated with hyperactive behavior. In fact, most well-conducted scientific studies show no effects of caffeine-containing foodsor any food or beverage, in generalon hyperactivity or attention deficit disorder in children. Scientific evidence suggests that children are no more sensitive to the effects of caffeine than adults. Most physicians and researchers today agree that it is perfectly safe for pregnant women to consume caffeine. Daily consumption of up to 300 mg per day (approximately two to three 8 oz cups of brewed coffee) has been shown to have no adverse consequences during pregnancy. However, it is wise for pregnant women to practice moderation in consumption of all foods and beverages. The weight of scientific research indicates that moderate caffeine consumption does not affect fertility, or cause adverse health effects in the mother or the child. Caffeine-containing foods and beverages, in moderation, can be enjoyed while breastfeeding. Studies have shown that although caffeine is passed to the infant through breast milk, the amount is minute and has no effect on the infant. Both the American Academy of Pediatrics and researchers of a review published in The American Journal of Clinical Nutrition confirm that caffeine consumption at usual amounts has no effect on the infant.

F.4

FIBOCYCSTIC BREAST DISEASE AND CAFFEINE CONSUMPTION

Fibrocystic breast disease (FBD) is a condition characterized by multiple cysts that can be felt throughout the breast and usually associated with pain and tenderness. Approximately 50 percent to 90 percent of women experience symptoms of FBD, which include cyclic breast pain and tenderness. There is no relationship between FBD, which is extremely common (occurring in up to 70 percent of normal women before menopause), and breast cancer. The condition improves or disappears in the majority of women after menopause. Both the National Cancer Institute and the American Medical Associations Council on Scientific Affairs have stated there is no association between caffeine intake and fibrocystic breast disease. Research has shown that caffeine does not cause or worsen the symptoms of fibrocystic breast disease. A worldwide investigation of 100,000 deaths due to breast cancer found no relationship between caffeine intake and the development of this disease.

F.5

OSTEOPOROSIS AND CAFFEINE CONSUMPTION

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Osteoporosis is a disease of the bone characterized by a decrease in bone density and the development of weak and brittle bones, which are more prone to fracture. While it is not exclusively a womens disease, osteoporosis occurs most frequently in women. Risk factors include inadequate calcium intake, high-protein intake, smoking, inadequate exercise, small body frame, low-estrogen levels and age. In addition, Caucasian and Asian women are at higher risk for osteoporosis than women of most other ethnic groups.

PHYSICIANS REFERENCE MANUAL A recent study of post-menopausal women demonstrated that caffeine intake is not associated with any change in bone density. Several other recent, well-controlled studies have concluded that consuming moderate amounts of caffeine do not increase a womans risk of osteoporosis.

F.5 - F.8

F.6

CAFFEINE AND BLOOD CHOLESTEROL

There is no evidence linking caffeine to changes in blood cholesterol. Consumption of coffee as typically prepared in the United States does not effect blood cholesterol levels. Studies from Scandinavia using boiled, unfiltered coffee have found an adverse effect on blood cholesterol, but this preparation method is rarely used in the United States.

F.7

CAFFEINE AND BLOOD PRESSURE

Caffeine does not cause chronic hypertension or any persistent increase in blood pressure. Some individuals sensitive to caffeine may experience a slight rise in blood pressure, usually not lasting more than several hours. Studies show any rise in blood pressure is modest and less than that normally experienced when climbing stairs. However, individuals with high blood pressure should consult their physician about caffeine intake.

F.8

CAFFEINE AND HEART DISEASE

There have been over 100 studies that have examined whether a relationship exists between exposure to caffeine and blood pressure, cardiac arrythmia or coronary heart disease. Most of this research has led to the conclusion that ingestion of moderate amounts of caffeine is not associated with any increase in cardiovascular disease risk.

