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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A segregating F(2) pedigree based on two mouse lines (DU6i and DBA/2) with extremely different growth characteristics was generated to search for loci affecting serum levels of insulin-like growth factor (IGF) binding proteins (IGFBPs) and to estimate their effects on growth and body composition. DU6i is characterized by high body mass and obesity associated with hyperinsulinemia, hyperleptinemia, and elevated serum IGF-I concentrations. Furthermore, significantly elevated serum levels of IGFBP-2, IGFBP-3, and IGFBP-4 were found in DU6i vs. DBA/2 mice. Linkage analysis identified loci with major effects on the serum level of IGFBP-3 on Chromosome 5 at 58 cM (Igfbp3q1; F = 9.9) and on Chromosome 10 at 46 cM (Igfbp3q2; F = 33.8). A locus significantly influencing serum IGFBP-2 levels in males was found on Chromosome 7. Additional linkage was detected in males and females for IGFBP-2 on Chromosomes 8, 11, 14, 17, and X, and for IGFBP-4 on Chromosome 4. Additional loci affecting IGFBPs acted in a sex-specific manner. The identified loci coincide in part with chromosomal regions controlling growth and obesity. Thus, multiple genes or pleiotropic gene effects may be assumed for these chromosomal regions. The identification of quantitative trait loci for IGFBPs as subcomponents of growth regulation and differentiation will further improve the understanding of complex trait regulation.
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PMID:Genome-wide search for loci controlling serum IGF binding protein levels of mice. 1129 58

Several recent epidemiological studies have shown an increase in breast cancer risk among women who have elevated plasma levels of testosterone, reduced levels of sex hormone-binding globulin (SHBG), and hence elevated levels of bioavailable androgens and estrogens not bound to SHBG. This endocrine profile is generally associated with obesity and chronic hyperinsulinemia, of which it is most likely a result. Lack of physical activity, obesity, and a diet rich in rapidly digestible carbohydrates and poor in fibre favour the development of insulin resistance and hyperinsulinemia. The elevated insulin levels, in turn are related to decreases in plasma and tissue levels of IGFBP-1 and IGFBP-2 (insulin-like growth factor-binding proteins), and this may increase the availability of insulin-like growth factor-I (IGF-I) to its receptors. Like insulin, IGF-I also inhibits the hepatic synthesis of SHBG, whereas both hormones stimulate the ovarian synthesis of sex steroids. Moreover, insulin and IGF-I can both enhance the development of breast tumours, through their cognate receptors within the mammary tissue. Taken together, these observations lead to the hypothesis that breast cancer risk may be increased in women with elevated plasma insulin levels, and/or with elevated levels of bioactive IGF-I. Hyperinsulinemia and an increased IGF-I bioactivity could thus be an important physiological link between a western lifestyle, overnutrition, a hyperandrogenic sex steroid profile, and increased breast cancer risk. Prospective cohort studies will be needed to test this hypothesis, and to study in greater detail the possible relationships of breast cancer risk with plasma levels of IGF-I and IGFBPs. Confirmation of a relationship of breast cancer risk with plasma insulin levels, on the one hand, or with total plasma IGF-I, on the other hand, could open up new perspectives for breast cancer prevention, either by changes in dietary intake patterns and physical activity, or by the use of certain chemopreventive drugs.
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PMID:[Plasma insulin, IGF-I and breast cancer]. 1130 43

