Exercises to Lose Belly Fat

Flat Belly Fix Review

In Flat Belly Fix program, you learn the easy, tested and trusted method that saved the creator of this program (Todd Lamb) beautiful wife Tara from a life battling Type 2 Diabetes and experiencing possibly death. It was a very nasty experience with the couple during those times, but with the determination of Todd, he labored ceaselessly to finding a way out for his depressed and unhappy wife. Now they live together both happy and contented. Having used the same technique for people around (seeing the wonders it did to his wife) and also recording so much success, Todd Lamb wants to relate this secret to the world, to create this same atmosphere of joy produced in his immediate environment. Hence, he was motivated to put together this workable program. You also get to learn the secret to having a flat belly, and a healthy and fit body that has been hidden from you for so long now. The creator if this program is positive about the efficacy of this program and is so excited for you to personally experience what happens when you apply The 21 Day Flat Belly Fix in your life. Continue reading...

Flat Belly Fix Review Summary

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My Flat Belly Fix Review Review

Highly Recommended

Recently several visitors of blog have asked me about this manual, which is being advertised quite widely across the Internet. So I decided to buy a copy myself to find out what all the excitement was about.

All the modules inside this ebook are very detailed and explanatory, there is nothing as comprehensive as this guide.

Insulin Resistance and Metabolic Syndrome

The incidence of PAD is greater in patients with diabetes or impaired glucose tolerance and insulin resistance 8 . The metabolic syndrome is also associated with a higher risk of vascular events 8 . The prevalence of the metabolic syndrome in a secondary prevention population has been reported as 58 in PAD patients, 41 in CHD patients, 43 in CVD patients and 47 in abdominal aortic aneurysm patients. With the increasing prevalence of the metabolic syndrome we expect to see more PAD associated with insulin resistance. Patients with the metabolic syndrome may have raised levels of urate and fibrinogen as well as impaired fibrinolysis 8 .

Measurement of Visceral

Radiographic imaging is the only in vivo method available to quantify visceral fat. Measurement of visceral fat in vivo has stimulated great interest because a plethora of data consistently demonstrates that visceral fat is an independent predictor of both morbidity (36-39) and mortality (12). In this way it is important to note that similar to waist circumference, there is no consensus as to the optimal location for measurement of visceral fat. It has been suggested that T10-T11 and L5-S1 may represent the anatomical boundaries for portally drained visceral fat, and that a contiguous image protocol within this region may represent the gold-standard measure. However, this approach is labor-intensive and, in the case of CT, would be associated with substantial radiation exposure. Consequently, visceral fat is normally assessed using a single MRI or CT image. Visceral fat measures at any given anatomical level using a single image are highly correlated with mass measures using multiple...

Waist Circumference

One might wonder what aspect of body composition is most closely associated with the adverse health risks attributable to excess body weight and whether BMI is the best measure for risk stratification. Is the critical factor total fat mass, the relative amount of subcutaneous versus intra-abdominal fat, or ectopic fat deposition, to name just a few possibilities A growing body of evidence suggests that adverse consequences of obesity are most closely associated with an accumulation of intra-abdominal fat (36-38). The adverse health effects of increases in intra-abdominal fat are independent of other factors such as total fat, insulin resistance, or serum levels of nonesterified fatty acids. This compartment of adipose tissue can be estimated by measuring waist circumference. Waist circumference is most easily measured with a tape measure parallel to the floor, at the level of the superior iliac crest, while the patient is standing, at the end of a relaxed expiration (Fig. 1). Waist...

Metabolic Syndrome and Lifestyle Change

Metabolic syndrome (MS) has been defined by the National Cholesterol Education Program (NCEP). It has been reported that the MS increases the risk of cardiovascular disease and the risk of cardiovascular disease mortality. In the DPP, 53 of the subjects had MS. Of the components, an elevated waist circumference was the most common (73 ) and high fasting glucose was the least common (33 ). The prevalence of MS between baseline and follow-up increased from 55 to 61 in the placebo group, remained unchanged in the metformin group (54 to 55 ), and was reduced in the lifestyle group from 51 to 43 . The study showed that an ILS intervention with weight loss and increased physical activity is more effective in reducing the onset of diabetes, but is also more effective in reducing the other components of MS. This may mean that, over the long run, it is more effective in reducing the incidence of cardiovascular disease.

Metabolic Syndrome

It is clear that obesity is often associated with a cluster of metabolic disorders that increase the risk of cardiovascular disease and diabetes. These include insulin resistance, glucose intolerance, hypertension, hyperlipidemia, activation of inflammatory pathways, endothelial dysfunction, and nonalcoholic steatohepatitis, to name just a few. This cluster of disorders has been called syndrome X, insulin resistance syndrome, and other names, but most now refer to this condition as metabolic syndrome. Initially proposed by a number of thoughtful clinical investigators including Dr. Gerald Reaven, metabolic syndrome came into broader awareness when formal diagnostic criteria were proposed first by the World Health Organization and then the National Cholesterol Education Program in its Adult Treatment Panel III guidelines (NCEP-ATPIII) (57). There have been a number of other diagnostic criteria proposed by a range of professional organizations since then. The most recent, and perhaps...

