Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Raloxifene Use for The Heart (RUTH) trial is a randomized, placebo-controlled, double-blind trial designed to determine whether raloxifene 60 mg/day compared with placebo lowers the risk of coronary events (coronary death, nonfatal myocardial infarction [MI], or hospitalized acute coronary syndromes other than MI) and reduces the risk of invasive breast cancer in women at risk for a major coronary event. Raloxifene is a selective estrogen receptor modulator that improves cardiovascular risk factors, reduces the risk of vertebral fracture, and is associated with a reduced incidence of invasive breast cancer in postmenopausal women with osteoporosis. Between June 1998 and August 2000, 10,101 women were enrolled at 187 sites in 26 countries. Approximately half of the women had documented coronary heart disease (CHD) (n = 5,031); the remainder had multiple CHD risk factors that increased their risk for a CHD event (n = 5,070). The mean age of participants was 68 years (39% were >70 years old), and did not differ between those with documented CHD and those at increased CHD risk. Most women were Caucasian (84%); 60% had a body mass index >/=27 kg/m(2), 46% had diabetes mellitus, 78% had systemic hypertension, and 14% had low-density lipoprotein cholesterol >160 mg/dl. Compared with women at increased CHD risk, women with documented CHD had higher cardiovascular risk scores, a higher prevalence of abnormal electrocardiograms, greater use of cardiovascular medications, were more likely to have had cardiac rehabilitation, and were more likely to have previously used estrogen or oral contraceptives, but had a slightly lower prevalence of CHD risk factors such as smoking, obesity, diabetes mellitus, and systemic hypertension, and had lower serum levels of total and low-density lipoprotein cholesterol. The RUTH cohort is the largest group of postmenopausal women at increased risk of CHD events ever assembled in a clinical trial, and is the first trial designed to determine the effect of a selective estrogen receptor modulator on the risk of CHD events.
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PMID:Baseline characteristics of participants in the Raloxifene Use for The Heart (RUTH) trial. 1245 May 99

Evidence is emerging that dietary phytoestrogens play a beneficial role in obesity and diabetes. Nutritional intervention studies performed in animals and humans suggest that the ingestion of soy protein associated with isoflavones and flaxseed rich in lignans improves glucose control and insulin resistance. In animal models of obesity and diabetes, soy protein has been shown to reduce serum insulin and insulin resistance. In studies of human subjects with or without diabetes, soy protein also appears to moderate hyperglycemia and reduce body weight, hyperlipidemia, and hyperinsulinemia, supporting its beneficial effects on obesity and diabetes. However, most of these clinical trials were relatively short and involved a small number of patients. Furthermore, it is not clear whether the beneficial effects of soy protein and flaxseed are due to isoflavones (daidzein and genistein), lignans (matairesinol and secoisolariciresinol), or some other component. Isoflavones and lignans appear to act through various mechanisms that modulate pancreatic insulin secretion or through antioxidative actions. They may also act via estrogen receptor-mediated mechanisms. Some of these actions have been shown in vitro, but the relevance of these studies to in vivo disease is not known. The diversity of cellular actions of isoflavones and lignans supports their possible beneficial effects on various chronic diseases. Further investigations are needed to evaluate the long-term effects of phytoestrogens on obesity and diabetes mellitus and their associated possible complications.
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PMID:Beneficial role of dietary phytoestrogens in obesity and diabetes. 1245 Aug 82

