We have determined whether insulin-like growth factor I (IGF-I), a wide-spectrum growth factor with angiogenic actions, participates in vascular remodeling in the adult brain. IGF-I induces the growth of cultured brain endothelial cells through hypoxiainducible factor 1a and vascular endothelial growth factor, a canonical angiogenic pathway. Furthermore, the systemic injection of IGF-I in adult mice increases brain vessel density. Physical exercise that stimulates widespread brain vessel growth in normal mice fails to do so in mice with low serum IGF-I. Brain injury that stimulates angiogenesis at the injury site also requires IGF-I to promote perilesion vessel growth, because blockade of IGF-I input by an anti-IGF-I abrogates vascular growth at the injury site. Thus, IGF-I participates in vessel remodeling in the adult brain.
Using age and sex matched subjects, we con®rmed that GH levels were reduced in the obese while `GHdependent' total IGF-1 levels were not signi®cantly different between obese and control subjects. Similar results have been reported previously,21±23 but the contradictory ®ndings of increased or decreased IGF-1 levels found by others, although due in part to important clinical differences in age, sex and degree of obesity in the different studies, could be profoundly in¯uenced by nutritional factors.24,25 In addition, the discordant relationship between GH and IGF-1 in obesity may be also explained by the hyperinsulinaemia present in obesity:26 insulin may increase hepatic IGF-1 production.27 We found a positive correlation between the serum total IGF-1and insulin concentrations. A small portion of circulating IGF-1 is detected in the free or readily dissociable state, which is thought to be the metabolically active form.28,29 In the present
study, free/dissociable IGF-1 was assessed by a twosite immunoradiometric assay. The absolute values for free/dissociable IGF-1 in both obese and control groups were higher than those reported by Frystyk et al30 using RIA after separation by centrifugal ultra®ltration. The difference between our results and theirs are mostly likely due to the ages of subjects; older subjects have lower total and free IGF-1.30 However, the ratios of free to total IGF-1 in both groups are similar between the two assay systems. The amount of free/dissociable IGF-1 in serum is dependent on a complex interplay between the production rate and the concentrations of IGF-1 and IGFBPs. IGFBP-3 serves as major stabilizer of the circulating IGF pool. Circulating IGFBP-3 might undergo limited proteolysis, which results in smaller molecular weight IGFBP-3 fragments that have lower af®nity for IGF-1 than the intact binding protein. Consequently, the levels of free/dissociable IGF-1 are elevated in situations where IGFBP-3 proteolysis is increased.31 Bereket et al32 showed that acute mealrelated hyperinsulinaemia did not increase IGFBP-3 proteolysis. However, it is not known whether IGFBP- 3 proteolysis increases in obese subjects. In contrast, IGFBP-1 exhibits marked diurnal variation in relation to meals.32 Insulin is the principal regulator of IGFBP-1 and is reported to inhibit hepatic IGFBP-1 synthesis.33 Because of this property, IGFBP-1 is thought to play an important role in the regulation of IGF bioactivity. Therefore, the obesityrelated hyperinsulinaemia may decrease circulating concentrations of IGFBP-1, which can result in elevated free IGF-1 in obesity. In our study, circulating IGFBP-1 concentrations in obese subjects were lower than normal controls. There were also negative correlations between free IGF-1 and IGFBP-1. IGFBP-2 is the second most abundant IGF-binding protein in serum.34 Several reports have shown that IGFBP-2 is differentially regulated by GH and IGF-1.12,34 Administration of GH causes a reduction in IGFBP-2, while the serum concentration of IGFBP-2 is high in states of GH de®ciency.34 In normal adults, the infusion of IGF-1 results in suppression of GH and an increase in IGFBP-2.38 The dissociation of the effect of GH and IGF-1 in regulating IGFBP-2 suggests that IGFBP-2 and the ratio of IGFBP-2 to IGF-1 may be useful in detecting GH de®ciency. Thus, based on the well-known GH hyposecretion in obesity, the levels of IGFBP-2 and the ratio of IGFBP-2 to IGF-1 would be expected to be high. However, we found that IGFBP-2 concentrations and the ratios of IGFBP-2 to IGF-1 were suppressed in obese subjects. These ®ndings indicate that factors other than GH may be regulating serum IGFBP-2 in obesity. Clemmons et al34 showed that acute stimulation of insulin did not suppress IGFBP-2, but IGFBP-2 concentrations were elevated after prolonged fasting. This suggests that prolonged changes in insulin secretion may result in a signi®cant change of IGFBP-2. It appears, therefore that the obesity-related chronic hyperinsulinaemia may result in suppression of IGFBP-2 in obesity. We also found a negative correlation between IGFBP-2 and free IGF-1 concentrations. This indicates that IGFBP-2 can quantitatively in¯uence IGF-1 transport and may have some role in regulating IGF-1bioavailability in obesity, because serum IGFBP-2 are
more abundant than IGFBP-1 in adults.34
Standard DIO Protocol
• Male B6 mice housed at recommended density and fed a high fat diet from 6-18 weeks of age
• Control mice fed a 10 kcal% fat diet
• Body weights measured at least three times during
• Mice shipped to your facility according to your schedule
• Rapid initiation of standard DIO protocols
• Conserves your animal room space
• Mice fed the diet of your choice
• Select from several JAX® Mice strains susceptible to DIO
• Mice supplied according to your schedule
• DIO mice available from either our Bar Harbor, ME or Sacramento, CA facilities
Obesity and Metabolic syndrome
Obesity is an increasingly significant U.S. health problem. Over 4 decades, the prevalence of obesity (body mass index [BMI] > 30) has increased from 13 percent to 31 percent in adults and the prevalence of overweight (BMI 25-29.9 kg/m2) has increased from 31 percent to 34 percent.1 Concurrent increases occurred in adolescents and children. Obesity is especially common in African Americans, some Hispanic populations, and Native Americans and some health sequelae reflect similar ethnic differences. Obesity is more common in women, and overweight is more common in men. Obesity is a risk factor for major causes of death, including cardiovascular disease, numerous cancers, and diabetes, and is linked with markedly diminished life expectancy. Osteoarthritis, gall bladder disease, sleep apnea, respiratory impairment, diminished mobility, and social stigmatization are associated with obesity.
Steps for Treating overweight and Obesity in the Primary care setting
Step 1: Measure height and weight so that you can estimate your patient's BMI
If pounds and inches are used
BMI = weight (pounds) x 703 / height squared (inches2)
Classification of BMI:
??Underweight <18.5 kg/m2 ??Normal weight 18.5–24.9 kg/m2 ??Overweight 25–29.9 kg/m2 ??Obesity (Class 1) 30–34.9 kg/m2 ??Obesity (Class 2) 35–39.9 kg/m2 ??Extreme obesity (Class 3) 40 kg/m2
Step 2: Measure waist circumference
??Excess abdominal fat is an independent risk factor for diabetes, dyslipidemia,
hypertension, and cardiovascular disease. ??It is particularly useful in patients who are categorized as normal or overweight. ??It is not necessary to measure waist circumference in individuals with BMIs 35 kg/m2
since it adds little to the predictive power of the disease risk classification of BMI. ??High Risk waist circumference :
o Men = > 40 inches, and
o Women = > than 35 inches.
Classification of Overweight and Obesity by BMI, Waist Circumference and Associated Disease Risk
Step 3: Assess co morbidities for the "Assessment of Risk Status."
The following diseases/risk factors place patient at a high absolute risk for subsequent mortality, and they require aggressive treatment: 1) Established coronary heart disease, other atherosclerotic diseases, DM-2, and sleep apnea 2) Three or more of the following are considered high risk,
b. cigarette smoking,
c. high low-density lipoprotein cholesterol (LDL-C),
d. low high-density lipoprotein cholesterol (HDL-C),
e. impaired fasting glucose,
f. family history of early cardiovascular disease, and age (male 45 years, female 55 years).
3) Other disease/conditions that denote high absolute risk but are not generally life threatening are:
c. stress incontinence, and
d. gynecological abnormalities such as amenorrhea and menorrhagia also increase risk.
Step 4: Decide if the patient should be treated?
Weight loss therapy is recommended for patients: 1) With a BMI > 30 and 2) For BMI between 25-29.9 3) Or a high risk waist circumference and 2 or more risk factors.
Step 5: Is the patient ready and motivated to lose weight? Evaluation of readiness should include the following:
1) reasons and motivation for weight loss, 2) previous attempts at weight loss, 3) support expected from family and friends, 4) understanding of risks and benefits, 5) attitudes toward physical activity, 6) time availability, and 7) Potential barriers to the patient's adoption of change.
If the answer is "yes" to treatment, decide which treatment is best using the following table.
A Guide to Selecting Treatment
Goals of therapy:
Goals of therapy are to reduce body weight and maintain a lower body weight for the long term; the prevention of further weight gain is the minimum goal. 1) An initial weight loss of 10 percent of body weight achieved over 6 months is a recommended target. 2) The rate of weight loss should be 1 to 2 pounds per week.
3) Greater rates of weight loss do not achieve better long-term results.
4) After the first 6 months of weight loss therapy, the priority should be weight maintenance achieved through combined changes in diet, physical activity, and behavior.
5) Further weight loss can be considered after a period of weight maintenance.
1) Caloric intake should be reduced by 500 to 1,000 calories per day (kcal/day) from the current level this will produce the recommended weight loss of 1-2 pounds per week..
2) The diet should be low in calories, but it should not be too low (less than 800 kcal/day). Diets lower than 800 kcal/day have been found to be no more effective than low-calorie diets in producing weight loss. They should not be used routinely, especially not by providers untrained in their use.
3) In general, diets containing 1,000 to 1,200 kcal/day should be selected for most women; 4) A diet between 1,200 kcal/day and 1,600 kcal/day should be chosen for men and may be appropriate for women who weigh 165 pounds or more, or who exercise regularly. 5) If the patient can stick with the 1,600 kcal/day diet but does not lose weight you may want to try the 1,200 kcal/day diet. 6) If a patient on either diet is hungry, you may want to increase the calories by 100 to 200 per day. Included in Appendix D are samples of both a 1,200 and 1,600 calorie diet.