Series Editors Introduction

Type 2 Diabetes, Pre-Diabetes, and the Metabolic Syndrome The Primary Care Guide to Diagnosis and Management is an important addition to the literature for primary care physicians. It covers concisely and with attention to clinical relevance the full spectrum of insulin resistance and diabetes. This book gives a practical, no-nonsense approach to understanding the basic pathophysiology of diabetes and the metabolic syndrome, an approach to treatment with oral agents and insulin, and an approach to risk factor management. By putting all this information in one readable text, Dr. Codario provides a service to us all, facilitating the understanding of a body of knowledge that cannot be obtained through any attempt to read portions of much larger textbooks in the field. This textbook will serve as a resource for medical students, residents in family medicine and internal medicine, and attending physicians who wish to update and improve their knowledge in the field of diabetes and the...

Continuing Medical Education

The overall goal of this activity is to update the knowledge of clinicians on strategies and techniques needed to comprehensively manage patients with type 2 diabetes, pre-diabetes, and or the metabolic syndrome. After completing this CME activity, participants should have improved their overall knowledge and attitudes in regard to treating type 2 diabetes, pre-diabetes, and or the metabolic syndrome. Specifically, participants should be able to Understand the pathophysiology of type 2 diabetes and metabolic syndrome Appreciate, understand and apply a comprehensive strategy for risk reduction in diabetes and metabolic syndrome

Of Lipidlowering Drugs that may Benefit PAD Patients

Patients with the metabolic syndrome have a clustering of many risk factors, such as hypertension, insulin resistance type 2 diabetes mellitus, dyslipidaemia and obesity 11 . Therefore, it not surprising that these patients are at increased risk of developing PAD 15, 28 . The prevalence of the metabolic syndrome in PAD patients in a cross-sectional survey 15 was 58 .

Weight concerns Overweight and obesity

The NHLBI guidelines recommend a two-step process of assessment and management. Treatment is recommended for patients with a BMI of25-29.9 or a high waist circumference, and two or more risk factors.10 Patients with a BMI of 30 or more should receive treatment regardless of risk factors. The initial goal for weight loss shouldbe to reduce body weight by 10 frombaseline (evidence level A). With success, further loss can be attempted, if warranted, based on further assessment. A combined intervention including caloric reduction, increased physical activity, and behavior therapy is recommended as most effective. This again raises the unbreakable link with activity levels the less active a person is, the less they can eat without gaining weight. Physical activity is recommended as part of a comprehensive weight-control program because it contributes to weight loss (evidence level A), may decrease abdominal fat (evidence level B), increases cardiorespiratory fitness (evidence level A), and...

Endocannabinoids and Energy Homeostasis

The body's endogenous endocannabinoid system includes two endogenous agonists for cannabinoid-(CB)-1 receptors, anadamide and 2-arachidonoyl-glycerol (2-AG). Both of these endocannabinoids (ECs) are fatty acid signals derived from cell membranes. They exert a coordinated action at multiple tissues to promote increased food intake, lipogenesis, and storage of fat. Endocannabinoids interact with multiple hypothalamic circuits and transmitter systems to stimulate food intake in general, and they also act in reward areas of the brain to selectively enhance intake of palatable foods. Activation of CB1 receptors increases enzyme activity that causes de novo fatty acids to be formed in the liver and circulating lipids to be taken up by fat cells. All these actions are reversed in animals lacking CB1 receptors, and there is growing evidence that activity of the endocannabinoid system is toni-cally increased in animal and human obesity. Acute or chronic administration of selective synthetic...

P Hydroxydehydrogenase1

In summary, adipocytes from obese individuals appear to express increased levels of 11PHSD-1, which converts inactive cortisol metabolites into cortisol. In rodents, adipocyte-specific overexpression of this enzyme mimics many attributes of metabolic syndrome. While the exact mechanisms are not yet clear, increased local levels of 11PHSD-1 in adipose tissue may promote metabolic syndrome. The identification of inhibitors of 11 HSD-1 is currently a research focus of pharmaceutical companies.

Ectopic Fat In Liver And Muscle

Skeletal muscle and liver normally contain small amounts of triglyceride, far smaller than that contained in adipose tissue. In obesity, these repositories can be greatly increased. Hepatic steatosis occurs commonly in obesity, especially in visceral obesity and especially in type 2 DM (36), and is strongly correlated with IR. In patients with type 2 DM, the amount of insulin required to achieve glycemic control is correlated to the amount of hepatic steatosis (37), indicating the importance of this depot to the pathogenesis of hepatic insulin resistance. Hepatic steatosis is also correlated with the severity of dyslipidemia (36).