The anti-diabetic thiazolidinediones (TZDs) are a class of compounds with insulin-sensitizing activity that were originally discovered using in vivo pharmacological screens. In subsequent binding studies, TZDs were demonstrated to enhance insulin action by activating peroxisome proliferator-activated receptor gamma (PPARgamma). PPARgamma is a member of the ligand-activated nuclear receptor superfamily that promotes adipogenesis and enhances insulin sensitivity by controlling the expression of genes in glucose and lipid metabolism. Given the large size of the ligand binding pocket in PPARgamma, novel classes of both full and partial agonists that are structurally distinct from TZDs have been discovered. These compounds have been effective tools in differentiating adipogenic and insulin-sensitizing activities as well as tissue selectivity of PPARgamma activation. This information has led to the hypothesis that one ligand can activate or inactivate PPARs depending upon the tissue in which the PPAR resides. Thus particular compounds can be designated selective PPAR modulators or SPPARMs, a concept similar to that observed with the activation of estrogen receptor (ER) by SERMS. Additionally, both preclinical and clinical data suggest that PPARgamma activation is useful for the prevention of atherosclerosis. However, the effects of TZDs on plasma lipid profiles do not solely account for their anti-atherogenic effects. Recent studies with macrophage cells and animal models for atherosclerosis indicate that TZDs reduce the size and number of lesions formed in the vessel wall by modulating foam cell formation and inflammatory responses by macrophages. Thus in addition to the treatment of type II diabetes, PPARgamma agonists can be potentially employed for the treatment of atherosclerosis in general population.
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PMID:Modulation of PPARgamma activity with pharmaceutical agents: treatment of insulin resistance and atherosclerosis. 1268 6

A well balanced body energy budget controlled by limitation of calorie uptake and/or increment of energy expenditure, which is typically achieved by proper physical exercise, is most effective against obesity and diabetes mellitus. Recently, peroxisome proliferator-activated receptor (PPAR) gamma, a member of the nuclear receptor, and its cofactors have been shown to be involved in lipid metabolism and in the control of energy expenditure. Here we show that PPARgamma coactivator 1 (PGC-1) beta functions as ERRL1 (for ERR ligand 1), which can bind and activate orphan ERRs (estrogen receptor-related receptors) in vitro. Consistently, PGC-1beta/ERRL1 transgenic mice exhibit increased expression of the medium-chain acyl CoA dehydrogenase, a known ERR target and a pivotal enzyme of mitochondrial beta-oxidation in skeletal muscle. As a result, the PGC-1beta/ERRL1 mice show a state similar to an athlete; namely, the mice are hyperphagic and of elevated energy expenditure and are resistant to obesity induced by a high-fat diet or by a genetic abnormality. These results demonstrate that PGC-1beta/ERRL1 can function as a protein ligand of ERR, and that its level contributes to the control of energy balance in vivo, and provide a strategy for developing novel antiobesity drugs.
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PMID:PPARgamma coactivator 1beta/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity. 1453 Mar 91

Bacterial aromatic polyketides such as tetracycline and doxorubicin are a medicinally important class of natural products produced as secondary metabolites by actinomyces bacteria. Their backbones are derived from malonyl-CoA units by polyketide synthases (PKSs). The nascent polyketide chain is synthesized by the minimal PKS, a module consisting of four dissociated enzymes. Although the biosynthesis of most aromatic polyketide backbones is initiated through decarboxylation of a malonyl building block (which results in an acetate group), some polyketides, such as the estrogen receptor antagonist R1128, are derived from nonacetate primers. Understanding the mechanism of nonacetate priming can lead to biosynthesis of novel polyketides that have improved pharmacological properties. Recent biochemical analysis has shown that nonacetate priming is the result of stepwise activity of two dissociated PKS modules with orthogonal molecular recognition features. In these PKSs, an initiation module that synthesizes a starter unit is present in addition to the minimal PKS module. Here we describe a general method for the engineered biosynthesis of regioselectively modified aromatic polyketides. When coexpressed with the R1128 initiation module, the actinorhodin minimal PKS produced novel hexaketides with propionyl and isobutyryl primer units. Analogous octaketides could be synthesized by combining the tetracenomycin minimal PKS with the R1128 initiation module. Tailoring enzymes such as ketoreductases and cyclases were able to process the unnatural polyketides efficiently. Based upon these findings, hybrid PKSs were engineered to synthesize new anthraquinone antibiotics with predictable functional group modifications. Our results demonstrate that (i) bimodular aromatic PKSs present a general mechanism for priming aromatic polyketide backbones with nonacetate precursors; (ii) the minimal PKS controls polyketide chain length by counting the number of atoms incorporated into the backbone rather than the number of elongation cycles; and (iii) in contrast, auxiliary PKS enzymes such as ketoreductases, aromatases, and cyclases recognize specific functional groups in the backbone rather than overall chain length. Among the anthracyclines engineered in this study were compounds with (i) more superior activity than R1128 against the breast cancer cell line MCF-7 and (ii) inhibitory activity against glucose-6-phosphate translocase, an attractive target for the treatment of Type II diabetes.
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PMID:Engineered biosynthesis of regioselectively modified aromatic polyketides using bimodular polyketide synthases. 1496 33