REFERENCES
Westerterp-Plantenga S, Lejeune MPGM, Kovacs EMR. Body Weight Loss and Weight Maintenance in Relation to Habitual Caffeine Intake and Green Tea Supplementation. Obes Res. 2005;13:1195-1204.

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G.

METABOLIC SYNDROME AND THE CO-MORBIDITIES OF OVERWEIGHT AND OBESITY

The risk of age-adjusted relative risk of diabetes mellitus increases above a Body Mass Index (BMI) of 27, which is overweight but not obese. Measures of body fat in these women would likely indicate higher than normal amounts of body fat and increased abdominal fat which is the primary depot involved in insulin resistance and the progression of diabetes. So, here is an example where waiting to see the blood sugar rise before initiating treatment is closing the barn door after the horse has run away. Identifying patients prior to the development of diabetes is one way to deal with this problem. For this reason, the diagnostic category called Dysmetabolic Syndrome X, or simply Metabolic Syndrome, has been developed with the following diagnostic criteria: THREE OF THE FIVE SPECIFIC CRITERIA BELOW: Blood Pressure > 140/90 Fasting Blood Sugar > 110 mg/dl Waist circumference > 35" in women, 40" in men Triglycerides (fasting) > 150 mg/dl HDL Cholesterol (fasting) < 50 mg/dl in a woman or < 40 mg/dl in a male

As the BMI increases, the risks of hypertension, coronary heart disease and cholelithiasis increase gradually. However, the risk of type 2 diabetes mellitus increases much more rapidly so that relative risks of diabetes with obesity are in the 40 to 100 fold range compared to the 4 to 6 range for other obesity-associated diseases.

OBESITY - ASSOCIATED TYPE 2 DIABETES

Overweight or Obesity with Genetic Predisposition Excess Adipokines Impaired Cell Function Endothelial Cell Dysfunction

Insulin Resistance and Hyperinsulinemia with Normal Glucose Tolerance and Dyslipidemia Multistep Process of Atherogenesis Insulin Resistance and Declining Insulin Levels with Impaired Glucose Tolerance

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Type 2 Diabetes

CVD Complications

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G.1 - G.2

G.1

DIABESITY

The strong correlation of diabetes and obesity is not merely a coincidence but highlights the common underlying pathophysiology of obesity causing the progression of a metabolic syndrome which results in type 2 diabetes. Type 2 diabetes is the cause of about 50 percent of all renal failure in the United States and in the next 10 years it is estimated that 70 percent to 80 percent of all heart disease will occur in patients with diabesity, or type 2 diabetes with obesity. Since diabetes mellitus is defined as an elevation in blood-sugar levels (>126 mg/dl fasting or >200 mg/dl 2 hours postprandial), researchers have identified the metabolic syndrome as a disorder which has different criteria than type 2 diabetes but is believed to be the precursor disease which lasts for eight to 10 years prior to the onset of diabetes mellitus. The development of type 2 diabetes mellitus in association with obesity is a global epidemic that is estimated to result in the vast majority of new cases of heart disease in the coming decades, with an estimated 300 million diabetic patients worldwide by the year 2025. Dietary modification and enhanced physical activity are the most effective methods to prevent or delay the onset of type 2 diabetes mellitus (T2DM) as illustrated by the Da Qing Impaired Glucose Tolerance Study, the Finnish Diabetes Prevention Study, and the Diabetes Prevention Program. Progression to T2DM in both of the latter studies was reduced by 58 percent with a modest lifestyle and diet intervention. The progression of glucose intolerance to T2DM involves a period of insulin resistance and progressive beta-cell failure as demonstrated in the landmark studies of Drenick and Johnson at UCLA in 1970. However, the tendency for the pancreatic b-cell to fail in the presence of chronic insulin resistance may be genetically determined. Progressive beta-cell failure is related to the high-secretory demands placed on the beta cell by insulin resistance.