Gestation Lactation And Maternal Environment

The majority of human beings are raised with their biological mothers. This means that they are exposed to the maternal environment throughout gestation and lactation, as well as through the rest of their formative years. Thus, outcome in humans is dependent not only on the biological effects of the perinatal maternal environment but also on a number of psychosocial and socioeconomic variables. Because these variables are not major factors in animal models, these models are best suited for investigating the effects of altering the metabolic perinatal environment on offspring outcome. Rodent models also have the advantage that lifelong patterns of food intake and body weight are generally established by the second week of life as long as dietary content is held constant thereafter (39,40). Whereas human studies can only suggest a relationship, it is clear that maternal obesity throughout gestation and lactation in rats leads to the development of obesity and metabolic syndrome in...

Postnatal Influences on Offspring

Although the prenatal environment has a major impact on the developing fetus, a number of postnatal factors can alter the development of ingestive behavior in neonates and predispose them to develop obesity and metabolic syndrome as adults. Metabolic, hormonal, and behavioral interactions of pups with their dams are critical factors in this regard. Maternal milk is composed primarily of fatty acids (104-106) and the composition of milk understandably has a major impact on the developing neonate. Because maternal milk contains more fat than carbohydrate, neonates utilize fatty acids and ketone bodies as their primary energy substrates. During suckling, neonates transport ketone bodies preferentially over carbohydrates across the blood-brain barrier, and ketone bodies serve as the primary energy substrate for neuronal and glial metabolism (107,108). Blockade of both fatty acid oxidation (lipoprivation) (109) and glucose oxidation (glucoprivation) (110) increase food intake in adults....

Anthropometry and Change in Body Composition in Obesity

Waist circumference is commonly used to assess change in abdominal obesity. Changes in waist circumference are associated with changes in visceral fat in response to diet and or exercise weight loss (Fig. 5) (35,50,52). It is reported that a 1-cm reduction in waist circumference corresponds to a 4 reduction in visceral fat however, there was a substantial amount of variance (standard deviation 4 ) in this relationship. The variation in this association is in part due to changes in subcutaneous fat and or lean mass that mask the ability of waist circumference to accurately distinguish changes in abdominal tissues. When examining the utility of WHR to estimate changes in body composition, a principal limitation of a ratio score becomes clear. Owing to the nature of ratio scores, changes in the ratio could be due to alterations in the numerator (waist) or the denominator (hip). For example, a reduction in the WHR after an exercise intervention could be due to reductions in the waist...

Guidelines For Exercise

Improved insulin sensitivity correlates with lowered cardiovascular risk. Weight loss combined with exercise and diet therapy significantly decreases intra-abdominal fat and is associated with a better sense of well-being, better mood, and higher self-esteem. The matter in which exercise is attempted is strictly the patient's preference. The participants in this study were young white and black men and women (ages 1830) who completed treadmill testing and then were followed from 1985 to 2001. Glucose, lipids, and blood pressures were measured and physical activity was assessed by interview and self-reporting. Outcome measurements included hypercholesterolemia, metabolic syndrome, hypertension, and type-2 diabetes. 2. Metabolic syndrome 10.2. Patients with low fitness (< 20th percentile) were three to six times more likely to develop diabetes, hypertension, and metabolic syndrome than patients with higher fitness (> 60th percentile). Adjustment for BMI lowered the strength of the...

Dualenergy Xray Absorptiometry

DEXA has also been used to measure abdominal adiposity. Within the abdominal region, DEXA measures of total abdominal fat correlate very well to measures by CT (r 0.87-0.98) (75,76) in both black and Caucasian men and women (75). However, DEXA can assess body composition only two-dimensionally. Thus, it is unable to differentiate subcutaneous fat from visceral fat. Accordingly, the association between DEXA measures of abdominal fat (r 0.51-0.90) (48,75-77) and CT- or MRI-measured visceral fat tend to be weaker than with total abdominal fat. In fact, some have argued that the associations between visceral fat and DEXA-measured abdominal fat is no better than those observed with simple anthropometry such as waist circumference (r 0.610.89) (75,76) and sagittal diameter (r 0.68-0.93) (48,75,76). In a study by Snijder et al. (75), DEXA-measured trunk fat explained only an additional 1 to 4 of the variance in visceral fat beyond sagittal diameter or waist circumference alone, in Caucasian...

Measurement of Abdominal Subcutaneous

Consensus is also lacking with respect to the ideal measurement protocol for abdominal subcutaneous fat. Although it is reported that there are metabolic differences in subcutaneous adipocytes within various regions within the abdomen (97), or between the upper and lower body (98), the anatomical borders that distinguish these different regions is unclear. It is not surprising that traditionally, abdominal subcutaneous fat is measured on the single image acquired to measure visceral fat. In a manner similar to visceral fat distribution, it is reported that substantial differences exist in the absolute amount of abdominal subcutaneous fat measured across the abdomen (Fig. 10). However, unlike visceral fat, the association between metabolic syndrome and abdominal subcutaneous fat appears to be similar across all measurement sites (Fig. 11) (96).

