Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0948265 (metabolic syndrome)
 24,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are important regulators of growth and metabolism and are the key mediators of the actions of growth hormone (GH). Children born small for gestational age (SGA) have a host of medical problems including an increased risk of poor growth later in life, a tendency to develop metabolic abnormalities and a high incidence of learning disabilities. IGFs and related molecules may be linked to all of these concerns. Mouse models of IGF-I and IGF-II deficiencies have phenotypes reminiscent of human SGA, including slow growth, insulin resistance, and mental dysfunction. Humans with IGF-I mutations are born SGA and exhibit very poor subsequent growth, metabolic syndrome and mental retardation. Current management of children born SGA who present with growth failure during childhood includes treatment with GH. SGA children usually have growth factor levels within the normal range; however, as a group, they display lower IGFBP-3 levels in relation to their IGF-I levels. GH is effective in improving growth in children born SGA, but higher doses of GH are required to achieve optimal outcome, suggesting a component of GH insensitivity in SGA children. As in other indications for GH, a rational monitoring approach (focusing on maintaining IGF levels in the high normal range) is prudent.
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PMID:Insulin-like growth factors and their binding proteins in children born small for gestational age: implication for growth hormone therapy. 1467 8

To delineate the roles of the lactogens and GH in the control of perinatal and postnatal growth, fat deposition, insulin production, and insulin action, we generated a novel mouse model that combines resistance to all lactogenic hormones with a severe deficiency of pituitary GH. The model was created by breeding PRL receptor (PRLR)-deficient (knockout) males with GH-deficient (little) females. In contrast to mice with isolated GH or PRLR deficiencies, double-mutant (lactogen-resistant and GH-deficient) mice on d 7 of life had growth failure and hypoglycemia. These findings suggest that lactogens and GH act in concert to facilitate weight gain and glucose homeostasis during the perinatal period. Plasma insulin and IGF-I and IGF-II concentrations were decreased in both GH-deficient and double-mutant neonates but were normal in PRLR-deficient mice. Body weights of the double mutants were reduced markedly during the first 3-4 months of age, and adults had striking reductions in femur length, plasma IGF-I and IGF binding protein-3 concentrations, and femoral bone mineral density. By age 6-12 months, however, the double-mutant mice developed obesity, hyperleptinemia, fasting hyperglycemia, relative hypoinsulinemia, insulin resistance, and glucose intolerance; males were affected to a greater degree than females. The combination of perinatal growth failure and late-onset obesity and insulin resistance suggests that the lactogen-resistant/GH-deficient mouse may serve as a model for the development of the metabolic syndrome.
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PMID:Roles of the lactogens and somatogens in perinatal and postnatal metabolism and growth: studies of a novel mouse model combining lactogen resistance and growth hormone deficiency. 1538 48

Hepatic sex-hormone binding globulin (SHBG) production is down-regulated by insulin and low levels reflect insulin resistance. Because insulin resistance is closely related to the development of cardiovascular disease in different ethnic groups we examined ethnic variation in SHBG across populations with different baseline cardiovascular risk and metabolic syndrome prevalence. Participants were population-based, of European (n = 142), Pakistani (n = 130), and African-Caribbean (AfC) origin (n = 193). SHBG, fasting lipids, and glucose concentrations plus insulin sensitivity (HOMA-S) were determined. Age adjusted SHBG was significantly lower in both Pakistani men and women. Circulating SHBG levels were lower in those with impaired vs. normal glucose homeostasis. SHBG correlated positively with HOMA-S (rho = 0.28, p < 0.001), and negatively with WHR (rho = - 0.38, p < 0.001), BMI (r = - 0.30, p < 0.001), and diastolic blood pressure (rho = - 0.14, p < 0.01) across all ethnic groups. In multivariate logistic regression analysis a low SHBG increased the likelihood of the metabolic syndrome (odds ratio [OR] = 0.42 [0.21 - 0.82], p = 0.01) as did higher fasting NEFA (OR 1.47 [1.04 - 2.08], p = 0.03), low IGFBP-1 concentrations (OR 0.6 [0.44 - 0.81], p = 0.001), age (OR 1.05 [1.02 - 1.09], p = 0.003), and Pakistani ethnicity (p = 0.001) in a model which also contained gender, lnCRP, IGF-I, and IGF-II. As ethnic differences in SHBG level closely parallel differences in insulin resistance. Its measurement may be useful in identifying individuals at particular risk of the metabolic syndrome, for early intervention.
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PMID:Low sex hormone binding globulin is a potential marker for the metabolic syndrome in different ethnic groups. 1623 54

Strong evidence suggests that systemic inflammation and central adiposity contribute to and perpetuate metabolic syndrome. All of these alterations predispose individuals to type 2 diabetes mellitus (T2DM), cardiovascular disease, as well as Alzheimer's disease (AD), all characterized by chronic inflammatory status. On the other hand, extensive abnormalities in insulin and insulin-like growth factor I (IGF-I) and IGF-II signaling mechanisms in brains with AD have been demonstrated, suggesting that AD could be a third form of diabetes. The Src homology domain-containing inositol 5-phosphatase 2 (SHIP2) has an important role in the insulin pathway because its over-expression causes impairment of insulin/IGF-1 signaling. Because some single-nucleotide polymorphisms (SNP) of the gene encoding SHIP2 were significantly associated in T2DM patients with metabolic syndrome and some related conditions, we decided to conduct a case-control study on this gene, analyzing AD and T2DM subjects as cases and young, old, and centenarians as controls. Our results suggest a putative correlation between the the rs144989913 SNP and aging, both successful and unsuccessful, rather than age-related diseases. Because this SNP is an insertion/deletion of 28 bp, it might cause an alteration in SHIP2 expression. It is noteworthy that SHIP2 has been demonstrated to be a potent negative regulator of insulin signaling and insulin sensitivity. Many studies demonstrated the association of the insulin/IGF1 pathway with aging and longevity, so it is tempting to speculate that the found association with SHIP2 and aging might depend on its effect on the insulin/IGF-1 pathway.
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PMID:SHIP2: a "new" insulin pathway target for aging research. 2431 49