G.2

HEART DISEASE AND HYPERTENSION

Obesity is related to the pathogenesis of heart disease through multiple pathways including hypertension, increased clottability of the blood, and dyslipidemia which is an abnormality of lipid metabolism in which there is overproduction of triglycerides with a depression of good HDL cholesterol and normal or increased bad LDL cholesterol. The hypertension that is seen in obesity is related to the hyperinsulinemia and increased secretion of catecholamines. These patients have elevated renin and angiotensin levels and the drugs of choice for hypertension in these patients are called angiotensin converting enzyme (ACE) inhibitors. Weight loss will also reduce blood pressure, but the new guidelines for these patients suggest that lifestyle and diet be used to lower blood pressure to less than 135/85 along with medications. Only 5 percent of all hypertension is due to salt sensitivity, but this disorder does occur. Salty foods will increase blood pressure in patients where obesity is the primary problem. However, low-salt diets have relatively little effect on blood pressure in these patients. A diet rich in calcium and fruits and vegetables, which supply potassium, will lower blood pressure significantly, compared to a usual diet as shown in the Dietary Approaches to Stop Hypertension (DASH) study, funded by the National Institutes of Health (NIH). Restricting salt had a small but significant additional effect beyond the DASH diet alone.

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G.3 - G.3.2

S E C T I O N I I : BACKGROUND

G.3

FATTY LIVER DISEASE AND CIRRHOSIS

The increased incidence of obesity has been paralleled by an increase in metabolic syndrome in the same cohort of patients. The net consequence of insulin resistance in a large majority of these obese individuals is hepatic steatosis, which, over time in a proportion of these patients, progresses to steatohepatitis and cirrhosis.

G.3.1

DIAGNOSING FATTY LIVER DISEASE

Despite the increased awareness among physicians regarding its presence, the diagnostic process has been hampered by the lack of sensitive and specific population-based screening tests. Liver biopsy remains the gold standard for diagnosis as well as for grading and staging of the disease process, but its precise role in the process of diagnosis continues to be debated. Moreover, because laboratory testing is routine, an abnormal serum transaminase or alkaline phosphatase in patients without clinical symptoms is not uncommon. Although liver function tests are critical in recognizing the presence of liver disease and its specific diagnosis, the interpretation of the tests may be confusing and difficult (Knight, 2005). Furthermore, not all persons with one or more test abnormalities actually have liver disease. Abnormal liver enzymes may also be present in the absence of symptoms and signs of liver disease. A good clinical history and physical examination are mandatory. If a systematic approach is adopted, based on additional non-invasive serological tests and imaging procedures covering the most frequent liver diseases, the cause is often apparent. The clinician should be aware of nonhepatic diseases that can cause abnormal liver enzymes, such as thyroid disorders and occult celiac disease. In those patients in which no explanation can be found at the time of the initial evaluation for these abnormal liver enzymes, there is a high probability of non-alcoholic fatty liver disease. The risks and benefits of a liver biopsy in this setting should be carefully considered, as it only seldom alters management (Verslype, 2004).

G.3.2

OTHER CAUSES OF FATTY LIVER AND LIVER FAILURE

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Fatty liver disease has traditionally been classified as alcoholic and nonalcoholic. While the gross and histologic appearance of the liver are similar in these conditions, the pathophysiologic processes and clinical features of the two conditions are not identical. The histologic spectrum of nonalcoholic fatty liver disease (NAFLD) includes both hepatic steatosis and steatohepatitis. The causes of fatty liver include: 1) Metabolic syndrome, which is the most common cause; 2) Alcohol-induced liver disease (very common); 3) Rare Metabolic Diseases including abetalipoproteinemia, Weber-Christian Syndrome and lipodystrophy; 4) Drugs, including amiodarone, tamoxifen, antiretroviral therapies; 5) Hypothyroidism; and 6) Unknown cause (idiopathic).