Computed Tomography Quantification of Ectopic

Obtaining a CT image that contains both liver and spleen presents a challenge variation exists not only in the vertical positioning of the spleen relative to the liver, but also in positioning of both organs within the abdominal cavity. As a multi-image approach is not feasible because of excess exposure (110), Davidson et al. proposed that a single axial image at the T12-L1 intervertebral space may provide the most optimal landmark for assessing both liver and spleen attenuation, as liver and spleen were identified at that level in approx 90 of the men and women studied (Fig. 13) (109). Interestingly, T12-L1 is also a good predictor of visceral fat volume and metabolic syndrome that was in a similar order of magnitude of L1-L2. As such, there is evidence that a single image in the abdomen could be used to accurately quantify liver fat, visceral fat, abdominal subcutaneous fat, and skeletal muscle. These studies are cross-sectional in nature, but provide very important insight into...

Special Considerations for Specific Ethnic Groups

Even though a growing body of data suggests that waist circumference is a better predictor of health risks associated with obesity as compared with BMI (39), it has become increasingly clear that the cut-points generally advocated for risk stratification have limitations. As one might expect, there appears to be a curvilinear relationship between waist circumference and health risks, as opposed to a threshold effect. This means that health risks rise incrementally as waist circumference increases. Recent evidence suggests that the generally advocated cut-points may be too conservative for Caucasians (39). There appear to be even greater concerns in the use of these cut-points for individuals from different ethnic groups. Zhu and coworkers examined data from NHANES to determine appropriate cutoffs for African Americans and Mexican Americans (40). They found that cutoffs for African American men were 5 to 6 cm lower than the value for Caucasian men. Mexican American men were...

Measures of Body Composition

Some have advocated the use of bioelectrical impedance in an effort to provide patients with more specific information on lean body mass as well as body fat content (44). Unfortunately, at this time there are technical limitations with this measure in those with a high BMI that limit its accuracy. As a result, there is not wide support for the use of bioelectrical impedance in the assessment of obese patients in clinical practice (45). Measurements of skinfold thickness, air displacement plethysmography, underwater weighing, and dual-energy X-ray absorptiometry all can provide information on body fat and regional fat distribution. However, in routine practice, BMI and waist circumference provide adequate information for clinical assessment and initial risk stratification.

Laboratory Evaluation of the Obese Patient

Although one could make a case for obtaining a large number of biochemical tests in the evaluation of an obese patient, a more limited initial screen seems warranted. A fasting sample of blood for glucose total, LDL, and HDL cholesterol and triglyceride levels is clearly indicated. These tests, along with an appropriate history, will provide the information necessary for cardiovascular risk stratification and can be used to rule out diabetes or impaired fasting glucose (25,57). Some have advocated obtaining a glycosylated hemoglobin (HbA1C) level to screen for diabetes. Although this test should be useful in the diagnosis of diabetes, the assay method has not been standardized and at this time there is no widely accepted diagnostic criteria for diabetes based on an HbA1C level. In addition, some have advocated obtaining a fasting insulin level to determine whether insulin resistance is present. Unfortunately, here again, methods for assaying insulin have not been standardized and...

Abnormal Glucose Metabolism and Type 2 Diabetes

Fat distribution is also very important in diabetes risk (22-25). Central or upper body fat deposition is independently associated with insulin resistance (23), diabetes (24,25), and cardiovascular disease (26). Intra-abdominal or visceral obesity is strongly associated with insulin resistance, as well as with dyslipidemia, hypertension, and glucose intolerance (27-30). In Japanese American men intra-abdominal fat deposition was closely correlated with type 2 diabetes, whereas subcutaneous fat deposits in the abdomen, thorax, or thigh were not statistically significant predictors (31). A lack of adequate physical activity is another important risk factor for the development of type 2 diabetes. Men who habitually engage in moderate levels of physical activity have a substantially reduced risk of diabetes compared with physically inactive men, even after adjustment for age, body mass index (BMI), and other risk factors (32). Physical training can reduce insulin resistance (33) and high...

Diseasespecific Guidelines

It is proposed that most individuals with type 2 diabetes have had a less severe abnormality of carbohydrate metabolism before progressing to diabetes.90 The transition from normal glucose tolerance to type 2 diabetes in genetically susceptible persons involves manifestations described as insulin resistance, a condition in which body cells lose sensitivity to insulin action, and insulin-stimulated glucose disposal is compromised. Insulin resistance is associated with a metabolic syndrome characterized by a cluster of atherogenic risk factors including hyperinsulinemia, obesity with an abdominal pattern of distribution, some degree of carbohydrate intolerance, hypertension, and an abnormal blood lipoprotein profile of increased triglycerides and decreased HDL cholesterol. Other features of the syndrome include easily oxidized small LDL particles, heightened blood-clotting activity (plasminogen-activating inhibitor-1), and elevated serum uric acid concentration. The negative effects are...