The purpose of this study was to investigate the vasorelaxing effect and mechanism of idoxifene (a new estrogen receptor modulator) on human internal mammary artery (HIMA). HIMA segments were harvested from men during coronary artery bypass grafting surgery. Patients with diabetes mellitus, hypercholesterolemia, hypertension, or smoking habit were excluded. The vasorelaxing effect of idoxifene on artery rings from HIMA with and without endothelium was measured by means of perfusion in vitro. Cumulative dose-response to idoxifene in the range of 0.01-10 micromol/L was observed in the presence and absence of NO synthase inhibitor L-NAME. It was also studied whether the vasodilation effect of idoxifene on HIMA was blocked by methylene blue (MB), an inhibitor of guanylate cyclase (GC). The results obtained from idoxifene were compared with those from 17beta-estradiol (E(2)). It was found that idoxifene caused a concentration-dependent relaxation on HIMA. The dose range was from 0.03 micromol/L (minimal vasodilatory concentration) to 3 mmol/L (maximal vasodilatory concentration). It was also found that the vasorelaxation effect of idoxifene on HIMA was dependent on endothelium. E(2) (0.1-100 micromol/L) also resulted in an endothelium-dependent vasorelaxation, but the vessels were 15-fold less sensitive to E(2) than to idoxifene in their vasorelaxation responses. The EC(50) for E(2) was 4.65+/-0.34 micromol/L, compared with 0.32+/-0.02 micromol/L for idoxifene. The mean maximal vasodilatory value of E(2) was 88.3+/-5.7%, compared with 88.6+/-7.2% for idoxifene. Pretreatment with L-NAME (100micromol/L) abolished idoxifene-induced vasodilation virtually by blocking nitric oxide production. The vasorelaxing effect of idoxifene disappeared in the presence of MB (10 micromol/L). These findings demonstrate that idoxifene results in an endothelium-dependent vasorelaxation of HIMA, like estrogen. The effect of idoxifene is more potent than that of traditional estrogen, and is possibly mediated by NO-GC-cGMP pathway.
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PMID:[Vasorelaxing effect of idoxifene on human internal mammary arteries]. 1498 23

Obesity, from declining estrogen levels after menopause, increases the risk of heart disease, diabetes, and hypertension. Ovariectomy (OVX) in rats is a good model of estrogen insufficiency. The ensuing mild obesity is useful to study how hypoestrogenism alters adiposity. This study examines the hypothesis that in ovariectomized (OVX) rats modification of estrogen levels or treatment with a selective estrogen receptor modulator, raloxifene (RAL), alters leptinemia and modulates leptin receptor (Ob-R) abundance in hypothalamus and white adipose tissue, similar to the modification of adipose status induced by hypoestrogenism. Mid- and long-term studies (7 and 22 wk) were conducted to monitor the change in leptinemia in rats after estrogen loss by OVX and after estrogen replacement by 17beta-estradiol (OVX+E(2)) or RAL treatment (OVX+RAL). Leptin was significantly higher in OVX rats vs. controls, in a time-dependent manner. This effect was reversed by both E(2) and RAL treatment at 7 wk (P < 0.05) and 22 wk (P < 0.001). Moreover, E(2) or RAL treatment reversed the OVX-induced increases in food intake, body weight, and fat mass content; the modifications of serum parameters were examined to evaluate the different lipid profiles. We also evaluated Ob-R expression in hypothalamus and adipose tissue by Western blot analysis. The expression of the long functional isoform (Ob-Rb) increased at 7 wk only in adipose tissue and decreased at 22 wk in OVX rats in both tissues; these effects were reversed by E(2) or RAL treatment. We provide evidence that central and peripheral Ob-Rb expression is related to modification of estrogen levels.
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PMID:Estrogen and raloxifene modulate leptin and its receptor in hypothalamus and adipose tissue from ovariectomized rats. 1505 58

