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

Postmenopausal overweight women have an increased risk of breast cancer. The link between obesity and breast cancer could be mediated through hyperinsulinemia. Insulin and insulin-like growth factor-1 (IGF-1) stimulate mammary cell proliferation in vitro, and cell proliferation is directly linked to the risk of breast cancer. Our objective was to investigate the relationship between breast cancer and body composition, IGF-1, proinsulin, C-peptide, and fasting insulin. A case-control study was conducted of 438 community-dwelling women aged 53-90 years in 1992-1994 who had no history of cancer at the baseline visit in 1972-1974. Women were excluded who were using estrogen replacement therapy (ERT) or tamoxifen at the 1992-1994 visit, when IGF-1, proinsulin, fasting insulin, and C-peptide levels were measured. Prior ERT, alcohol and tobacco use, exercise, and reproductive history were recorded. Weight, height, and waist/hip ratio were measured. The 45 women with breast cancer had similar baseline body mass indices to the 393 women without breast cancer but had gained significantly more weight between the baseline visit in 1972-1974 and 1992-1994, (age-adjusted relative risk [RR] 1.05/kg, 95% confidence interval [CI] 1.01-1.09, p = 0.016). Proinsulin, fasting insulin, and C-peptide were each significantly positively correlated with both current weight and weight gain. However, levels of these hormones and IGF-1 did not differ significantly between women with and without breast cancer (all 95% CI within 0.996-1.004). Past ERT was significantly more common among women with breast cancer (p = 0.015), and duration of use was significantly longer (age-adjusted RR 1.13 per year of use, 95% CI 1.08-1.18, p = 0.000). The risk of breast cancer was significantly increased in women who had gained weight or used ERT. This increased risk was not associated with circulating levels of IGF-1, fasting insulin, proinsulin, or C-peptide.
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PMID:Obesity, weight change, fasting insulin, proinsulin, C-peptide, and insulin-like growth factor-1 levels in women with and without breast cancer: the Rancho Bernardo Study. 1064 34

During embryonic development, insulin-like growth factor-II (IGF-II) participates in the regulation of islet growth and differentiation. We generated transgenic mice (C57BL6/SJL) expressing IGF-II in beta cells under control of the rat Insulin I promoter in order to study the role of islet hyperplasia and hyperinsulinemia in the development of type 2 diabetes. In contrast to islets from control mice, islets from transgenic mice displayed high levels of IGF-II mRNA and protein. Pancreases from transgenic mice showed an increase in beta-cell mass (about 3-fold) and in insulin mRNA levels. However, the organization of cells within transgenic islets was disrupted, with glucagon-producing cells randomly distributed throughout the core. We also observed enhanced glucose-stimulated insulin secretion and glucose utilization in islets from transgenic mice. These mice displayed hyperinsulinemia, mild hyperglycemia, and altered glucose and insulin tolerance tests, and about 30% of these animals developed overt diabetes when fed a high-fat diet. Furthermore, transgenic mice obtained from the N1 backcross to C57KsJ mice showed high islet hyperplasia and insulin resistance, but they also developed fatty liver and obesity. These results indicate that local overexpression of IGF-II in islets might lead to type 2 diabetes and that islet hyperplasia and hypersecretion of insulin might occur early in the pathogenesis of this disease.
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PMID:Transgenic mice overexpressing insulin-like growth factor-II in beta cells develop type 2 diabetes. 1072 41

We reported a boy with panhypopituitarism after removal of a suprasellar teratoma and pituitary stalk transection at the age of 3 months. His growth was accelerated after 5 years of age without growth hormone (GH) therapy, although he had poor height growth until age 4 under treatment with hydrocortisone, levothyroxine sodium, and desamino-D-arginine vasopressin (DDAVP). Hyperphagia and obesity developed after surgery. Endocrinological examination revealed no GH response to glucagon, low serum levels of insulin-like growth factor (IGF)-1 and IGF binding protein-3 (IGFBP-3). Serum prolactin was normal, but serum insulin was high. Some patients who received an operation for craniopharyngioma were reported to achieve normal growth without GH secretion, but the mechanism is still unknown. High serum levels of prolactin or insulin can be associated with normal IGF in GH deficient patients. This patient had obesity and high serum insulin, which may be related to growth without GH secretion.
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PMID:A boy with normal growth in spite of growth hormone deficiency after resection of a suprasellar teratoma. 1089 Jan 95