Efficacy Of Lowcarbohydrate Diets On Weight Loss

Body mass index (BMI) and ages ranged from 33 to 43 kg m2 and 43 to 54 yr, respectively, in all five studies. Although there were many similarities in diet prescriptions and participant characteristics, a few differences emerged. The majority of the studies consisted of female participants (8,9,12,13) except for one (10,11). Comorbidities and amount of clinician contact also differed slightly between these studies. Two of the investigations evaluated effects in obese but otherwise healthy adults (8,9) three examined effects in adults with significant comorbidities such as diabetes, metabolic syndrome (MetS) (10,11), hyperlipidemia (12), and other cardiovascular risk factors (13). Treatment occurred primarily in a self-help setting in one study (8) and in individual and or group treatment in the others (9-13). Only three studies evaluated effects at 1 yr (8,11,13). Findings of these studies are summarized in Table 1.

Peripheral Arterial Disease

The patient with type 2 diabetes is more prone to atherogenic dyslipidemia and the metabolic syndrome and has a fourfold increased risk of developing peripheral arterial disease, with the symptoms in patients with diabetes not directly correlating with gly-cemic control.

Algorithm For Using Currently Available Drugs

The first step is to measure height and weight to establish the body mass index (BMI) for the patient. If the BMI, the weight in kilograms divided by the square of the height in meters (kg m2) (weight in pounds divided by square of the height in inches times 703), is higher than 30, the patient is by definition in the obese category and medications can be considered. Not mentioned in this guideline is the essential next step of measuring waist circumference (for individuals with a BMI < 35 if the BMI is above 35, the waist circumference will almost certainly be increased). The currently recommended upper limit for waist circumference is 102 cm (40 in.) for a man and 88 cm (35 in.) for a woman. Values above these numbers have the same meaning as a BMI 30 kg m 2 Another important initial step is to assess the associated (comorbid) conditions by measuring blood pressure, glucose, and lipids, and, when indicated, performing other tests. With this laboratory panel and the waist...

Medications Monotherapy

Along with the dyslipidemia associated with diabetes, the metabolic syndrome, and insulin resistance, come vascular hypertrophy, accelerated atherogenesis, excessive angio-tensin II production, sodium retention, increased sympathetic outflow, and increased mortality and morbidity. The importance in treating hypertension in the diabetic patient cannot be minimized. End-organ damage and medical complications are plentiful when we look at this patient population. Cardiovascular complications include congestive heart failure and its sequelae, cardiomyopathies, peripheral vascular disease, and generalized arteriosclerotic vascular disease. Patients are prone to cerebral vascular infarctions, ischemic events, hemorrhages, and carotid and intracerebral arteriosclerotic vascular disease.

Critical Growth Periods

Examination of the pattern of change in BMI over the first 7 yr of life reveals a typical increase in BMI following the initial postinfancy nadir that occurs in the second to third year of life. The adiposity rebound then occurs between about 5 and 7 yr of age, with children whose adiposity rebound occurs earliest showing the greatest risk of obesity in the late teen years. Pubertal timing may also play a role in adiposity development, as early menarche has been shown to increase the risk of obesity and the metabolic syndrome (25).

Drugs on the Near and Distant Horizons

The results of four phase III trials of rimonabant for the treatment of obesity have been presented. These reports are posted on the Sanofi website (82) only one exists in the form of a peer-reviewed publication at the time of this writing (82,83). The summary of these trials, therefore, comes primarily from these Sanofi press releases. The first trial to be announced was called the Rio-Lipids trial. This was a 1-yr trial that randomized 1018 obese subjects equally to placebo, 5 mg d rimonabant, or 20 mg d rimonabant. The subjects in this trial had untreated dyslipidemia, a BMI between 27 and 40, and a mean weight of 96 kg. Weight loss was 2 in the placebo group and 8.5 in the 20-mg rimonabant group. In the 20 mg d rimonabant group, waist circumference was reduced 9 cm, triglycerides were reduced by 15 , and HDL cholesterol was increased by 23 , compared with 3.5 cm, 3 ,and 12 respectively in the placebo group. In the 20 mg d group the LDL particle size increased, adiponectin...

Nicole H Rogers MS Martin S Obin PhD and Andrew S Greenberg md

There are currently more than 50 known adipokines, as well as locally generated hormones and metabolites that, together, affect multiple physiological functions including food intake, glucose homeostasis, lipid metabolism, inflammation, vascular tone, and angiogenesis. Because they affect such diverse and important processes, regulation of adipokine secretion from AT is critically important to regulating systemic metabolism. Notably, increased AT mass (as in obesity) induces characteristic qualitative and quantitative changes in adipose tissue metabolism and adipokine secretion. These changes are now implicated in the development of metabolic syndrome and its progression to more severe obesity-associated pathologies, including type 2 diabetes and cardiovascular disease.