7) Long-term changes in food choices are more likely to be successful when the patient's preferences are taken into account and when the patient is educated about food composition, labeling, preparation, and portion size.
8) Although dietary fat is a rich source of calories, reducing dietary fat without reducing calories will not produce weight loss. 9) Frequent contact with practitioners during the period of diet adjustment is likely to improve compliance.
Increasing physical activity has direct and indirect effects: 1) Increases the energy expenditure and helps in weight loss. 2) Reduces the risk of heart disease more than that achieved by weight loss. 3) Physical activity should be increased gradually in an obese individual to avoid any
injury. 4) All adults should set a long term goal to accumulate at least 30 minutes or more of moderate intensity physical activity on most and preferably all, days of the week. Check Guide to physical activity appendix -1
Strategies, based on learning principles such as reinforcement, that provide tools for overcoming barriers to compliance with dietary therapy and/or increased physical activity are helpful in achieving weight loss and weight maintenance.
Specific strategies include 1) self-monitoring of both eating habits and physical activity, 2) stress management, 3) stimulus control, 4) problem solving, 5) contingency management, 6) cognitive restructuring, and7) social support.
Check guide to behavior change appendix 2
Drugs can be used as an adjunct to diet, physical activity changes and behavior therapy in some patients. The decision to add a drug should be made after consideration of all potential riska and benefits and only after all behavioral options have been exhausted. Currently, there use is limited to those patients:
1) who have a BMI of > 30, or 2) >27 if concomitant obesity related disease or risk factors exist. 3) It should be considered in patients in whom life style changes of 6 months
duration did not promote any weight loss. Drugs currently approved by FDA are:
Weight loss surgery should be reserved for patients in whom efforts at medical therapy have failed and who are suffering from the complications of extreme obesity. Gastrointestinal surgery (gastric restriction [vertical gastric banding] or gastric bypass [Roux-en Y]) is an intervention weight loss option for motivated subjects with acceptable operative risks. An integrated program must be in place to provide guidance on diet, physical activity, and behavioral and social support both prior to and after the surgery. Surgery is an option for the following patients:
1) BMIs >= 40 or 2) >= 35 with comorbid conditions.
Gastric Bypass Surgery Complications: 14-Year Follow-Up
Review the Weekly Food and Activity Diary with the patient. 1) Remind the patient that record-keeping has been shown to be one of the most successful behavioral techniques for weight loss and maintenance. 2) Write down the diet, physical activity, and behavioral goals you have agreed on at the bottom.
Give the patient copies of the 1) dietary information 2) the Guide to Physical Activity (appendix 1) 3) the Guide to Behavior Change (appendix 2) 4) the Weekly Food and Activity Diary
Enter the patient's information and the goals you have agreed on in the Weight and Goal Record 1) It is important to keep track of the goals you have set and to ask the patient about them at the next visit to maximize compliance. 2) Have the patient schedule an appointment to see you or your staff for follow up in 2 to 4 weeks.
Several studies have demonstrated an association between metabolic syndrome and increased intima-media thickness, higher urinary albumin excretion and left ventricular hypertrophy in hypertensive subjects without manifest vascular disease.25,26,29 In this population, presence of metabolic syndrome was also associated with an increased amount of cardiovascular events.
Obesity is severe excess body fat. Complications include cardiovascular disorders, diabetes mellitus, many cancers, cholelithiasis, fatty liver and cirrhosis, osteoarthritis, psychologic disorders, and premature death. Diagnosis is based on body mass index (BMI—calculated from height and weight) and waist circumference. Blood pressure, fasting blood glucose, and lipid levels should be measured. Treatment includes exercise, dietary and behavior modification, and sometimes drugs or surgery.
Prevalence of obesity in the US is high and is increasing. Age-adjusted prevalence was 22.9% in 1988 to 1994, increasing to 30.5% in 1999 to 2000. Prevalence of overweight (less severe excess body fat) increased from 55.9 to 64.5% during this period. Prevalence is more than twice as high at age 55 than at age 20. Obesity is twice as common among women with a lower socioeconomic status as among those with a higher status. Prevalence among black and white men does not differ significantly, but it is higher among black women than white women. More than half of black women aged = 40 yr are obese; > 80% are overweight. Obesity and its complications cause as many as 300,000 premature deaths each year, making it second to cigarette smoking as a cause of death.
Almost all cases of obesity result from chronic overeating plus inadequate exercise and a genetic predisposition. Genetic, metabolic, and other determinants usually play minor roles.
Genetic determinants: Heritability of BMI is about 33%. Genetic factors may affect the many signaling molecules and receptors used by parts of the hypothalamus and GI tract to regulate food intake ( see Sidebar 1: Obesity and the Metabolic Syndrome: Pathways Regulating Food Intake ). Rarely, obesity results from abnormal levels of peptides that regulate food intake (eg, leptin) or abnormalities in their receptors (eg, melanocortin-4 receptor). Genetic factors also regulate energy expenditure, including BMR, diet-induced thermogenesis, and nonvoluntary activity–associated thermogenesis. Genetic factors may play a larger role in determining body fat distribution, particularly abdominal fat (see Obesity and the Metabolic Syndrome: Metabolic Syndrome), than the amount of body fat
Environmental determinants: Overweight results much more often from excess caloric intake than from slow metabolism. Diets high in fat and refined carbohydrates promote weight gain; those high in fresh fruit and vegetables, fiber, and complex carbohydrates minimize weight gain. A sedentary lifestyle promotes weight gain.
Regulatory determinants: Maternal obesity, maternal smoking, intrauterine growth restriction, drugs, and, rarely, brain damage and endocrine disorders can disturb weight regulation. About 15% of women permanently gain = 20 lb with each pregnancy. Infant or childhood obesity makes weight loss in later life more difficult.
Drugs, including corticosteroids, lithium, traditional antidepressants (tricyclics, tetracyclics, and monoamine oxidase inhibitors [MAOIs]), benzodiazepines, and antipsychotic drugs, often cause weight gain. Rarely, brain damage caused by a tumor (especially a craniopharyngioma) or an infection (particularly affecting the hypothalamus) can stimulate consumption of excess calories. Hyperinsulinism due to pancreatic tumors may result in weight gain. Hypercortisolism due to Cushing's syndrome produces predominantly abdominal obesity. Hypothyroidism is rarely a cause of substantial weight gain. Psychologic and behavioral determinants: Psychologic and behavioral factors are believed to be limited largely to two pathologic eating patterns: binge eating disorder and night-eating syndrome. Similar but less extreme patterns, classified as eating disorders not otherwise specified, probably contribute to excess weight gain in more people.
Binge eating disorder is consumption of large amounts of food quickly with a subjective sense of loss of control during the binge and distress after it (see Mood Disorders). This disorder does not include compensatory behaviors, such as vomiting. Prevalence is 1 to 3% among both sexes and 10 to 20% among people entering weight reduction programs. Obesity is usually severe, large amounts of weight are frequently gained or lost, and pronounced psychologic disturbances are present.
The night-eating syndrome consists of morning anorexia, evening hyperphagia, and insomnia. At least 25 to 50% of daily intake occurs after the evening meal. About 10% of people seeking treatment for severe obesity may have this disorder. However, nocturnal eating contributes to excess weight gain in many other people.
Insulin resistance, dyslipidemias, and hypertension develop, ultimately predisposing to diabetes mellitus and coronary artery disease. Complications are more likely if fat is concentrated abdominally. Obesity is also a risk factor for nonalcoholic fatty liver, which may lead to cirrhosis. Obstructive sleep apnea can result if excess fat in the neck compresses the airway during sleep. Breathing stops for moments, as often as hundreds of times a night (see Sleep Apnea: Obstructive Sleep Apnea). This disorder, often undiagnosed, can cause loud snoring and excessive daytime sleepiness. In the obesity-hypoventilation syndrome (Pickwickian syndrome), impaired breathing leads to hypercapnia, reduced sensitivity to CO2 in stimulating respiration, hypoxia, cor pulmonale, and risk of premature death. This syndrome may occur alone or secondary to obstructive sleep apnea.
Degenerative arthritis, particularly affecting weight-bearing joints, may result from obesity. Skin disorders are common; increased sweat and skin secretions, trapped in thick folds of skin, are conducive to fungal and bacterial growth, making intertriginous infections especially common. Being overweight probably predisposes to cholelithiasis, polycystic ovary syndrome, gout, deep venous thrombosis and pulmonary embolism, and many cancers.
Obesity leads to social, economic, and psychologic problems as a result of prejudice, discrimination, poor body image, and low self-esteem.
In adults, overweight or obesity is determined by BMI, defined as weight (kg) divided by height (m)2. BMI of 25 kg/m2 to 29.9 kg/m2 indicates overweight; BMI = 30 kg/m2 indicates obesity (see Table 1: Obesity and the Metabolic Syndrome: Body Mass Index (BMI) ). BMI is age- and race-specific; its use is limited in children and the elderly. In children and adolescents, overweight is BMI = 95th percentile based on age- and sex-specific CDC growth charts. Asians, Japanese, and many aboriginal populations have a lower cut-off (23 kg/m2) for overweight. Large muscle mass without excess body fat may result in a high BMI.
In whites, a waist circumference > 93 cm (> 36.3 in), particularly > 101 cm (> 39.4 in), in men or > 79 cm (> 30.8 in), particularly > 87 cm (> 33.9 in), in women is a risk factor for complications of obesity.
Body composition analysis: Body composition—the percentage of body fat and muscle—is also considered when obesity is diagnosed. The percentage of body fat can be estimated by measuring skinfold thickness or determining mid upper arm area (see Undernutrition: Physical examination). The appropriate percentage is based on the patient's demographic group. Ranges are higher for women and the elderly.