We explored the relationship between insulin-like growth factor-1 (IGF-1) concentrations and breast cancer risk. Also, we examined whether obesity, sex hormone-binding globulin (SHBG), and estradiol influenced IGF-1 concentrations. A pilot study of 60 postmenopausal African-American women (30 cases and 30 controls) was used. Plasma concentrations of IGF-1 were higher among the cases, as compared to the controls. A negative trend was seen for plasma concentrations of IGF-1 and TNM (tumor-node-metastasis) stage and IGF-1 and body mass index. IGF-1 was found to be associated negatively with SHBG. After adjustment, plasma concentrations of IGF-1 remained significantly and positively associated with breast cancer risk (odds ratio, 1.183; 95% confidence interval, 1.167-1.201). No significant associations for breast cancer risk were observed for estradiol, SHBG, and body mass index. Further research with a larger sample is needed to clarify the relationships between obesity and IGF-1 concentrations to breast cancer risk in this population.
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PMID:Insulin-like growth factor-1 and breast cancer risk in postmenopausal African-American women. 1097 80

Short stature, decreased muscle mass (hypotonia), increased body fat, decreased bone mineral density and other somatic abnormalities are major causes of morbidity and social limitation in individuals with Prader-Willi syndrome. Detailed studies indicate that two major endocrine pathologies may account for many of these somatic abnormalities. A true deficiency of the growth hormone (GH)-insulin-like growth factor axis is a principal cause of the short stature and is probably a major contributor to the decreased muscle mass and osteopenia. Hypogonadotropic hypogonadism is the probable primary cause of osteopenia and osteoporosis. No other endocrine abnormalities have been specifically identified in Prader-Willi syndrome, although there may be increased risks of premature adrenarche and type 2 diabetes mellitus, both secondary to obesity. GH replacement therapy is effective in normalizing linear growth and also has positive effects on muscle mass and function, and on bone mineralization. Judicious gonadal steroid replacement may be effective in treating the osteopenia and preventing osteoporosis. GH and gonadal steroid replacement therapy should be considered for all patients with Prader-Willi syndrome.
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PMID:Effects of growth hormone treatment in children with Prader-Willi syndrome. 1098 58

Controversial effects of weight reduction on gonadotropin secretion in obesity have been reported. As a result of pulsatility, single serum samples or frequent sampling studies are somewhat limited with regard to monitoring LH and FSH concentrations. We studied follicular phase nocturnal urinary (nu) LH and FSH secretion and glucose metabolism (150-min euglycemic hyperinsulinemic clamp) during 1 menstrual cycle/30-day period before and after weight reduction in 10 severely overweight infertility patients (age, 29 +/- 3.1 yr; body mass index, 37.1 +/- 3.3 kg/m2; +/-SEM). A 6-week very low calorie diet was followed by a 4-week normocaloric period. The urinary LH and FSH results reported represent samples taken 12 to 2 days before the LH surge, or 10 consecutive samples in the case of amenorrhea. We observed a decrease of 8% (P < 0.001) in percent body fat mass and a 5% (P < 0.005) reduction in waist to hip ratio. Mean nu-LH decreased by 45% [6.06 +/- 1.05 (+/-SEM) to 3.22 +/- 0.71 IU/L], whereas mean nu-FSH remained unchanged. Insulin-stimulated glucose uptake increased by 41% (P < 0.01), which was accounted for by a significant increase in nonoxidative glucose disposal (P = 0.003). Serum sex hormone-binding globulin concentrations increased by 39% (P < 0.01), and insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1) levels increased by 46% (P < 0.05). Fasting serum insulin concentrations decreased by 38%, those of leptin by 37%, those of androstenedione by 32%, those of testosterone by 20% (all P < 0.01), and those of dehydroepiandrosterone sulfate by 13% (P < 0.05). The percent change in nu-LH correlated negatively with glucose uptake (r = -0.76; P < 0.01) and the increase in serum sex hormone-binding globulin (r = -0.85; P < 0.005) and positively with the percent change in waist to hip ratio (r = 0.79; P < 0.01). The absolute nu-LH levels after weight reduction correlated significantly with fasting insulin concentrations (r = 0.88; P < 0.001) and negatively with glucose uptake (r = -0.67; P < 0.05). No significant relationships were found between absolute levels or changes in nu-LH concentrations and leptin, IGF-I, IGFBP-3, or IGFBP-1 concentrations. Our findings suggest that weight reduction with a very low calorie diet results in a decrease in nu-LH concentrations, a reduction in the LH/FSH ratio, and FSH predominance favoring folliculogenesis. The decrease in LH concentrations is inversely related to the severity of insulin resistance. It is possible that the decrease in LH secretion with weight reduction is more dependent on the absolute levels of insulin sensitivity than on the degree of general adiposity.
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PMID:The decrease in luteinizing hormone secretion in response to weight reduction is inversely related to the severity of insulin resistance in overweight women. 1099 21