Physiological Activities

A puzzling observation made a decade ago was that glitazones, which were developed for the treatment of insulin resistance, are PPARg-selective ligands. The link between the promotion of adipocyte differentiation and lipid storage by PPARg and the antidiabetic effects of these compounds is not fully understood. One hypothesis is fat redistribution from muscle to adipose tissue more particularly to subcutaneous fat, which is itself more sensitive to insulin than visceral fat (Gurnell et al., 2003 Wajchenberg, 2000). Alternately, some data support the hypothesis that adiponectin, an adipokine with insulin-sensitizing property and a PPARg target gene, might be a crucial component connecting PPARg activation in the adipose tissue and the metabolic response of the peripheral organs (Gurnell et al., 2003). Other possibilities are the inhibition of hepatic neoglucogenesis or induction of a futile cycle, as mentioned above. Unexpectedly, PPARy+' heterozygous mice, rather than being prone to...

George A Bray md and Frank L Greenway md

Obesity is increasing in prevalence and its medical liabilities are largely related to central adiposity and the associated insulin resistance. The present drugs available for the treatment of obesity and metabolic syndrome are few in number and limited in efficacy. This chapter reviews the drugs approved by the US Food and Drug Administration (FDA) to treat obesity, drugs approved by the FDA for other indications than weight loss, drugs in the late development process that have not been approved by the FDA, drugs in earlier stages of drug development for which clinical information is limited, drugs that have been dropped from development, and new potential drug targets for which essentially no clinical data yet exist. We also review the nonprescription products sold for the treatment of obesity and metabolic syndrome. The developmental pipeline of drugs for the treatment of obesity and the metabolic syndrome is rich. Because drugs to treat obesity are being developed in an era...

Multiple Riskfactor Reduction

Animal models of atherosclerosis have demonstrated that the TZD can inhibit macrophage accumulation, thus reducing atherosclerosis, and also improving lipid profiles and reducing the levels of various inflammatory markers. Activation of the PPAR system is associated with various pleiotropic benefits, especially in individuals with diabetes and the metabolic syndrome. TZD activation of PPAR-y reduces C-reactive protein, decreases inflammation, and increases adiponectin levels, thus inhibiting atherosclerosis and preventing restenosis. The positive influence of TZD on lipid subfractions and the reduction in hyperplasia in the vascular intima supports their potential for cardiovascular benefit. Future trials are in progress to provide evidence-based data for TZD.

The Natural History Of Type 2 Diabetes

Although the triple disturbance of insulin resistance, increased hepatic glucose production, and impaired insulin secretion critical to the development of type 2 diabetes has received a great deal of attention in research, the etiological sequence of events resulting in the diabetic state is also of compelling interest . Accelerated hepatic gluconeogenesis and glycogenolysis do not seem to exist in the state of impaired glucose tolerance, where insulin resistance and impaired insulin secretion predominate in fact, these two abnormalities precede the onset of hyperglycemia in the diabetic type 2 phenotype. Prediabetic individuals have severe insulin resistance, whereas insulin secretion tends to be normal or increased in the prediabetic or impaired glucose tolerant state, including first-phase insulin responses to intravenous challenges. Thus, the type 2 diabetic phenotype evolves from the individual with impaired glucose tolerance and insulin resistance. Although the genetic factors...

Introduction To Adipose Tissue

There are currently more than 50 known adipokines, as well as locally generated hormones and metabolites that, together, affect multiple physiological functions including food intake, glucose homeostasis, lipid metabolism, inflammation, vascular tone, and angiogenesis (Fig. 1) (1). Because they affect such diverse and important processes, regulation of adipokine secretion from AT is critically important to regulating systemic metabolism. Notably, increased AT mass (as in obesity) induces characteristic qualitative and quantitative changes in adipose tissue metabolism and adipokine secretion. These changes are now implicated in the development of metabolic syndrome and its progression to more severe obesity-associated pathologies, including type 2 diabetes and cardiovascular disease.

Daniel H Bessesen md

There is a growing consensus on the importance of addressing obesity in clinical practice. This consensus is the product of clear evidence that obesity has become an extremely common condition, that it is associated with adverse health consequences, and that treatment modalities are available that can not only reduce weight, but improve some of the associated comorbidities. in this chapter, some of the evidence that obesity, as defined by body mass index and waist circumference, is associated with adverse health consequences will be reviewed. An approach to the assessment of the obese patient that involves a focused weight history, evaluating diet and physical activity habits, and determining the patient's goals and readiness for treatment will be discussed. Assessing for secondary causes of weight gain and risk stratification based on a history, physical exam, and laboratory evaluation are also discussed. The role of other health professionals in a multidisciplinary approach to...

Diagnosing Diabetes

Curiously, minimal overlap between the two impaired states exists, with only 16 of individuals possessing both IFG and IGT, whereas 23 have IFG alone and 60 have IGT alone. Individuals with IGT have a 3.6-8.7 year chance of developing diabetes. These individuals frequently have the metabolic syndrome that will be discussed in detail in Chapter 5.

Interleukin6

Similar to observations for TNF-a, serum levels of IL-6 are also correlated with obesity-associated sleep apnea and have been implicated in its pathogenesis (104-107). Increased cytokine levels and associated sleep disturbances have been proposed to be consequences of metabolic syndrome (108).