Skinfold thickness estimates body fat stores. On average, about 50% of adipose tissue is beneath the skin. This figure can vary in the elderly because of age-related atrophic changes. Skinfold thickness (consisting of a double layer of skin and subcutaneous fat) can be measured with a special caliper at subscapular, posterior triceps (triceps skinfold [TSF]), lower thoracic, iliac, and abdominal sites. A single measurement of the TSF is acceptable; this area is easily accessible and usually edema-free. Typical ranges for TSF are 0.5 to 2.5 cm (average, 1.2 cm) in healthy men and 1.2 to 3.4 cm (average, 2.0 cm) in healthy women. TSF varies with age. In the elderly, the subscapular region is more reliable.
Bioelectrical impedance analysis (BIA) can estimate percentage of body fat simply and noninvasively. BIA estimates percentage of total body water directly; percentage of body fat is derived indirectly. BIA is most reliable in healthy people and people with a limited number of chronic disorders that do not change the percentage of total body water (eg, moderate obesity, diabetes mellitus). Whether measuring BIA poses risks in people with implanted defibrillators is unclear.
Underwater (hydrostatic) weighing is the most accurate method for measuring percentage of body fat. Costly and time-consuming, it is used more often in research than in clinical care. To be weighed accurately while submerged, a person must fully exhale beforehand.
Imaging procedures, including CT, MRI, and dual-energy x ray absorptiometry (DEXA), can also estimate the percentage and distribution of body fat but are usually used only for research.
Other testing: Obese patients should be screened for sleep apnea with an instrument such as the Epworth Sleepiness Scale. If the respiratory distress index is > 6, a polysomnographic sleep study should be done. Fasting blood glucose and plasma lipids should be measured routinely in obese patients.
Exercise, healthful eating, and behavior changes, which improve general health, are recommended. They can control weight even in healthy people and help prevent obesity and diabetes mellitus. Also, exercise decreases the risk of cardiovascular disorders; dietary fiber decreases the risk of colon cancer and cardiovascular disorders.
Untreated, obesity tends to progress. After weight loss, most people return to their pretreatment weight within 5 yr. The probability and severity of complications are proportional to the severity of obesity and, independently of sex, to the waist circumference. In men, mortality and morbidity are worse, probably because abdominal adiposity is greater. However, most people treated for obesity are women, who are less likely to develop its complications.
Weight loss of even 5 to 10% seems to improve health, increase longevity, and decrease risk of complications. In obstructive sleep apnea, a much greater weight loss is required.
Support from health care practitioners, peers, and family members and various structured programs can help with weight loss and weight maintenance.
Weight loss requires dietary modification and increased physical activity, usually with behavioral therapy. Sometimes drugs or surgery is required.
Diet: Low-fat and healthful diets, modest calorie restriction (to 1000 to 1400 kcal/day), and the substitution of some protein for carbohydrate appear to have the best long-term outcome. Fresh fruits and vegetables and fiber should be substituted for refined carbohydrates and processed food, and water for soft drinks or juices. Foods with a low glycemic index (see Table 1: Nutrition: General Considerations: Glycemic Index of Some Foods ) and marine fish oils or monounsaturated fats derived from plants (eg, olive oil) reduce the risk of cardiovascular disorders and diabetes.
Diets that require atypical eating habits should be avoided. They are unlikely to be maintained, and weight increases when the patient resumes previous poor eating habits. Calorie restriction to < 1200 kcal/day cannot be sustained, but such diets are sometimes needed to achieve rapid short-term weight loss (eg, before surgery or for obstructive sleep apnea). Diets of < 800 kcal do not produce greater weight loss and are less well tolerated.
Physical activity: Exercise increases energy expenditure, BMR, and diet-induced thermogenesis. Exercise also seems to regulate appetite to more closely match caloric needs. Other benefits include increased insulin sensitivity, improved plasma lipid profile, reduced blood pressure, better aerobic fitness, and improved psychologic well-being. Strengthening (resistance) exercises increase muscle mass. Because muscle tissue burns more calories at rest than fat tissue, increasing muscle mass produces lasting increases in BMR. Exercise that is interesting and enjoyable is more likely to be sustained.
Behavioral therapy: Behavioral therapy aims to improve eating habits and physical activity level. Rigid dieting is discouraged in favor of healthy eating. Common-sense measures include avoiding high-calorie snacks, choosing healthful foods when dining out, eating slowly, and substituting a physically active hobby for a passive one. Social support, cognitive therapy, and stress management may help, particularly during the lapses usually experienced during any long-term weight loss program.
Drugs: Drugs are indicated if BMI is > 30 or if BMI is > 27 and there are complications (eg, hypertension, insulin resistance). Most weight loss due to drug treatment is modest (5 to 10%) and occurs during the first 6 mo; drugs are more useful for maintaining weight loss. Premenopausal women taking systemically acting drugs for weight control should use contraception.
Sibutramine is a centrally acting appetite suppressant that produces dose-related weight loss. The usual starting dose is 10 mg po once/day; the dose can be decreased to 5 mg or increased to 15 mg. Common adverse effects are headache, dry mouth, insomnia, and constipation; the most common serious one is hypertension. Cardiovascular disorders, particularly poorly controlled hypertension, are contraindications.
Orlistat inhibits intestinal lipase, decreasing fat absorption and improving blood glucose and lipids. Because orlistat is not absorbed, systemic effects are rare. Flatus, oily stools, and diarrhea are common but tend to resolve during the second year of treatment. A dose of 120 mg po tid should be taken with meals that include fat. A vitamin supplement should be taken at least 2 h before or after taking orlistat. Malabsorption and cholestasis are contraindications; irritable bowel syndrome and other GI disorders may make orlistat difficult to tolerate.
OTC weight-loss drugs are not recommended. Some (eg, caffeine, ephedrine, guarana, phenylpropanolamine) may be marginally effective, but their adverse effects outweigh their advantages. Others (eg, brindleberry, l carnitine, chitosan, pectin, grapeseed extract, horse chestnut, chromium picolinate, fucus vesiculosus, ginkgo biloba) have not been shown to be effective and may have adverse effects.
Surgery: Surgery is indicated if exercise, diet, and behavioral therapy are ineffective in patients who are very obese (BMI > 40) or have serious complications. Weight loss (usually 40 to 60 kg) is proportional to the severity of obesity; losses appear to be maintained for the long term. The Roux-en-Y gastric bypass is most effective. Adjustable gastric bands placed via a laparoscope, a reversible procedure, are also effective.
Weight loss after surgery is rapid at first, slowing gradually over 2 yr. Many complications of obesity resolve; mood, self-esteem, body image, activity levels, and interpersonal and vocational effectiveness improve. If experienced surgeons perform surgery, preoperative and operative mortality is usually < 1% and operative complications are < 10%. Chronic complications depend on the procedure and may include vomiting, diarrhea, and dumping syndrome (see Gastritis and Peptic Ulcer Disease: Surgery). Vitamin and iron deficiencies may occur but are rare if the diet is nutritionally balanced and supplements are taken.
Obesity is a particular concern in children and the elderly.
Children: Childhood obesity is even more worrisome than adult obesity. For obese children, complications are more likely because they are obese longer. About 20 to 25% of children and adolescents are overweight or obese. Risk factors for obesity in infants are low birth weight and maternal obesity, diabetes, and smoking. After puberty, food intake increases; in boys, the extra calories are used to increase protein deposition, but in girls, fat storage is increased.
For obese children, psychologic and musculoskeletal complications can develop early. Respiratory, metabolic, and hepatic complications may also develop. Some musculoskeletal complications, such as slipped capital femoral epiphyses, occur only in children. The risk of cardiovascular, respiratory, and other obesity-related complications increases during adulthood.
The risk of obesity persisting into adulthood is low if obesity first develops during infancy, 25% if between 6 mo and 5 yr, > 50% if after 6 yr, and > 80% if during adolescence and a parent is obese.
In children, preventing further weight gain, rather than losing weight, is a reasonable goal. Diet should be modified, and physical activity increased. Increasing general activities and play is more likely to be effective than a structured exercise program. Participating in physical activities during childhood may promote a lifelong physically active lifestyle. Drugs and surgery are avoided but, if complications of obesity are life threatening, may be warranted.
Measures that control weight and prevent obesity in children may benefit public health the most. Such measures should be implemented in the family, schools, and primary care programs.
The elderly: With aging, body fat increases and is redistributed to the abdomen, and muscle mass is lost, largely because of physical inactivity. The risk of complications depends on body fat distribution (increasing with a predominantly abdominal distribution), history of obesity, and associated sarcopenia. Increased waist circumference better predicts morbidity and mortality risk in the elderly than BMI. For the elderly, mortality risk is greater when BMI decreases; thus, increased physical activity is preferable to dietary restriction unless mobility is restricted. Physical activity also improves muscle strength, endurance, and overall well-being. Activity should include strengthening and endurance exercises. Use of weight-loss drugs has not been evaluated in the elderly; surgery is best avoided.
Table 1.. Diet composition
Next table | Figure and tables index
Nutrient (% by mass) HFD D12451 Control
Protein 23.7 20.9
Carbohydrate 41.4 67
Starches 8.5 44.8
Sugars 21.8 4.7
Fat 23.6 3.8
Fat (% by energy) 44.7 9.2
Fiber 5.8 4.1
Minerals 5.2 4.2
Energy content (kcal/g) 4.98 4.07
Food quotient 0.83 0.93
Diet Source Lard Soybean Oil Control Unknown
87.70% 12.30% 100%
Saturated 39.2 14.4 19.9
Monounsaturated 45.1 23.3 37
Polyunsaturated 11.2 57.9 43.3
Capric acid (C10:0) 0.1 0 0
Lauric acid (C12:0) 0.2 0 1.1
Myristic acid (C14:0) 1.3 0 5.3
Palmitic acid (C16:0) 23.8 9.7 11.7
Stearic acid (C18:0) 13.5 3.5 1.8
Myristoleic acid (C14:1) 0 0 0.4
Palmitoleic acid (C16:1) 2.7 0 4.3
Oleic acid (C18:1) 41.2 25.2 32.3
Gadoleic acid (C20:1) 1 0.2 0
Linoleic acid (C18:2) 10.2 55.2 31.6
Linolenic acid (C18:3) 1 6.4 3.9
Arachidonic acid (C20:4) 0 0 6.7
Clupanodonic acid (C22:5) 0 0 1.1
Composition for lard and soybean oil were taken from the U.S. Department of Agriculture National Nutrient Database for Standard Reference, Release 15 (August 2002), http://www.nal.usda.gov/fnic/.