PHYSICIANS REFERENCE MANUAL The global emergence of obesity as an epidemic has made fatty liver disease a public health problem in the Western world and in emerging economies where obesity is becoming more prevalent. At the same time, the number of cases of idiopathic liver disease have increased. While there are documented cases of toxic liver disease due to a limited number of herbal products as well as what appear to be allergic reactions, the practice of ascribing idiopathic cases to herbal hepatoxicity is not warranted in the absence of particular criteria including the identification of the hepatotoxic ingredient, and proof of its hepatotoxicity. Given the prevalence of use of herbal medicines and the increasingly common occurrence of liver disease worldwide, there have been a number of misclassifications of liver disease as being due to herbal toxicity.

G.4

G.4

CANCER

Cancer is due to accumulation of DNA mutations that confer a growth advantage and invasive properties on clones of cells. A variety of external factors, including nutrients in the environment interacting with genetic susceptibility, influence the accumulation of mutations in cells. Nutrition is important at every stage of carcinogenesis from initiation to promotion to progression and metastasis. The primary risk factor for cancer is aging. All data demonstrating nutritional influence utilize age-adjusted cancer incidence. Through primary prevention as well as nutritional effects on patients with early treated cancer, the hope is to reduce the duration of morbidity as well as lengthen survival. This has not yet been demonstrated in clinical trials, but is the ultimate goal of research in nutrition and cancer. International correlation data in the late 1960s demonstrated a relationship of ageadjusted breast cancer incidence to dietary fat intake. This correlation marked a dietary pattern rather than a specific effect of dietary fat. Later studies pinpointed a correlation with meat-protein rather than vegetable-protein intake. Migration data also demonstrate that individuals moving from a high-risk to a low-risk country, or vice versa, take on the risk of the country to which they migrate within one generation. International correlation data also show a relationship of adult height to the ageadjusted rate of breast cancer. Adult height is a marker of pre-pubertal nutrition. With an increase in childhood obesity incidence in a country, there is a concomitant increase in adult height. The incidences of obesity and obesity-related cancers have increased in Japan in the last 20 years as has adult height. There is evidence that childhood obesity confers a lifelong increased risk of common forms of cancer. There is significant evidence that major forms of cancer are affected by diet and lifestyle. Obesity is a risk factor for common forms of cancer including breast, prostate, colon, uterine, kidney, gallbladder and pancreatic. Ad lib intake of excess calories in animal models has also been associated with enhanced tumorigenesis for breast, colon and skin cancer. Since laboratory animals tend to develop obesity with age, the preventive effects of calorie reduction in animals are likely to be analogous to the prevention and treatment of obesity in humans by either reduction in caloric intake or an increase in physical activity.

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G.5

S E C T I O N I : BACKGROUND

G.5

CHANGES WITH AGING IN BODY FAT AND CHRONIC DISEASE RISK

All of the chronic diseases discussed above increase in incidence with aging. With age there is a reduction in lean-body mass in both men and women. The decrease is associated with reduced calorie requirements and increased risk of developing common forms of cancer. The reduced muscle mass may be associated with increased insulin and reproductive hormone levels in some aging individuals. Lean-body mass decreases with aging in males as they tend to become less active. There may also be age-related decreases in hormones mediating muscle growth and maintenance. These changes in body composition affect the levels of sex hormones, insulin and growth factors which may affect chronic diseases, including diabetes, cardiovascular disease and common forms of cancer. Efforts at diet and lifestyle change with aging to prevent chronic diseases, including cancer, need to include interventions to maintain or increase lean body mass.

REFERENCES
Knight JA. Liver function tests: Their role in the diagnosis of hepatobiliary diseases. J Infus Nurs. 2005 Mar-Apr;28(2):10817. Verslype C. Evaluation of abnormal liver-enzyme results in asymptomatic patients. Act Clin Belg. 2004 Sep-Oct; 59(5):285-9.

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2007 Herbalife International of America, Inc. All rights reserved. Printed in USA.

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