Conclusion

Although historically adipocytes have been thought of basically as a reservoir of triglyceride, it is clear that AT can synthesize and secrete local as well as systemic mediators of metabolism. Thus, AT can be viewed as an endocrine organ. In lean individuals small adipocytes secrete adipokines, such as leptin and adiponectin, which promote healthy metabolic homeostasis. However, with the onset of obesity, a macrophage-mediated profile is observed in AT. Multiple cytokines, such as TNF-a and IL-6, are secreted, with some acting locally in AT and some being released into the circulation to act at distal sites. In addition, these cytokines can act locally to increase adipocyte release of fatty acids and to reduce adiponectin levels. Chronically, this altered adipokine secretion that accompanies obesity significantly contributes to the development of insulin resistance, metabolic syndrome, atherosclerosis, and diabetes.

Waistto Hip Ratio

Another anthropometric measure used for characterizing obesity phenotype is the waist-to-hip ratio (WHR). Several prospective epidemiological studies in the 1980s reported that WHR was a significant predictor of type 2 diabetes (6), coronary heart disease (46), cardiovascular disease, and death (10,11) in both men and women. Subsequently a plethora of studies have confirmed these initial observations. In particular, a recent large epidemiological study reported that WHR was a significant predictor of myocardial infarction in a sample of 27,000 men and women with a large range in age and adiposity from 52 countries. In fact it was reported that WHR was a stronger predictor myocardial infarction than BMI or waist circumference alone (47). Similar to waist circumference, WHR is a significant correlate of visceral fat in men (r 0.56-0.90) (32-35,48-50) and women (r 0.31-0.68) (29,32,35,48-50). Similarly, WHR is a significant correlate of abdominal subcutaneous fat (r 0.42-0.76) (3335,51)....

Body Diameters

Selected body diameters, commonly taken in the sagittal plane in the abdominal area, are associated with cardiovascular disease (53) and mortality (54). As with waist circumference and WHR, abdominal sagittal diameters are associated with visceral (29,31,32, 34,55,56) and abdominal subcutaneous fat (34,55). Although there is some variability in the literature, waist circumference and abdominal sagittal diameters generally show similar associations with visceral fat (sagittal diameters r 0.60-0.95, waist circumference r 0.66-0.97) (29,31,32,34,55,56), and abdominal subcutaneous fat (sagittal diameters r 0.92-0.95, waist circumference r 0.91) (34,55). Perhaps owing to simplicity of measurement, waist circumference is a more common measure of abdominal obesity in clinical settings. To date there are no established values for sagittal diameter that denote health risk and or abdominal obesity for a given individual or population. Fig. 7. Absolute fat loss across the body as measured using...

Weight Reduction

A study comparing low-carbohydrate diets (< 30 g day) with a low-fat, calorie-restricted diet in 132 severely obese patients with a mean BMI of 43 and a high prevalence of diabetes and the metabolic syndrome showed that after 6 months, the 43 patients still on the low-carbohydrate diet lost a mean of 5.8 kg, compared with 1.9 kg lost by the 36 patients still on the low-fat, low-calorie diet. 1. Assessing the patient by identifying any biological, genetic, or behavioral risk factors (including accurate measurements of height, weight, waist circumference, and BMI), and identifying the presence of any other behavioral mediators, such as barriers to weight loss, social support, or change of status or occupation. It is the duration of physical activity, not the intensity, that correlates with benefit. Physical activity will reduce abdominal fat and improve insulin sensitivity and overall Waist circumference

Obesity

BMI is not a perfect measure, however, because it does not consider body fat distribution. In women, a BMI less than 21 kg m2 is associated with the greatest protection from CHD. However, for some women, a BMI near 30 kg m2 may not be of serious concern if the increased body fat is in the pelvis and not in the abdomen.28 An increased waist circumference or an increased waist-to-hip ratio predicts morbidity and mortality from CHD.28 The risk of CHD rises steeply among women whose waist-to-hip ratio is higher than0.8.29 In general, the target BMI should be less than 25 kg m2 and the waist circumference should be less than 88 cm in women.12 Gradual and sustained weight loss is the goal.

Anti Obesity Drugs

Apart from diet, combination with pharmacological treatment with metformin or with weight-reducing agents has been used when required for further weight reduction. It has been reported that the combination of a low-calorie diet with metformin treatment induced greater reduction of body weight and visceral obesity in women with PCOS compared with a low-calorie diet and placebo treatment (136). Weight-reducing agents have been shown to increase the effect of lifestyle modification in reducing the incidence of type 2 diabetes in obese patients (137), and similar effects have been noted in women with PCOS. Sibutramine treatment alone and in combination with ethinyl estradiol and cyproterone acetate in obese women with PCOS has been found to have positive effects on clinical and metabolic risk factors for cardiovascular disease (decrease in waist-to-hip ratio, blood pressure, triglycerides, and insulin levels) (138). Furthermore, orlistat treatment in obese women with PCOS induced a more...