Tingginya kadar lemak di jaringan adiposa merupakan ciri penderita obesitas. Dampak utamanya adalah gangguan pada sistem regulasi hormon. Salah satunya adalah disfungsi pada hormon pertumbuhan (GH/Growth Factor) yang diproduksi oleh kelenjar pituitary di otak. Proses metabolisme dari GH dipengaruhi oleh Insulin-like Growth Factor-1 (IGF-1). Dalam kerjanya, IGF-1 mesti berikatan terlebih dahulu dengan reseptornya di membran sel, yaitu reseptor IGF-1. Pada penderita obesitas, jumlah reseptor IGF-1 di tiap sel adiposanya berkurang. Karena reseptor IGF-1 juga merupakan reseptor untuk insulin (Gambar 1), maka kekurangan reseptor ini juga berakibat negatif pada regulasi hormon insulin.
Tubuh merespons kekurangan reseptor IGF-1 dengan cara memproduksi secara berlebih hormon insulin sehingga terjadi hiperinsulinemia. Hiperinsulinemia menyebabkan reseptor IGF-1 di sel selain sel adiposa menjadi rusak. Kerusakan terjadi karena pengaturan kerja insulin menjadi kacau untuk sel-sel tersebut.
Reseptor insulin atau reseptor IGF-1 merupakan glikoprotein dengan struktur tetramerik, yaitu terdiri dari empat rantai polipeptida (22) yang distabilkan oleh ikatan disulfida. Terikatnya insulin pada rantai reseptor ini menyebabkan perubahan konformasi atau bentuk reseptor dan mengaktifkan fosforilasi dari rantai. Perubahan ini mengaktifkan tirosin kinase, suatu enzim yang terikat pada ujung rantai. Enzim tirosin kinase yang teraktifkan akan memicu transmisi sinyal intraseluler yang memfosforilasi senyawa-senyawa protein lain, salah satunya adalah insulin-receptor substrate -1 (IRS-1). Fosforilasi dari IRS-1 akan menghasilkan sinyal sekunder yang berperan dalam menstimulasi sistem transportasi glukosa sehingga akhirnya glukosa dari darah dapat dimasukkan ke dalam sel dalam jumlah banyak (Gambar 2).
Dengan adanya kerusakan pada reseptor insulin atau reseptor IGF-1, maka ikatan antara insulin-reseptor tidak terjadi. Aktivitas tirosin kinase juga hilang dan transmisi sinyal tidak terjadi. Hal ini mengakibatkan keseimbangan glukosa dan glikogen terganggu walaupun terdapat insulin dalam tubuh. Glukosa dalam tubuh akan terakumulasi di darah sehingga mengakibatkan Diabetes melitus tipe 2 (Non-Insulin Dependent Diabetes).
This study was designed to investigate its effects on insulin -like growth factors (IGFs) and their binding protein-3 (IGFBP-3 ) proteins secretion and also apoptosis induction in the human prostate cancer cell line, PC-3. We report insulin-like growth factor-binding protein-3 (IGFBP-3 ) as an effector of quercetin-induced apoptosis in human prostate cancer cell lines in a p53 -independent manner. 
In summary, this is an initial description of the successful therapeutic use of IGFBP-3 [?] as a cancer therapy in vivo, and shows that combination treatment of IGFBP-3 [?] and RXR ligand has a synergistic effect on apoptosis induction leading to substantial inhibition of prostate cancer [?] xenograft growth. In this study, the endogenous expression of IGF-binding protein (IGFBP)-3 was examined in human retinal endothelial cells (HRECs), the direct effects of IGFBP-3 on HRECs were evaluated, and the possible involvement of IGFBP-3 in mediating the growth inhibitory effects of SST receptor (SSTR ) agonists in HRECs was assessed. BACKGROUND: The insulin-like growth factors IGF-I and IGF-II and their major binding protein IGFBP-3 influence the growth of breast cancer cells in vitro. IGF-1 and IGFBP-3 may influence risk of prostate cancer [?] through their roles in cellular growth, metabolism and apoptosis, however, epidemiologic results have been inconsistent. 
Insulin-like growth factors (IGFs) reduce IGF-binding protein-4 (IGFBP-4 ) concentration and stimulate IGFBP-3 independently of IGF receptors in human fibroblasts and epidermal cells. 
Interactions between insulin-like growth factor-I (IGF-I) and the system of plasminogen activators and their inhibitors in the control of IGF-binding protein-3 production and proteolysis in human osteosarcoma cells. CONCLUSION: A high IGFBP-3 level might affect LUTS by decreasing the bioavailability of IGF-1 or independent of IGF-1 by up-regulating apoptosis, and, thus, limiting its growth promoting effects on the prostate. 
BACKGROUND: Insulin -like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3 ) appear to influence the growth of breast cancer cells in vitro, and epidemiological studies suggest higher serum IGF-I levels increase the risk of breast cancer. CONCLUSIONS: FSH enhances the action of IGF-I in human granulosa cells by inhibiting the secretion of IGFBP-1 and the binding activity of IGFBP-3 by stimulating the proteolysis of IGFBP-3 . Expression of the cDNA clones in mammalian tissue culture cells results in the secretion into the culture medium of ALS activity that can form the expected complex with IGF-I and IGF-binding protein-3 . Also, our results suggest that serum levels of testosterone, IGF-1 and IGFBP-3 might not be significantly associated with known prognostic factors of clinically localized prostate cancer [?] in Korean men. In human RCC cells, we recently showed that insulin -like growth factor I (IGF-I) has growth-promoting effects regulated by IGF-binding protein 3 (IGFBP-3 ). TGF-beta is also a potent growth inhibitor in human breast cancer cells in vitro and regulates IGFBP-3 production in different cell systems, suggesting that IGFBP-3 is a major anti-proliferative factor and a key element for TGF-beta -induced growth inhibition in human breast cancer cells. We conclude that increases in IGF-I and intact IGFBP-3 levels are positively associated with the presence of CaP in this group of patients with low to moderately elevated PSA , and that their measurements in relation to PSA may help improve diagnostic discrimination between BPH and prostate cancer. Prostate specific antigen (PSA ) is an insulin-like growth factor (IGF) binding protein-3 (IGFBP-3 ) protease found in seminal plasma and produced by prostatic epithelial cells (PC-E) in vivo. 
Transfection of p53 negative T47D breast cancer cells to express IGFBP-3 leads to induction of the apoptotic protein bax and an increase in sensitivity to ionising radiation. 
We conclude that such agents as dexamethasone, 1,25-(OH)2D3, and PTH differentially regulate IGFBP-3 secretion in human osteosarcoma cells in vitro. In this study, we show that IGFBP-3 binds to ECM deposited by human breast epithelial and cancer cells and neonatal human fibroblasts. Insulin-like growth factor binding protein-3 mediates 1 alpha,25-dihydroxyvitamin d(3) growth inhibition in the LNCaP prostate cancer cell line through p21 /WAF1 . OBJECTIVE: Insulin like growth factor 1 (IGF-1 ) is recognized as a potent mitogen for many cancer cell lines and there is good evidence that lung cancer cells produce both IGF-1 and insulin like growth factor binding protein 3 (IGFBP-3 ). Serum IGFBP-3 levels were not significantly associated with increased risk of disease, and adjustment for IGFBP-3 had little effect on the association between IGF-1 levels and risk of prostate cancer. Apart from GH regulation the hormonal control of IGFBP-3 production is not well established and although the liver is considered to be the main source of circulating IGFBP-3 , there are no in vitro studies of the effect of both insulin and IGFs on the IGFBP-3 produced in human hepatoma cells. IGF-1 and IGFBP-3 gene variants influence on serum levels and prostate cancer [?] risk in African-Americans. Human growth hormone at 10 micrograms/l decreased the amount of IGFBP-4 but had no effect on the IGFBP-3 level in the conditioned medium of low density cultures of TE89 cells and human bone cells derived from rib. 
Based on the above findings, we conclude that the production of both IGFBP-3 and IGFBP-4 is regulated in bone cells and that local and systemic agents may modulate the responsiveness of bone cells to IGFs by regulated secretion of IGFBP-3 and IGFBP-4 . The present data support the hypothesis that the combination of TNFalpha and IFN-gamma with retinoic acid exert their anti-proliferative effect on HSG cells by reducing the mitogenic effect of IGF-I due to a shift in IGF-I from the free to the IGFBP-3 -bound form. 
We conclude that endogenous IGFBP-3 directly inhibits proliferation of human intestinal smooth muscle cells by activation of TGF-betaRI and Smad2 , an effect that is independent of its effect on IGF-I-stimulated growth. 
These results suggest that IGFs may regulate their own activity in breast cancer cells, preventing IGFBP-3 proteolysis by a mechanism that is not receptor mediated and does not require IGF-IGFBP interaction. These results provided circumstantial evidence that IGFBP-3 may mediate RA and TGF-beta2 growth inhibitory actions in human breast cancer cells. Osteogenic protein-1 stimulates production of insulin-like growth factor binding protein-3 nuclear transcripts in human osteosarcoma cells. Insulin-like growth factor binding protein 3 mediates retinoic acid- and transforming growth factor beta2-induced growth inhibition in human breast cancer cells. In a previous study, weight gain, insulin growth factor-1 (IGF-1 ) and insulin growth factor binding protein-3 (IGFBP-3 ) were increased in rats fed suboptimal levels of energy and administered 0.1 mg/100 g of body weight of recombinant human growth hormone (rhGH). 