The discovery of a link between in utero experience and later metabolic and cardiovascular disease is one of the most important advances in epidemiology research of recent years. There is increasing evidence that alterations in the fetal environment may have long-term consequences on cardiovascular, metabolic, and endocrine pathophysiology in adult life. This process has been termed programming, and we have shown that undernutrition of the mother during gestation leads to programming of hyperphagia, obesity, hypertension, hyperinsulinemia, and hyperleptinemia in the offspring. Using this model of maternal undernutrition throughout pregnancy combined with postnatal hypercaloric nutrition of the offspring, we examined the effects of IGF-I therapy. Virgin Wistar rats (age 75 +/- 5 d, n = 20 per group) were time mated and randomly assigned to receive food either ad libitum or 30% of ad libitum intake (UN) throughout pregnancy. At weaning, female offspring were assigned to one of two diets (control or hypercaloric [30% fat]). Systolic blood pressure was measured at day 175 and following infusion with 3 microg/g per day recombinant human IGF-1 (rh-IGF-I) by minipump for 14 d. Before treatment, UN offspring were hyperinsulinemic, hyperleptinemic, hyperphagic, obese, and hypertensive on both diets, compared with ad libitum offspring and this was exacerbated by hypercaloric nutrition. IGF-I treatment increased body weight in all treated animals. However, systolic blood pressure, food intake, retroperitoneal and gonadal fat pad weights, and plasma leptin and insulin concentrations were markedly reduced with IGF-I treatment. IGF-I treatment resulted in a 3- to 5-fold increase in 38--44 kDa and 28--30 kDa IGF binding proteins, although in UN animals, there was an impaired and differential up-regulation of these insulin-like growth factor binding proteins following IGF-I treatment. The 24-kDa IGF binding protein representing IGF binding protein-4 was down-regulated in all IGF-I-treated animals, but the decrease was more marked in UN animals. Our data suggest that IGF-I treatment alleviates hyperphagia, obesity, hyperinsulinemia, hyperleptinemia, and hypertension in rats programmed to develop the metabolic syndrome X.
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PMID:IGF-I treatment reduces hyperphagia, obesity, and hypertension in metabolic disorders induced by fetal programming. 1151 75

South Asians who immigrate to the United States have a propensity toward insulin resistance, central obesity, and elevated total cholesterol:high-density lipoprotein (HDL) ratio. To evaluate whether these alterations are apparent at a younger age, we studied 32 offspring of South Asian immigrants and compared them with 29 of European descent between 18 to 30 years of age. American-born South Asian males had significantly higher total cholesterol, low-density lipoprotein (TC:LDL) ratios, triglycerides, and fasting insulin levels (13.9 +/- 7.1 and 10.0 +/- 5.5 microU/mL, P <.01) than their European counterparts. The South Asian females only had increased plasma insulin levels (15.3 +/- 8.8 and 10.0 +/- 5.1 microU/mL, P =.05). The entire South Asian group had higher truncal skinfold thickness (40.1 +/- 18.1 and 30.3 +/- 12.6 mm, P = <.05) and lower insulin-like growth factor binding protein (IGFBP)-1 levels (46.8 +/- 33.4 and 56.0 +/- 33.4 microg/L, P =.05). Plasma leptin levels were also significantly higher in both males (4.3 +/- 2.5 v 2.8 +/- 1.3 ng/mL, P =.0001) and females (20.5 +/- 10.3 v 10.3 +/- 6.3 ng/mL, P =.002) South Asian subjects. A significant correlation between plasma leptin and insulin, triglycerides, TC, and body mass index (BMI) was seen in the South Asian males. South Asians born in the United States show evidence for an altered metabolic profile in young adulthood. The relative contributions of inheritance and nutritional practices early in life to this alteration remain unclear.
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PMID:Altered lipid profile, leptin, insulin, and anthropometry in offspring of South Asian immigrants in the United States. 1158 93

Insulin and insulin-like growth factor (IGF) axes are major determinants of proliferation and apoptosis and thus may influence carcinogenesis. In various animal models, modulation of insulin and IGF-1 levels through various means, including direct infusion, energy excess or restriction, genetically induced obesity, dietary quality including fatty acid and sucrose content, inhibition of normal insulin secretion and pharmacologic inhibition of IGF-1, influences colonic carcinogenesis. Human evidence also associates high levels of insulin and IGF-1 with increased risk of colon cancer. Clinical conditions associated with high levels of insulin (noninsulin-dependent diabetes mellitus and hypertriglyceridemia) and IGF-1 (acromegaly) are related to increased risk of colon cancer, and increased circulating concentrations of insulin and IGF-1 are related to a higher risk of colonic neoplasia. Determinants and markers of hyperinsulinemia (physical inactivity, high body mass index, central adiposity) and high IGF-1 levels (tall stature) are also related to higher risk. Many studies indicate that dietary patterns that stimulate insulin resistance or secretion, including high consumption of sucrose, various sources of starch, a high glycemic index and high saturated fatty acid intake, are associated with a higher risk of colon cancer. Although additional environmental and genetic factors affect colon cancer, the incidence of this malignancy was invariably low before the technological advances that rendered sedentary lifestyles and obesity common, and increased availability of highly processed carbohydrates and saturated fatty acids. Efforts to counter these patterns are likely to have the most potential to reduce colon cancer incidence, as well as cardiovascular disease and diabetes mellitus.
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PMID:Insulin, insulin-like growth factors and colon cancer: a review of the evidence. 1216 83