Subfractions

In addition to elevated fasting cholesterol, LDL cholesterol concentrations and inflammatory markers, increased large very-low-density lipoprotein (VLDL) particle concentration, increased chylomicron concentration, small particle size diameter, and elevated postprandial lipemia are associated with increased risk for cardiovascular disease. Lipids and lipoprotein subfractions (i.e., chylomicrons and VLDL, LDL, and HDL subfractions) were evaluated in one study in which 78 obese individuals were randomly assigned to a low-carbohydrate (< 30g d) or low-fat (< 30 energy from fat) diet for 6 mo (37). Forty percent of these participants had diabetes and 77 of those who did not have diabetes had metabolic syndrome. After 6 mo, participants in the low-carbohydrate group lost more weight than those in the low-fat group (-8.5 9.3 kg vs -3.5 4.9 kg). At 6 mo more participants in the low-carbohydrate group had detectable chylomicron concentrations. In addition, greater decreases in large VLDL...

Risk Determinants

The metabolic syndrome is soon to be elevated to a coronary artery disease equivalent. The presence of multiple risk factors can increase risk to greater than 20 in a 10-year period. From Type 2 Diabetes, Pre-Diabetes, and the Metabolic Syndrome The Primary Guide to Diagnosis and Management By R. A. Codario Humana Press Inc., Totowa, NJ

Clinical Trials

An interesting sidelight of this study was the presence of the metabolic syndrome in 69 of the 160 patients. Of these 69 patients, 32 received simvastatin and niacin. In the metabolic syndrome patients, combination therapy reduced LDL by 40 , triglycerides by 30 , and increased HDL by 26 . Of greater importance was the fact that patients with the metabolic syndrome had a significantly higher rate of atherosclerotic progression and a twofold higher rate of clinical events than patients that did not have the metabolic syndrome. Even in this high-risk population, treatment with simvastatin and niacin reduced CHD progression by 90 and clinical events by 40 . The combination of simvastatin and niacin did not significantly affect glucose and insulin levels.

Suggested Reading

Bjorntorp P. (2001) Heart and soul stress and the metabolic syndrome. Scand Cardiovasc J 35 172-177. From Type 2 Diabetes, Pre-Diabetes, and the Metabolic Syndrome The Primary Guide to Diagnosis and Management Written by R. A. Codario Humana Press Inc., Totowa, NJ Despres JP. (1998) The insulin resistance-dyslipidemic syndrome of visceral obesity effect on patient's risk. Obes Res 6 8S-17S. Ford ES, et al. (2002) Prevalence of the metabolic syndrome among US adults findings from the third National Health and Nutrition Examination Survey. JAMA 287 356-359. Ginsberg HS. (2003) Treatment for patients with the metabolic syndrome. Am J Cardiol 91 29E-39E. Grundy SM. (1997) Atherogenic dyslipidemia and the metabolic syndrome. Circulation 95 1-4. Kendall DM, Harmel AP. (2002) The metabolic syndrome, type 2 diabetes, and cardiovascular disease understanding the role of insulin resistance. Am J Manag Care 8(20 Suppl) S635-653. Lopez-Candales A. (2001) Metabolic syndrome X a comprehensive...

Serum lipids

Lipid management is also critically important in patients with the metabolic syndrome, because it maybe involved in most premature CHD in women.17 The metabolic syndrome exists in women when more than three of the following are present abdominal obesity (waist circumference > 88 cm), triglycerides above 150 mg dl or 17 mmol l, HDL cholesterol below 50 mg dl or 1.3 mmol l, blood pressure above 130 > 85 mmHg, and fasting glucose above 110 mg dl or 1.0 mmol l. Approximately 24 of American adults and 43 over the age of 60 have the metabolic syndrome.18 Women with the metabolic syndrome should be treated promptly with a diet of less than 7 saturated fat and dietary cholesterol less than 200 mg dl. They should be encouraged to change their diet to lower LDL by eating 5-10 g day of soluble fiber and 2 g day of plant stanols sterols, found in commercial margarines, in fruits and vegetables, or in the form of soy protein (25-40 g day) to replace animal food products. These patients should...

Adiponectin

Adiponectin, like leptin, has a critical role in whole-body metabolism and insulin sensitivity. This adipocyte hormone appears to significantly affect liver metabolism, where it suppresses hepatic glucose output (31). The antidiabetic drugs, TZDs, are known to increase adiponectin expression (32). Like leptin and TZDs, adiponectin has been shown to activate AMPK. In fact, in adiponectin-deficient mice, TZDs cannot activate AMPK in liver and muscle (33). Unlike leptin, adiponectin levels decrease with obesity (34). Such reduced levels of adiponectin have been suggested to significantly increase the risk of developing metabolic disorders such as metabolic syndrome, diabetes, and atherosclerosis. Studies of adiponectin polymorphisms pointed toward the importance of alterations in this protein in promoting deleterious metabolic disorders and obesity. Kissebah et al. used genetic mapping techniques to demonstrate that the chromosomal adiponectin gene location is strongly correlated with...

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