BACKGROUND: Insulin-like growth factor binding protein-3 (IGFBP-3 ) is the chief binding protein for insulin -like growth factors 1 and 2 (IGF-1 and IGF-2 ). Circulating insulin -like growth factor-I (IGF-I) and its major binding protein IGF binding protein-3 (IGFBP-3 ) have been associated with increased risk of premenopausal breast cancer, although risk estimates varied broadly. OBJECTIVE: Insulin -like growth factor (IGF-I) and IGF binding protein-3 (IGFBP-3 ) are GH-dependent and their concentrations have been used in the diagnosis of GH deficiency. 
On Hs578T cells, IGFBP-3 bound to caveolin-1 and beta1-integrins, enhancing their aggregation, the recruitment of focal adhesion kinase, and the activation of MAPK [?] . In addition to IGFBP-2 , a 35-45 kDa IGFBP identified by immunoprecipitation as IGFBP-3 was variably present on ligand blots of control conditioned medium and was consistently found in medium from cells treated with IGF-I or IGF-II (ED50 3 ng/mL) but not with insulin at 2 mg/mL. 
The aim of the present study was to evaluate the mediating role played by obesity on the relationship of free insulin -like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3 ) with muscle strength and physical performance. Serum Insulin -like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3 ) in growing preterm infants on enteral nutrition. Since IGFBP-3 can control IGF-1 bioavailability, the lowered IGFBP-3 could explain in part the increased risk of prostate cancer in AA men. The IGF-induced increase in proliferation of HL-60 promyeloid cells was inhibited by soluble IGF-binding protein-3 (500 ng/ml) when these cells were stimulated with 10 ng/ml of either IGF-I (53 +/- 8%) or IGF-II (59 +/- 8%), but not with des-IGF-I (3 +/- 1%). 
Serum levels of IGF-I and especially IGF-II and their major growth hormone dependent binding protein (IGFBP-3 ) were significantly reduced, although growth hormone secretion after a pharmacological stimulus was normal. 
The use of recombinant human (rh)GH has been reported to alleviate hypoglycaemia in non-islet cell tumour hypoglycaemia, and the mechanism is thought to relate to GH-mediated increments in serum levels of IGF-binding protein-3 (IGFBP-3 ), thereby reducing the bioavailability of IGF-II . Induction of IGF-BP3 gene expression by wild-type but not mutant p53 is associated with enhanced secretion of an active form of IGF-BP3 capable of inhibiting mitogenic signalling by the insulin-like growth factor IGF-1 . IGF-binding protein-3 (IGFBP-3 ) is a multifunctional protein that regulates the potent mitogenic and antiapoptotic effects of IGF-I and IGF-II and exerts bioactivity independent of modulating IGF receptor activation. After i.v. injection into adult rats, human insulin-like growth factor-binding protein-3 (hIGFBP-3 ) forms 150-kDa complexes with excess endogenous rat acid-labile subunit (ALS ) within 2 min (Lewitt et al., 1993, Endocrinology 133:1797). Here we show that recombinant human IGFBP-3 inhibits 125I-transforming growth factor (TGF)-beta1 binding to the type V TGF-beta receptor (Mr 400,000) in mink lung epithelial cells. We speculate that PSA may serve to modulate IGF function within the reproductive system or in prostate cancer by altering IGF-IGFBP-3 interactions. Herein, we report that IGFBP-3 mRNA and protein were induced upon growth factor deprivation in primary and immortalized human esophageal cells through mechanisms requiring p53 -independent de novo mRNA transcription and protein synthesis. 
Human PTC secreted transforming growth factor-beta1 (TGF-beta1 ) and the AB heterodimer of platelet-derived growth factor (PDGF-AB) in a time-dependent fashion and the augmentation of cortical fibroblasts mitogenesis, collagen synthesis and IGFBP-3 secretion induced by PTC-CM was replicated by exogenous TGF-beta1 and PDGF . The ability of IGFBP-3 to inhibit tumor growth has been demonstrated in many cancers including prostate cancer [?] (PCa [?] ). Expression of insulin-like growth factor binding protein-3 (IGFBP-3 ) in human keratinocytes is regulated by EGF and TGFbeta1. 
In our study, high levels of IGFBP-3 but not IGF-I were associated with an increased risk of prostate cancer [?]. Multiple studies suggest that higher IGF-I and/or lower IGFBP-3 serum levels are positively associated with prostate cancer [?] risk. 
Greater levels of IGF-I and lower levels of IGFBP-3 have been associated with an increased risk of prostate cancer [?] in many studies. 
These findings confirm that IGFBP-3 is essential for TNF-alpha -induced apoptosis in PC-3 cells and that this IGFBP-3 effect includes the inactivation of Bcl-2 through serine phosphorylation. In summary, these data support a novel mechanism for TNF-alpha -induced mesangial cell apoptosis mediated by IGFBP-3 and present regulation of pThr308 activity as a novel mechanism underlying IGFBP-3 action. Insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3 ) binds to fibronectin (FN ): demonstration of IGF-I/IGFBP-3 /fn ternary complexes in human plasma. Transferrin binds insulin-like growth factors and affects binding properties of insulin-like growth factor binding protein-3 . In conclusion, OP-1 treatment stimulates IGFBP-3 expression in human osteoblastic cells by a mechanism that largely promotes the production of IGFBP-3 nuclear transcripts, a process that requires de novo protein synthesis, and overrides an OP-1-induced targeted degradation of IGFBP-3 steady-state mRNA. IGFBP-3 has an important role in cancer cell apoptosis mediated via the nuclear retinoid X receptor alpha (RXRalpha ). Since IGFBP-3 failed to stimulate PI 3-kinase [?] activity in MDA-MB 231 breast carcinoma cells, its effects in MCF-7 cells could be considered as cell-type-specific. 
By using quantitative real time-RT-PCR before and after mRNA amplification the insulin-like growth factor binding protein-3 (IGFBP-3 ) gene expression was shown to be down-regulated in three out of five cases and DD3 was up-regulated in cancer tissues in all cases. 
Functional cloning of IGFBP-3 from human microvascular endothelial cells reveals its novel role in promoting proliferation of primitive CD34+CD38- hematopoietic cells in vitro. Insulin-like growth factor-binding protein 3 (IGFBP3 ) is also regulated by HIF1 but works in a completely different manner by modulating the activities of insulin-like growth factors and inducing apoptosis. Overexpression of a constitutively active Akt but not a constitutively active MEK-1 [?] rescued H460 cells from apoptosis induced by single or combined treatment of Ad-IGFBP3 and SCH66336. These results demonstrate that the serum of pregnant women, post-operative patients and patients with cancer contain circulating proteases which cause fragmentation of IGFBP-3 but have little effect on IGFBP-1 . In summary, these studies have shown that rat IGFBP-1 [?] is phosphorylated on two sites by reactions that occur in different secretory organelles and that similar to human IGFBP-3 , but unlike human IGFBP-1 , phosphorylation does not affect its affinity for IGF-I [?] . Finally, IGFBP-3 -induced Ewing cell apoptosis relies on both IGF-1 -dependent and -independent pathways. In contrast, IGF-II at an equimolar dose had little effect on proteolysis of recombinant human IGFBP-3 , whereas excess IGF-II reproducibly inhibited recombinant human IGFBP-3 proteolysis by pregnancy serum. 
CONCLUSIONS: Ethnic differences in IGFBP-3 and associated IGF-II levels may affect the inter-relationships of IGFs and their binding proteins and need to be considered when interpreting IGF data on growth and metabolism. 
On the other hand the decrease during IGF-I administration and concomitant suppression of GH secretion may denote either that GH activity is not completely blocked in this syndrome or that there are additional mechanisms regulating IGFBP-3 synthesis. 
Parallel application of IGFBP-3 had borderline inhibitory effects while the addition of 40ng/mL of IGFBP-5 enhanced the chemotactic effect of IGF-I on MPC. 
Changes in media IGFBP-3 [?] protease activity were examined further to explain the observed effects of TNF-alpha on production and destruction of IGFBPs in media. 
Effects of the IGF-I/IGFBP-3 complex on GH and ghrelin nocturnal concentrations in low birth weight children. Conclusions These findings indicate that the IGF-I/IGFBP-3 complex appears to have opposite effects on circulating GH and ghrelin concentrations in low birth weight children, suggesting that, in addition to its known negative feed-back effect on GH, IGF-I and/or IGFBP-3 may have a positive feed-back effect on ghrelin . These effects on cell survival are paralleled by acute effects on integrin receptor function; IGFBP-3 and -5 were able to either enhance or inhibit cell attachment in the presence of fibronectin . Estrogen treatment of estrogen receptor -positive MCF-7 cells enhanced acid-activatable IGFBP-3 proteolysis in the cell-conditioned medium but had no effect on proteolytic activity in estrogen receptor -negative Hs578T cells. The OP-1 stimulated induction of IGFBP-3 nuclear transcript and mRNA expression was dependent on de novo protein synthesis. 
Retinoic acid and basic fibroblast growth factor had only minor effects on IGFBP-3 and dexamethasone had no effect. 
The aim of this work was to investigate interactions between IGF-I and the PA/PAI system and their influence on IGFBP-3 production and proteolysis in this cell model. 
Although hOB cells secrete an acid-activated IGFBP-3 protease and an IGF-dependent IGFBP-4 protease , GC had little effect on these protease activities and did not alter degradation of the secreted IGFBPs. 
MMP-19 promotes proliferation of keratinocytes by cleaving the insulin-like-growth factor binding protein-3 , thereby causing the release of IGF-1 , which is a potent growth factor for these cells. 
IGFBP-3 activates TGF-beta receptors and directly inhibits growth in human intestinal smooth muscle cells. Previous studies have demonstrated that these inhibitory effects of RA, and the combination of TNFalpha and IFN-gamma are associated with increased accumulation of IGFBP-3 in the culture medium of HSG cells. 