Low birth weight and length for gestational age are associated with a high risk of short stature and metabolic syndrome in adulthood. The mechanisms that link prenatal growth to adult stature and metabolic syndrome have not yet been entirely clarified. The aim of our study was to evaluate the relationship between standardized anthropometric measures at birth and insulin-like growth factor (IGF)-I, IGF-II, insulin, adiponectin, and non-esterified fatty acid (NEFA) cord blood levels in the general population. One hundred fifty-eight random newborn subjects (77F, 81M) from Genoa, Italy, were analyzed. Anthropometric parameters were measured and standardized according to standard Italian tables. Insulin values were treated as categorical, since in several cases the results fell below detection cut-off. Mean birth weight was 3,214.23&#x2213;488.99 gr and mean length was 49.82&#x2213;2.17 cm. Females had higher mean IGF-I (p=0.04), and were more likely to have insulin values either <2 &#956;U/ml or >4.5&#956;U/ml (p= 0.04) compared to males. Weight and length SD scores (SDS) were higher in subjects with elevated insulin levels (p=0.002). A moderate correlation was found between weight and IGF-II (r=0.354). Multivariable analysis demonstrated that standardized birth weight was associated with IGFII and insulin values. Our data highlight the importance of IGF-II in fetal growth and suggest that gender differences should be taken into consideration when evaluating prenatal growth.
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PMID:Growth factors and metabolic markers in cord blood: relationship to birth weight and length. 2500 56

The rapid rise in obesity, metabolic syndrome and type 2 diabetes is one of the major healthcare problems of the Western world. Affected individuals are often treated with statins (3-hydroxy-3-methylglutaryl co-enzyme A [HMG CoA] reductase inhibitors) to reduce circulating cholesterol levels and the risk of developing cardiovascular disease; given the evolving demographic profile of these conditions, such drugs are increasingly prescribed to women of reproductive age. We have previously shown that exposure of placental tissue to statins inhibits the action of insulin-like growth factors (IGF)-I and -II which are key regulators of trophoblast proliferation and placental development. N-linked glycans in the IGF receptor, IGF1R, influence its presentation at the cell surface. This study aimed to determine whether statins, which are known to affect N-glycosylation, modulate IGF1R function in placenta. Treatment of first trimester villous tissue explants with statins (pravastatin or cerivastatin) or inhibitors of N-glycosylation (tunicamycin, deoxymannojirimycin or castanospermine) altered receptor distribution in trophoblast and attenuated proliferation induced by IGF-I or IGF-II (Ki67; P < 0.05, n = 5). Decreased binding of Phaseolus vulgaris lectin and phytohaemagglutinin to IGF1R immunoprecipitated from treated explants demonstrated reduced levels of complex N-linked glycans. Co-incubation of tissue explants with statins and farnesyl pyrophosphate (which increases the supply of dolichol intermediates), prevented statin-mediated disruption of IGF1R localization and reversed the negative effect on IGF-mediated trophoblast proliferation. These data suggest that statins attenuate IGF actions in the placenta by inhibiting N-linked glycosylation and subsequent expression of mature IGF1R at the placental cell surface.
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PMID:Statins inhibit insulin-like growth factor action in first trimester placenta by altering insulin-like growth factor 1 receptor glycosylation. 2530 81

In vitro cell model studies have shown that oxidative stress may affect beta-cell function. It is unknown whether oxidative stress may affect metabolic health in human fetuses/newborns. In a singleton pregnancy cohort (n = 248), we studied maternal (24-28 weeks gestation) and cord plasma biomarkers of oxidative stress [malondialdehyde (MDA), F2-isoprostanes] in relation to fetal metabolic health biomarkers including cord plasma glucose-to-insulin ratio (an indicator of insulin sensitivity), proinsulin-to-insulin ratio (an indicator of beta-cell function), insulin, IGF-I, IGF-II, leptin, adiponectin and ghrelin concentrations. Strong positive correlations were observed between maternal and cord plasma biomarkers of oxidative stress (r = 0.33 for MDA, r = 0.74 for total F2-isoprostanes, all p < 0.0001). Adjusting for gestational age at blood sampling, cord plasma ghrelin concentrations were consistently negatively correlated to oxidative stress biomarkers in maternal (r = -0.32, p < 0.0001 for MDA; r = -0.31, p < 0.0001 for F2-isoprostanes) or cord plasma (r = -0.13, p = 0.04 for MDA; r = -0.32, p < 0.0001 for F2-isoprostanes). Other fetal metabolic health biomarkers were not correlated to oxidative stress. Adjusting for maternal and pregnancy characteristics, similar associations were observed. Our study provides the first preliminary evidence suggesting that oxidative stress may affect fetal ghrelin levels in humans. The implications in developmental "programming" the vulnerability to metabolic syndrome related disorders remain to be elucidated.
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PMID:Perinatal Oxidative Stress May Affect Fetal Ghrelin Levels in Humans. 2664 95