In peripheral tissues, corticosteroid hormone action is determined, in part, through the activity of 11beta-hydroxysteroid dehydrogenases (11beta-HSD), two isozymes of which interconvert hormonally active cortisol (F) and inactive cortisone (E). 11beta-HSD type 2 (11beta-HSD2) inactivates F to E in the kidney, whilst 11beta-HSD type 1 (11beta-HSD1) principally performs the reverse reaction activating F from E in the liver and adipose tissue. Alteration in expression of these 11beta-HSD isozymes in peripheral tissues modifies corticosteroid action: loss of 11beta-HSD2 activity in the kidney results in cortisol-induced mineralocorticoid excess, and loss of hepatic 11beta-HSD1 activity improves insulin sensitivity through a reduction in cortisol-induced gluconeogenesis and hepatic glucose output. Conversely, overexpression of 11beta-HSD1 in omental adipose tissue can stimulate glucocorticoid-induced adipocyte differentiation which may lead to central obesity. Patients with hypopituitarism have many clinical features in common with patients with Cushing's syndrome--notably visceral obesity, insulin resistance, osteoporosis and increased vascular mortality. Our hypothesis was that many of these features may be explained by an effect of growth hormone (GH) on the 11beta-HSD isozymes. As assessed by urinary free cortisol/urinary free cortisone ratios and endorsed through in vitro studies, neither GH nor insulin-like growth factor (IGF)-I affect 11beta-HSD2 activity. Patients with acromegaly show a reduction in hepatic-derived metabolites of cortisol/cortisone - levels return to normal when GH concentrations are normalized. Conversely, patients with GH deficiency in the setting of hypopituitarism demonstrate an increased cortisol/cortisone metabolite ratio and reduction in circulating cortisol concentrations in patients on hydrocortisone replacement. Treatment with low-dose GH replacement reverses these abnormalities. These clinical data suggest that GH (and/or IGF-I) inhibits 11beta-HSD1 (i.e. E to F conversion) (parallel in vitro studies suggest that IGF-I and not GH inhibits 11beta-HSD1). These findings have important clinical ramifications. Firstly, the GH-mediated increase in cortisol metabolism (mediated via reduced E to F conversion) may precipitate adrenal insufficiency in hypopituitary patients with partial adrenocorticotropic hormone deficiency commencing GH therapy. Secondly, many of the phenotypic features of hypopituitarism can be explained by an alteration in 11beta-HSD1 activity: GH deficiency effectively increases cortisol production in key target tissues including liver and adipose tissue, promoting insulin resistance and visceral adiposity. Thirdly, the reported beneficial effects of GH on cardiovascular risk factors in patients with hypopituitarism may be an indirect effect via alterations in cortisol metabolism. Finally, the GH/IGF-I modulation of cortisol metabolism may underpin the pathogenesis of common diseases such as central obesity and idiopathic osteoporosis. Patients with central obesity but with no evidence of hypopituitarism have relative GH deficiency and it is exciting to speculate that low-dose GH treatment in this group, by inhibiting cortisol generation within omental fat, may offer a novel therapeutic approach.
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PMID:Growth hormone, insulin-like growth factor-I and the cortisol-cortisone shuttle. 1178 77

The metabolic syndrome is associated with a marked increase in risk of type 2 diabetes and atherosclerotic vascular disease (AVD). The mechanism responsible for the metabolic syndrome is uncertain, but recent evidence suggests that a combination of low birth weight and adult obesity is associated with a markedly increased prevalence. Insulin resistance is the cardinal feature of the metabolic syndrome. Several hormones, have modes of action that either potentiate or reduce the biological actions of insulin and, therefore, attenuate or induce insulin resistance. Since insulin action may be modified, these hormones potentially contribute to the pathogenesis of the metabolic syndrome. The purpose of this review is to discuss programming of hormones that modulate insulin action. The review focuses on two major endocrine pathways: (i) glucocorticoid hormone action; and (ii) the growth hormone (GH)-insulin-like growth factor (IGF-1) axis, and discusses mechanisms linking abnormal activity of these pathways with reduced early growth, adult obesity and the metabolic syndrome.
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PMID:Programming other hormones that affect insulin. 1180 24