Metabolic acidosis in humans results in a significant decrease in serum IGF-1 concentration without a demonstrable effect on IGF binding protein 3 , and is related to a resistance to the hepatocellular action of growth hormone. 
It is thought that PSA cleaves insulin-like growth factor binding protein-3 (IGFBP-3 ), providing increased local levels of IGF-1 , leading to tumor growth. Due to their essential roles in development we examined levels of insulin -like growth factor-I (IGF-I) as well as its main binding protein (IGFBP-3 ) in a group of AT patients. OBJECTIVE: The aim of the study was to determine whether the serum concentration of insulin -like growth factor-I (IGF-I) and its binding protein-3 (IGFBP-3 ) correlates with the mineral metabolism markers in children with idiopathic decrease in bone mass. 
Insulin growth factor 3 (IGFBP3 ) negated the invasive and adhesive effects of transferrin . BACKGROUND: This study aims to determine the relation between anabolic hormones, Insulin -like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3 ), growth parameters, and clinical status in prepubertal cystic fibrosis (CF) patients. Identification of upstream stimulatory factor binding sites in the human IGFBP3 promoter and potential implication of adjacent single-nucleotide polymorphisms and responsiveness to insulin . Recombinant human IGFBP-3 was cleaved by PSA , then incubated with 125I-IGF-I or -II in the presence of varying concentrations of unlabelled peptides, and then cross-linking electrophoresis and densitometric analysis were performed. 
On the other hand, one of the functions of prostate-specific antigen (PSA ) is to cleave IGFBP-3 . In summary, this study demonstrates the existence of considerable IGFBP-1 production from the liver during insulinopenia and the complete blocking of splanchnic IGFBP-1 production and increases in serum levels of IGF-I by insulin despite no effect on IGFBP-3 levels. Conclusions Seven days treatment with IGF-I/IGFBP-3 complex enhanced overnight insulin sensitivity and reduced GH levels, but there was no effect on glomerular hyperfiltration or albumin excretion rates. 
The formation of the 150-kD IGFBP complex with 125I-recombinant human IGFBP-3 is impaired in tumor serum. 
Taken together, these results indicate that the principal IGFBP secreted by Swiss 3T3 cells is probably the N-glycosylated IGFBP-3 . These results demonstrate antagonism of steroid stimulated proliferation by an IGF binding protein and are compatible with the hypothesis that antiestrogen-induced accumulation of IGF-BP3 in the conditioned media of MCF7 cells contributes to the cytostatic action of these drugs. 
IGF1 and IGFBP3 tagging polymorphisms are associated with circulating levels of IGF1 , IGFBP3 and risk of breast cancer. Our data indicate that common variants in the IGF1 and IGFBP3 genes are associated with differences in circulating levels of IGF1 and IGFBP3 and with breast cancer risk. 
Thus, in contrast to findings with some cell types, IGFBP-3 expression in cervical cells is associated with augmented IGF-1 signaling and cell proliferation and correlates with the timing of cellular immortalization. 
Consistent with a causal relationship between IGFBP-3 expression and enhanced IGF-1 responses, we found that early-passage cells could be converted to the late-passage, IGF-1 -responsive phenotype by preincubation with IGFBP-3 . Both vitamin D analogues inhibited IGF-1 stimulated growth of MCF-7 cells and enhanced the production of IGFBP-3 as determined by Western-ligand blotting. 
OBJECTIVE: Insulin-like growth factor-1 (IGF-1 ) and its principal binding protein-3 (IGFBP-3 ) are central in the mediation of the effect of growth hormone, and the IGF system has been reported to play a role in the pathogenesis of childhood leukemia. 
The circulating levels of IGF-1 and IGFBP-3 stimulated by the reduction in BMD and IGF-1 secretion are increased in order to restore bone formation. PATIENTS AND METHODS: Using a quantitative sandwich immunoassay technique (ELISA) (Quantikine, Human IGF-1 and IGFBP-3 , R&D Systems), we measured the concentration of IGF-1 and its major binding protein IGF-binding protein 3 (IGFBP-3 ) in serum drawn at the time of diagnosis from 77 Binet stage A CLL patients. 
The results of this study suggest that a marked reduction of serum IGF-1 seen in burn patients is associated with a significant reduction of IGFBP-3 , a major IGF-1 binding protein in human serum. 
This study examines the serum concentrations of DHEA-sulfate (DHEAS), IGF1 and IGF1 binding protein-3 (IGFBP3 ) in 20 patients with CFS and in 12 normal controls. 
As determined by ligand blot of CM from confluent cells 72 h after the addition of peptides to serum-free medium, IGF-I and IGF-II potently stimulated IGFBP-3 in both cell lines, but otherwise IGFBP regulation in the two cells diverged. This suggests that the decrease in serum IGFPB-3-bound IGF-I and IGFBP-3 -bound IGF-II might have a negative effect for growth promotion and other biological effects of IGF-I and IGF-II . By binding to its receptor, GH1 stimulates the production of IGF-I and its binding protein IGFBP3 , resulting in the regulation of cell proliferation, differentiation and apoptosis. Our aim was to study the prognostic value of growth hormone (GH ) -stimulated insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3 ) generation in patients with compensated [group 1 (N = 8) with a Child-Pugh (CP) score of 5-8] and decompensated postnecrotic liver cirrhosis [group 2 (N = 7) with a CP score of 9-12]. 
IGFBP-3 levels (as assessed by immunoblot analysis as well as by 125I-IGF II ligand blotting) decreased markedly during pregnancy in both patients, suggesting that the placenta rather than pituitary GH regulates IGFBP-3 proteolysis in human pregnancy. 
Stimulation of the 150-kilodalton insulin-like growth factor-binding protein-3 ternary complex by continuous and pulsatile patterns of growth hormone (GH) administration in GH-deficient patients. 
Growth hormone stimulates IGF-I secretion and that of its major binding protein IGFBP-3 . We have previously shown that the major correlates of growth following growth hormone (GH) therapy in growth hormone-deficient (GHD) children are changes in circulating insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3 ), suggesting a synergistic interaction between IGF-I and IGFBP-3 (1). 
CEE increased the proportional contribution of IGFBP-1 [?] and IGFBP-4 to total IGFBP [?] binding and decreased the IGFBP-3 [?] contribution. Tumour-derived IGF-II has a higher than normal molecular weight (big 'IGF-II ') and an impaired ability to form the normal ternary 150 kD complex with IGF binding protein-3 (IGFBP-3 ) and the acid-labile subunit (ALS ). We also demonstrated that large amounts of one of the IGFBP-3 APs and small amounts of ALS were coimmunoprecipitated with IGFBP-3 from human serum. 
Because their previous in vitro studies indicated that hIGFBP-3 only bound to ALS in the presence of IGF-I , and because little free IGF-I is present in plasma, the authors postulated that IGF-I had been mobilized to the circulation to saturate the 150-kDa hIGFBP-3 complexes. We report that ALS mRNA is expressed in term fetal rat liver at 30% of the levels in adult liver, that radioiodinated rat ALS is not proteolyzed by incubation with fetal rat serum, and that sufficient functional ALS is present in fetal rat serum to form 150-kDa complexes with recombinant human IGFBP-3 . Androgen receptor-negative PC3 cells secrete IGFBP-3 , IGFBP-4 , and IGFBP-5 , as determined by immunoprecipitation of the serum-free conditioned medium with specific IGFBP antibodies. Processed ADAM28s digested insulin-like growth factor binding protein-3 (IGFBP-3 ) in both free and complex forms with IGF-I or IGF-II , and the digestion was prevented with EDTA, 1,10-phenanthroline, KB-R7785, tissue inhibitor of metalloproteinases-3 (TIMP-3 ), and TIMP-4 . TGF-beta regulated the endogenous IGFBP-3 levels in these RCC cells as neutralizing anti-TGF-beta(1-3) antibodies strongly reduced the basal IGFBP-3 level. In some systems, IGFBP-3 mediates the effects of TGF-beta . The 125I-IGFBP-3 affinity-labeled putative receptor can only be detected in cells expressing the type V TGF-beta receptor, but not in cells lacking the type V TGF-beta receptor. The 125I-IGFBP-3 affinity labeling of the putative receptor and IGFBP-3 -induced growth inhibition as measured by DNA synthesis in these cells is blocked by a TGF-beta1 peptide antagonist. 
We also demonstrated that IGFBP3 [?] is an important effector of the apoptosis induced by N- and C-terminally truncated p53 [?] , such that knockdown of IGFBP3 [?] by using an IGFBP3 [?] neutralizing antibody or IGFBP3 [?] small interfering RNA partially rescues the cell death induced by N- and C-terminally truncated p53 [?] . These results suggest that one mechanism by which PKCalpha produces its antiapoptotic activity in GBM cells is by suppressing the p53-mediated activation of IGFBP3 . In this study we have shown that the level of IGFBP-3 protein expression in colonic epithelial cells correlates with the p53 status of the cells; wildtype p53 cells secrete higher levels of IGFBP3 protein than mutant p53 cell lines. These results suggest that IGFBP-3 enhances the p53-dependent apoptotic response of colorectal cells to DNA damage. In summary, turning p53 in two foil neoplastic cell models induced IGFBP-3 expression and increased apoptosis during serum starvation, an effect inhibited by insulin-like growth factor-I treatment and specific IGFBP-3 blockade. Serum- and EGF -stimulated cells produced higher levels of about 50K BP-53 , and an additional peak of immunoreactivity at 150K was present in serum-stimulated, but not EGF -stimulated, samples. 
This finding is consistent with experimental data that indicate that IGFBP-3 can inhibit cellular proliferation and induce apoptosis independent of IGF-I and the IGF-I receptor . In this report, we demonstrate the role of IGFBP-3 as a mediator of apoptosis induced by TNF-alpha and elucidate the process involved in its signaling mechanism. 
TNF-alpha -induced apoptosis was prevented by cotreatment with IGFBP-3 neutralizing antibodies or IGFBP-3 -specific antisense thiolated oligonucleotides. 