Severe dietary restriction, catabolic states and even short-term caloric deprivation impair fertility in mammals. Likewise, obesity is associated with infertile conditions such as polycystic ovary syndrome. The reproductive status of lower organisms such as Caenorhabditis elegans is also modulated by availability of nutrients. Thus, fertility requires the integration of reproductive and metabolic signals. Here we show that deletion of insulin receptor substrate-2 (IRS-2), a component of the insulin/insulin-like growth factor-1 signalling cascade, causes female infertility. Mice lacking IRS-2 have small, anovulatory ovaries with reduced numbers of follicles. Plasma concentrations of luteinizing hormone, prolactin and sex steroids are low in these animals. Pituitaries are decreased in size and contain reduced numbers of gonadotrophs. Females lacking IRS-2 have increased food intake and obesity, despite elevated levels of leptin. Our findings indicate that insulin, together with leptin and other neuropeptides, may modulate hypothalamic control of appetite and reproductive endocrinology. Coupled with findings on the role of insulin-signalling pathways in the regulation of fertility, metabolism and longevity in C. elegans and Drosophila, we have identified an evolutionarily conserved mechanism in mammals that regulates both reproduction and energy homeostasis.
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PMID:IRS-2 pathways integrate female reproduction and energy homeostasis. 1101 93

Sgk (serum- and glucocorticoid-induced protein kinase) is a serine/threonine-specific protein kinase that is transcriptionally regulated by serum, glucorticoids, and mineralocorticoids. Sgk regulates the amiloride-sensitive sodium channel in kidney principal cells. Insulin and insulin-like growth factor-1 stimulate activity of Sgk by a mechanism mediated by phosphoinositide-dependent kinases (PDK)-1 and -2. In this study, we demonstrate that incubation of transfected cells with 8-(4-chlorophenylthio)-cAMP (8CPT-cAMP; 0.2 mm) led to a 2-fold activation of recombinant Sgk expressed in COS7 cells. Furthermore, the combination of insulin plus 8CPT-cAMP elicited a larger response than either agent alone. The effect of insulin was inhibited by wortmannin (100 nm), but not by the cyclic AMP-dependent protein kinase (PKA) inhibitor, H89 (10 microm). As expected, the effect of 8CPT-cAMP was completely blocked by H89. Surprisingly, the effect of 8CPT-cAMP was also inhibited by wortmannin, suggesting that phosphorylation of Sgk by PDK-1 and/or -2 is required for activation by 8CPT-cAMP. Mutational analysis led to similar conclusions. The Thr(369) --> Ala mutant, lacking the PKA phosphorylation site, was activated by insulin but not 8CPT-cAMP. In contrast, the Ser(422) --> Ala mutant, lacking a PDK-2 phosphorylation site, was inactive and resistant to activation by either insulin or 8CPT-cAMP. In summary, Sgk is subject to complex regulatory mechanisms. In addition to regulation at the level of gene expression, the enzymatic activity of Sgk is regulated by multiple protein kinases, including PKA, PDK-1, and PDK-2. Cross-talk among these signaling pathways may play an important role in the pathogenesis of the hypertension associated with hyperinsulinemia, obesity, and insulin resistance.
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PMID:Activation of serum- and glucocorticoid-induced protein kinase (Sgk) by cyclic AMP and insulin. 1109 81