Insulin, insulin-like growth factor-1 (IGF-1), IGF binding protein-3 (IGFBP-3), and obesity, and in particular visceral obesity, are putative cancer risk factors. Little is known, however, about the relationship between IGFs and obesity. We investigated the relationship between adipose tissue distribution and IGF-1 and IGFBP-3. Single-slice abdominal computed tomography scanning through the L4-L5 interspace was used to measure visceral adipose tissue (VAT) and subcutaneous adipose tissue (SQAT) in 432 community-based subjects (267 men, 165 women; ages, 55-77), participating in a cancer screening trial. Insulin, IGF-1, IGFBP-3, and the ratio of IGF-1:IGFBP-3, measured by radioimmunoassay, were compared with age, body mass index, absolute and relative VAT and SQAT, and total abdominal fat. We found that men had a higher mean IGF-1 (129.5 versus 108.9 ng/ml; P < 0.0001) and more VAT (201.5 cm(3) versus 166.6 cm(3); P < 0.0001) than women. In men and women, there was no correlation between IGF-1, IGFBP-3, or the ratio of IGF-1:IGFBP-3 with body mass index, total fat, VAT or SQAT, or fasting insulin. In contrast, fasting insulin was highly correlated to all measures of obesity (P = 0.0001). We conclude that obesity, adipose tissue distribution, and in particular VAT are not correlated with IGF-1, IGFBP-3, or the molar ratio of IGF-1:IGFBP-3. The lack of association between obesity and the IGF-1 axis suggests that the IGF-1 axis is not a likely mediator between VAT and disease.
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PMID:Lack of association between adipose tissue distribution and IGF-1 and IGFBP-3 in men and women. 1281 10

Childhood obesity frequently is associated with an increase in height velocity and acceleration of epiphyseal growth plate maturation despite low levels of serum growth hormone (GH). In addition, obesity is associated with higher circulating levels of leptin, a 16-kDa protein that is secreted from the adipocytes. In this study, we evaluated the direct effect of leptin on the chondrocyte population of the skeletal growth centers in the mouse mandibular condyle, a model of endochondral ossification. We found that chondrocytes in the growth centers contain specific binding sites for leptin. Leptin, at a concentration of 0.5-1.0 microg/ml, stimulated in a dose-dependent manner the width of the chondroprogenitor zone (up to 64%), whereas higher concentrations had an inhibitory effect. Leptin induction of both proliferation and differentiation activities in the mandibular condyle was confirmed by our findings of an increase in bromodeoxyuridine (BrdU) incorporation into DNA and in (acidic) Alcian blue (AB) staining of the cartilaginous matrix. Leptin also increased the abundance of the insulin-like growth factor (IGF) I receptor and IGF-I receptor messenger RNA (mRNA) within the chondrocytes and the progenitor cell population. Our results indicate that leptin acts as a skeletal growth factor with a direct peripheral effect on skeletal growth centers. Some of its effects on the growing bone may be mediated by the IGF system via regulation of IGF-I receptor expression. We speculate that the high circulating levels of leptin in obese children might contribute to their growth.
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PMID:Leptin acts as a growth factor on the chondrocytes of skeletal growth centers. 1205 58

Somatostatin (SMS) is a potent inhibitory molecule. It inhibits both exocrine and endocrine secretory functions of the pancreas, suppresses growth hormone secretion and reduces the level of insulin-like growth factor-1. Long-acting somatostatin analogues were currently investigated for potential clinical benefits in two settings: (a) control of hyperinsulinaemia in obesity and (b) control of an excess of pro-angiogenic factors in diabetes-associated retinal complications. In two randomized, controlled trials the long-acting somatostatin analogue octreotide retarded progression of the microvascular complications in pre-proliferative and advanced stages of diabetic retinopathy. Inhibition of the early phase of insulin secretion by use of octreotide in patients with hypothalamic obesity resulted in weight loss and improved quality of life. Efficacy of octreotide correlated to residual beta-cell activity prior to the treatment. Obesity and diabetes mellitus are the most common chronic metabolic disorders in the world. The use of somatostatin analogues addressing the various hormonal imbalances of these disorders may provide a novel concept for their pharmacological treatment.
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PMID:Use of somatostatin receptor ligands in obesity and diabetic complications. 1207 71


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