These results suggest that IGFBP-3 enhances apoptosis by reducing bioavailability of ligands for the IGF-I receptor and suggest that modulation of IGFBP-3 expression by ICI contributes to apoptosis induced by this compound. We report that accumulation of IGFBP-3 in the conditioned media of MCF-7 cells is increased over control values in the presence of TNF-alpha . Anti-sense IGFBP-3 oligo at 10 microg/mL significantly inhibited apoptosis induced by 100 ng/mL TNF-alpha , serum-free conditions, or high (25 mM) glucose. Here we demonstrate that IGFBP-3 mediates p53-induced apoptosis during serum starvation using two foil neoplastic cell models: one which introduces p53 activity and one which eliminates it. 
The presence of IGF-I/IGFBP-3 /FN ternary complexes in human plasma was demonstrated by coimmunoprecipitation of IGFBP-3 and [(125)I]IGF-I with anti-FN monoclonal antibody. 
Compared with estrogen receptor (ER)-positive samples, ER -negative breast cancer cell lines and tumors express higher levels of IGFBP-3 . CONTEXT: GH insensitivity syndrome (GHIS), Laron syndrome, is characterized by severe short stature, high serum GH levels, and very low serum IGF-I and IGF-binding protein-3 (IGFBP-3 ) levels associated with a genetic defect of the GH receptor . Western and ligand blot analyses of RPE cell conditioned medium confirmed that IGF-I stimulated VEGF and IGFBP-3 secretion. rhVEGF stimulated IGFBP-3 secretion in an IGF-I- and HIF-1alpha -independent manner, whereas rhIGFBP-3 attenuated IGF-I-induced VEGF secretion. Plasminogen binds the heparin-binding domain of insulin-like growth factor-binding protein-3 . Therefore, we hypothesize that the mechanism of action by which IGFBP-3 and 1,25-(OH)(2)D(3) induce growth inhibition is the induction of p21 /WAF1 because IGFPB-3 immuno-neutralizing antibodies completely abrogate the 1,25-(OH)(2)D(3) mediated up-regulation of p21 /WAF1 and growth inhibition. 
In addition, 125I-IGFBP-3 affinity-labeled TbetaR-V in Mv1Lu cells is immunoprecipitated by antibodies to LRP-1 and TbetaR-V. 
No IGFBP-3 was secreted by any culture but 24-kDa IGFBP-4 was found in 3 out of 10 normal and 5 out of 10 cancer tissues. 
We now describe the purification of full-length recombinant ADAM 12-S and demonstrate that it cleaves insulin-like growth factor binding protein-3 (IGFBP-3 ). An antisense STAT-1 oligonucleotide abolished the IGF-independent cell apoptosis induced by IGFBP-3 . The IGFBP-3 -promoted apoptosis in the presence of IFN-gamma could also be abrogated by blockade of the mTOR pathway with its pharmacological inhibitors, LY294002 or rapamycin. 
However, insulin-like growth factor binding protein 3 mRNA was the most strongly differentially expressed gene in both arrays and this confirmed its upregulation in urine of bladder cancer patients (n=157, P<0.01). Matrix metalloproteinase 3 cleaves insulin-like growth factor-binding protein-3 (IGFBP-3 ) into six fragments, four of which bind heparin-Sepharose (Fowlkes, J. L., Enghild, J. J., Suzuki, K., and Nagase, H. (1994) J. Biol. Chem. 269, 25742-25746). 
Suppression of IGFBP-3 internalization by TfR1 blockade inhibited IGFBP-3 -induced apoptosis. ADAM28 is activated by MMP-7 (matrilysin-1) and cleaves insulin-like growth factor binding protein-3 . These data suggest that IGFBP-3 is a target of transcriptional repression by DeltaNp63alpha and that this repression represents a mechanism by which tumors that overexpress p63 may be protected from apoptosis. IGFBP-3 mediates p53-induced apoptosis during serum starvation. 
Cellular SLPI levels negatively influenced the anti-proliferative and pro-apoptotic insulin-like growth factor-binding protein-3 expression. IGFBP-3 also inhibited the growth of PLC/PRF/5 cells and of Hep G2 cells. 
Several cell lines derived from normal or tumor cells responsive to IGF-I were used to show that IGFBP-3 -stimulated PTPase is cell type-specific. 
By plasmon resonance experiments, we show that the isolated hemopexin-like domain is able to bind to the insulin-like-growth factor binding protein-3 . In the present study, the changes in circulating IGF-1 and its binding protein IGFBP-3 were determined in adult patients with active inflammatory bowel disease (IBD) in order to assess the effect of this inflammatory condition on the IGF system. 
Accordingly, the slow increase in serum IGF-II , which paralleled that of IGFBP-3 , could indicate that serum IGF-II levels mainly depend on the concentration or binding site availability of IGFBP-3 . IGF-I and IGFBP-1 had no effect on IGFBP-3 binding to FN . This data suggests that IGFBP-4 proteolysis is regulated in a novel manner by IGFBP-3 which is dependent on the relative proportions of the different binding proteins and the levels of IGFs. 
Our results indicate that IGF-BP3 may link p53 to potential novel autocrine/paracrine signalling pathways and to processes regulated by or dependent on IGF(s), such as cellular growth, transformation and survival. 
IGFBP-3 and nuclear localization signal mutant IGFBP-3 stimulated the activation of the plasminogen activator inhibitor-1 promoter but was not additive with TGF-beta , suggesting that this end point is not a direct marker of the IGFBP-3 effect on cell proliferation. Data from this study suggest that changes in IGFBP-3 and, to a lesser extent, IGF-I are the major correlates of growth rate, and that down-regulation of the IGF-I receptor may have relatively little influence on growth rate compared with changes in IGFBP-3 and IGF-I. The effect of TNF-alpha on Bcl-2 serine phosphorylation was blocked by IGFBP-3 antisense oligomers. IGFBP-3 levels were inversely related to the number of IGF-I binding sites on erythrocytes and to the K(d) of the IGF-I receptor on PBMCs. These experiments showed that fibronectin enhanced the inhibitory effect that low concentrations of IGFBP-3 had on matrix synthesis. 
Nuclear localization of exogenously added IGFBP-3 was rapid, occurring within 15 min, inhibited by co-incubation and extracellular sequestration with IGF-I, and dependent on the transferrin -binding C-terminal peptide region of IGFBP-3 . Football training decreased significantly the exercise-stimulated GH levels all along the football season but did not have any significant effect on IGF-1 levels or on basal IGFBP3 levels. 
IL-6 infusion had no effect on GH binding protein, IGFBP-3 , and acid-labile subunit levels. rhIL-6 levels similar to the levels found after strenuous exercise induced a typical exercise-associated GH-->IGF-I axis response (increase GH , decreased IGF-I, and elevated IGFBP-1 ). Such an effect could perhaps explain the reduction in the incidence of mammary carcinoma observed in the Multiple Outcomes of Raloxifene Evaluation study probably due to the direct antiestrogenic activity of raloxifene on mammalian tissue and/or its indirect activity increasing SHBG levels or modifying the IGF-1 /IGFBP-3 ratio. IGF binding protein (IGFBP)-3 mRNA and secreted IGFBP-3 in conditioned media were increased in NF cocultured with KK compared with NF but markedly reduced in KF cocultured with KK or normal keratinocytes (NK). In SCL-1 cells, IGF-I and IGF-II were virtually identical in stimulating a mean 200% increase in IGFBP-3 (n = 5 experiments). 
To further examine the utility of IGF-F1-1 as an IGF-1 antagonist we tested its ability to inhibit IGFBP-2 and IGFBP-3 binding to IGF-1 , (125)I-IGF-1 binding to IGF-1Rs and to block IGF-1 induced Akt activation, cell cycle changes and [(3)H]thymidine incorporation in MCF-7 cells. 
We suggest that after GH treatment IGF-II is sequestered by stimulated IGFBP-3 in association with a pre-existing acid-labile subunit to form high molecular weight complexes which prevent IGF-II gaining access to tissues receptors through which it exerts its hypoglycaemic effects. 
It is unclear whether in humans IGFBP-3 production is directly regulated by GH or mediated via IGF-I. RESULTS: 1,25D decreased mRNA levels of the growth stimulatory IGFBP-2 and induced IGFBP-3 mRNA in LNCaP and C4-2 cells. 
Exogenous addition of IGFBP-3 markedly blocked IGF-I and IGF-II -stimulated cell growth of KYN-2 and HepG2 cells, and moderately stimulated that of KIM-1 and HAK-1B cells, but no growth of the KYN-1, KYN-3 and HAK-1A cell lines was observed. 
In addition, the PI3 kinase [?] inhibitor, LY294002, upregulates IGFBP-3 expression but downregulates IGF-I and IGF-II , indicating that PTEN controls IGFBP-3 and IGFs by an Akt-dependent pathway. 
Prostate-specific antigen (PSA ) enzymatically cleaves IGFBP-3 into fragments (BP3-FR). Interestingly, amongst the six IGFBPs, only IGFBP-3 was upregulated by PTEN , whereas IGFBP-4 and -6 were reduced. 
Other growth-inhibitory and apoptosis-inducing agents such as tumor necrosis factor-alpha (TNF-alpha ) and the tumor suppressor gene p53 also induce IGFBP-3 . Like TGF-beta1 , natural and recombinant IGFBP-3 stimulated the time- and dose-dependent phosphorylation of TGF-betaR1 as well as Smad2 and Smad3 . However, unlike other cell types where IGFBP-3 exerts antiproliferative effects, neither wild-type nor GGG mutant IGFBP-3 alone affected cell proliferation or EGFR activity. 