HIV-lipodystrophy (HIV-LD) is characterized by the loss of body fat from the limbs and face, an increase in truncal fat, insulin resistance, and hyperlipidemia, factors placing affected patients at increased risk for vascular disease. This study evaluated insulin sensitivity and inflammatory status associated with HIV-LD and provides suggestions about its etiology. Insulin sensitivity and immune activation markers were assessed in 12 control subjects and 2 HIV-positive groups, 14 without and 15 with LD syndrome. Peripheral insulin sensitivity (mostly skeletal muscle) was determined with the hyperinsulinemic-euglycemic clamp. Circulating insulin-like growth factor (IGF) binding protein-1 (IGFBP-1) and free fatty acid (FFA) levels, and their response to insulin infusion were indicative of insulin responsiveness of liver and adipose tissue, respectively. Serum levels of soluble type 2 tumor necrosis factor-alpha (TNF-alpha) receptor (sTNFR2) were used as an indicator of immune activation. HIV-LD study subjects had significantly reduced (twofold) peripheral insulin sensitivity, but normal levels of FFA and reduced levels of IGFBP-1, relative to the nonlipodystrophy groups, indicating that the loss of insulin sensitivity was more pronounced in skeletal muscle than in liver or fat. The significant loss of peripheral fat in the HIV-LD group (34%; p <.05) closely correlated with the reduced peripheral insulin sensitivity (p =. 0001). Levels of sTNFR2 were elevated in all HIV-infected study subjects, but they were significantly higher in those with lipodystrophy than without, and sTNFR2 levels strongly correlated with the reduction in insulin sensitivity (p =.0001). Loss of peripheral fat, normal levels of FFA, and reduced levels of IGFBP-1 indicate that insulin resistance in HIV-LD is distinct from type 2 diabetes and obesity. The relationship between the degree of insulin resistance and sTNFR2 levels suggests an inflammatory stimulus is contributing to the development of HIV-associated lipodystrophy.
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PMID:Association of severe insulin resistance with both loss of limb fat and elevated serum tumor necrosis factor receptor levels in HIV lipodystrophy. 1151 29

Neuropeptide Y (NPY) in the hypothalamus exerts multiple physiological functions including stimulation of adipogenic pathways such as feeding and insulin secretion as well as inhibition of the somatotropic and gonadotropic axes. Since hypothalamic NPY-ergic activity is increased by negative energy balance, NPY enables coordinated regulation of growth and reproduction in parallel with energy availability. Chronic pathological increases in central NPY-ergic activity contribute to obesity. Many of the adipogenic effects of NPY are specifically dependent on adrenal glucocorticoids. However, in the current study we show that central NPY does not require adrenal hormones to inhibit the somatotropic and gonadotropic axes in rats. Male adrenalectomized and sham-operated normal rats were intracerebroventricularly (ICV) infused with NPY (15 microg/day) or saline for 5-7 days, and plasma leptin, insulin-like growth factor (IGF-1) and testosterone were assayed, and epididymal white adipose tissue (WATe) was weighed. In normal intact rats, WATe weight and leptinemia were significantly increased by NPY, and these effects were prevented by adrenalectomy. In normal rats, NPY markedly reduced plasma IGF-1 levels (470 +/- 40 versus 1260 +/- 90 ng/ml) and testosterone (0.53 +/- 0.28 versus 5.4 +/- 0.80 nmol/l in saline-infused controls, p < 0.0001). Adrenalectomy decreased plasma IGF-1 concentrations to 290 +/- 30 (p < 0.0001 versus normal rats), which were significantly reduced further by NPY. However, adrenalectomy had no significant effect on basal nor on NPY-induced plasma testosterone concentrations. In conclusion unlike the stimulatory effects of NPY on fat mass and leptinemia, NPY-induced inhibition of the somatotropic and gonadotropic axes in male rats do not require adrenal hormones.
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PMID:Inhibitory effects of central neuropeptide Y on the somatotropic and gonadotropic axes in male rats are independent of adrenal hormones. 1128 3


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