The IGFBP-3 promoter activity assay and Western immunoblotting demonstrate that PTEN regulates IGFBP-3 at the transcriptional level. We demonstrate that insulin, insulin-like growth factor (IGF)-1, and IGF-2 induce expression of HIF-1alpha , which is required for expression of genes encoding IGF-2 , IGF-binding protein (IGFBP)-2 and IGFBP-3 . In vitro and in situ experiments demonstrated that PAPP-A cleaves insulin-like growth factor-binding protein (IGFBP)-2, but not IGFBP-3 , in the conditioned medium of C2C12 myoblasts. Circulating levels of insulin -like growth factor-I (IGF-I) and its principal binding protein IGFBP-3 are reduced, whereas those of the inhibitory binding protein, IGFBP-1 , tend to be high in children and adolescents with type 1 diabetes mellitus (T1DM). 
Insulin and GH have both been shown to stimulate hepatic production of IGF-I and these results suggest that insulin may also be involved in the regulation of IGFBP-3 and ALS in vivo. 
We have previously shown that IGF-I cell binding was enhanced in the presence of IGFBP-3 at low pH and now show that this binding is IGFBP -mediated as it is inhibited by Y60L-IGF-I, a mutant with reduced affinity for the IGF receptor (IGF-IR), and unaffected by insulin , which binds but not IGFBPs. Serum concentrations of IGF-I and IGF-II were significantly lower and insulin and C-peptide levels significantly increased in CF compared with healthy controls whereas IGFBP-3 serum concentrations were similar, with comparable IGF-I/IGFBP-3 and decreased IGF-I/IGFBP-2 and IGF-II /IGFBP-2 molar ratios. 
Finally, we showed that IGFBP-3 [?] inhibited insulin -stimulated glucose uptake in omental but not s.c. adipose tissue explants. 
Insulin -like growth factor I (IGF-I) and IGF binding protein 3 (IGFBP-3 ) are measured to diagnose disorders of the somatotropic axis in children and adults. 
A mutant form of IGFBP-3 [?] that does not translocate to the nucleus or bind retinoid X receptor-alpha [?] was able to inhibit insulin -stimulated glucose uptake, indicating that nuclear translocation and retinoid X receptor-alpha [?] binding are not essential for this IGFBP-3 [?] action. In summary, we report a methylation-dependent USF binding site influencing the basal and insulin -stimulated transcriptional activity of the IGFBP3 promoter. Autoradiographs measuring IGFBP-3 protease activity demonstrated that purified PSA cleaved IGFBP-3 , yielding a cleavage pattern identical to that of seminal plasma. NTX treatment reduced fasting insulin levels in patients with EO (P < .05) and restored a normal GH response to GHRH without affecting IGF-1 and IGFBP-3 levels. Western ligand blotting of column effluent samples revealed 37-/43-kDa IGFBP-3 primarily in the 150-kDa complex in serum and a marked reduction in the amount of the 37-/43-kDa IGFBP in PF. 
[125I] IGFBP substrate zymography combined with fragment blotting showed that the 1,10-phenanthroline-sensitive 50-kDa protease activity purified by chromatofocusing also cleaved IGFBP-3 and -5. In this study we report that exogenous and endogenous IGFBP-3 inhibit production of an IGF inducible IGFBP . In the presence of excess (250 ng/ml) IGF-I, IGFBP-3 had approximately 20-fold reduced potency in inhibiting 29-31 kDa IGFBP . IGFBP-1 was expressed only in the hepatocytes and IGFBP-3 mRNA was modestly expressed within the kidney (developing nephrons, collecting system mesenchyme), and liver (hepatocytes). Whilst all the characterized enzymes tested also fragmented IGFBP-3 and plasmin cleaved IGFBP-1 , none of these acted in the same way as either circulating or cell line-derived proteolytic activity. 
This IGFBP co-migrated with a pure IGFBP-3 standard. 
Levels of proteolytic activity directed against insulin-like growth factor binding protein 3 (IGFBP-3 ) and the distribution of phosphorylated isoforms of IGFBP-1 were assessed in matched sample sets of maternal serum, coelomic fluid and amniotic fluid from 21 pregnancies at 6-12 weeks gestation. Serum was analysed for free and total IGF-I and -II, free plus dissociable IGF-I, IGFBP-1 , -2 and -3, IGFBP-1 -bound IGF-I as well as IGFBP-3 proteolysis. IGFBP-3 ternary complex formation and IGFBP-1 phosphovariants were analysed by non-denaturing PAGE. 
IGFBP-3 synthesis was stimulated by exogenous IGF-1 . Having an IGF-1 genotype other than homozygous for the 19-repeat allele was associated with higher IGFBP-3 levels (1,945 versus 2,052 ng/mL). 
Multiple logistic regression analysis revealed that the IGFBP-3 level was associated with a ninefold (95% confidence interval 2.6-31) higher risk of carotid plaque formation compared with LDL cholesterol or IGF-1 levels. Prostaglandin E2 (PGE2) stimulates IGF-1 production by articular chondrocytes and we determined whether the eicosanoid could regulate IGFBP-3 and, as such, act as a modifier of IGF-1 action at a different level. CONCLUSION: The difference in serum IGF-1 concentrations between irradiated subjects and controls was greater than the difference in serum IGFBP3 . CONCLUSION: Both raloxifene and oral testosterone increased serum testosterone, but raloxifene significantly decreased serum IGF-1 levels without affecting IGFBP-3 . The metabolic half-life of circulating IGF-1 is prolonged by its binding to IGFBP-3 . The insulin-like growth factor 1 (IGF1 ) and its binding protein IGFBP3 (insulin-like growth factor binding protein 3 ) play a pivotal role during the growth and development of tissues. 
It is concluded that (1) the CNS maturational events which change the regulation of serum IGF-1 and IGFBP-3 are induced by the pubertal increase in sex steroids in a nonreversible way and (2) the high adrenal steroid levels present in CAH induce a nonreversible activation of the GH-IGF-1 axis and of the GnRH pulse generator. 
The increase of IGF-1 and IGFBP-3 levels was seen also in control groups B and C when compared with control group A. IGF-1 and IGFBP-3 were positively correlated with age both in patients and in controls. 
The bioavailability of IGF1 is regulated by the binding protein IGFBP3 . Furthermore, IGF-1 (CA)19 genotypes were significantly associated with lower IGFBP-3 serum levels (P = 0.003). 
The increase in IGF-1 and IGFBP-3 levels was seen also in control groups B and C when compared with control group A. IGF-1 and IGFBP-3 were positively correlated with age both in patients and in controls. 
Ligand blot analysis revealed a significant increase in IGF-II binding to a 29-31 kilodalton region where positive staining with specific antibodies to IGFBP-3 or IGFBP-1 was observed. 
Serum concentrations of IGFBP-3 are regulated by growth hormone (GH ) and IGF-1 levels. IGFBP-2 and IGFBP-3 tended to be more highly expressed in cirrhotic liver and IGFBP-1 was more highly expressed in normal liver, although there were no significant differences. 
Tumor big IGF-II and IGF-II were equally effective in forming the 150-kDa complex with purified IGFBP-3 and 125I-labeled alpha subunit. 
Since IGFBP-3 must bind IGF-I or IGF-II to form a complex with the acid-labile subunit (alpha-subunit), we have used ternary complex formation from [125I]alpha-subunit as a measure of IGF binding to serum IGFBP-3 . These experiments showed that IGF-I and IGF-II bind to IGFBP-3 with affinities of 4-5 x 10(9) M(-1) and similar binding kinetics. Neither IGF-I nor IGFBP-3 was associated with risk in postmenopausal women and serum IGF-II concentration was not associated with risk in pre- or postmenopausal women. 
However, IGFBP-3 does inhibit the stimulation of growth by IGF-II . Possibly, the interaction of IGFBP-3 with heparin or heparin-like structures in vivo can lead to the selective release of IGF-II from this binding protein. The sum of IGF-I and IGF-II (expressed as nmol/l) correlated with IGFBP-3 ; r = 0.47 in controls and 0.60 in diabetics. The IGFBP-3 gene is coexpressed with the IGF-2 gene in proliferative cytotrophoblasts of the embryonic placenta. Postoperative samples showed a shift in IGF-II which became increasingly associated with IGFBP-3 in both low and high molecular weight complexes. In control subjects, 89.8 +/- 4.47% of serum total IGF-I and 77.3 +/- 9.4% of serum total IGF-II were bound to serum IGFBP-3 . In patients with GHD, the mean serum IGFBP-3 -bound IGF-I and IGFBP-3 -bound IGF-II were 8.63 +/- 8. As a result, serum IGFBP-3 -bound IGF-I and IGFBP-3 bound IGF-II , the main reservoirs of serum IGFs, were severely affected. 
Finally, the estimation of serum IGFBP-3 -bound IGF-I, or the percentage of total IGF-I and IGF-II bound to IGFBP-3 , might be useful markers in the diagnosis of GHD. 
We have used an equation derived from the law of mass action to estimate serum IGFBP-3 -bound IGF-I and IGFBP-3 -bound IGF-II , as well as serum free IGF-I and free IGF-II , in 129 control children and adolescents (48 girls and 81 boys) and in 13 patients with GHD. 
In controls, serum total IGF-I, total IGF-II , IGFBP-3 , IGFBP-3 -bound IGF-I, IGFBP-3 -bound IGF-II and free IGF-I increased linearly with age, from less than 1 to 15 years, in the two sexes. 
Height in adulthood was not associated with IGF-I, IGF-II , or IGFBP-3 and was inversely associated with IGFBP-2 (P = 0.05) after additionally controlling for childhood height. 
OBJECTIVE: To describe in a 5-year-old Caucasian male with mitochondrial cytopathy, a biochemical growth hormone (GH) deficiency associated with normal GH biological activity as evaluated by Nb2 cell bioassay and normal serum IGF-I and IGFBP3 values increasing slightly after GH administration. 
IGFBP-3 in the ternary complex increased significantly after GH administration [by 44% (P = 0.048) during infusion and by 62% (P = 0.004) during bolus]. 
Similarly, constant GH delivery induced higher IGFBP-3 levels (P < 0.05, by analysis of variance). We conclude that continuous sc infusion of GH induced serum IGF-I and IGFBP-3 levels more effectively than daily sc injections.