This article describes the development and validation of two fluorescent receptor assays for the hRec-estrogen receptor subtypes alpha and beta. As a labelled ligand an autofluorescent phyto-estrogen (coumestrol) has been used. The estrogen receptor (ER) belongs to the nuclear receptor family, a class of soluble DNA binding proteins, mainly present in the cytoplasm of the cell, that act as ligand-activated enhancer factors. It consists of two different forms, expressed as ER-alpha (66 kDa) and ER-beta (59 kDa). The ER-alpha is mainly located in the uterus and the ER-beta can be found in vascular tissue. Detection and identification of compounds having estrogenic effects is of importance in drug discovery programmes within the pharmaceutical industry for their search for ER-subtype selective (ant)agonists which may prove to be of therapeutic value in treating a variety of estrogen-linked pathologies (breast cancer, osteoporosis, cardiovascular disease, type II diabetes and Alzheimer disease). Furthermore, interactions of (xeno-)estrogens with the endogenous hormonal system of the exposed organism can affect embryos, gonads, and reproductive behaviour. The latter can eventually lead to reduced reproduction and deterioration of a population. For that reason, monitoring of (xeno-)estrogens in food products and in the environment, attracts considerable attention by health councils throughout the world. The following characteristics were obtained for the human recombinant (hRec) estrogen receptor-beta assay, which is suitable for ER subtype selective drug-discovery purposes (IC50 values for 17-beta-estradiol and genistein were 5.1 nM and 25 nM, respectively): goodness of fit (R2) was always > 0.98 (x = 0.9933, n = 10). LLOQ of the assay is typically > or = 500 picomolar, whereas the ULOQ of the assay is < or = 20.0 nanomolar. For the hRec-estrogen receptor-alpha assay, which is suitable for monitoring of (xeno-)estrogens (IC50 values for 17-beta-estradiol and genistein were 0.68 nM and 65 nM, respectively) the following characteristics were obtained: goodness of fit (R2) was always > 0.96 (x = 0.9838, n = 10). LLOQ of the assay is typically > or = 200 picomolar, whereas the ULOQ of the assay is < or = 5.0 nanomolar.
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PMID:Development and validation of fluorescent receptor assays based on the human recombinant estrogen receptor subtypes alpha and beta. 1512 23

Autocrine activation of the IGF-I system in mesangial cells (MC) promotes glomerular scarring in a model of type 1 diabetes. Although estrogens protect against progressive nondiabetic glomerulosclerosis (GS), women with diabetes seem to loose the estrogen-mediated protection against cardiovascular disease. However, little is known about the local IGF-I system and its interactions with estrogens in the pathogenesis of type 2 diabetic GS. Therefore, we examined db/db B6 (db/db) mice, a model of type 2 diabetes and diabetic GS. The IGF-I system was activated in the glomeruli and MC of female diabetic db/db mice, but not in nondiabetic db/+ littermates. We found increased IGF-I receptor (IGFR) expression and activation, including activation of MAPK. Surprisingly, estrogens, via an estrogen receptor (ER)-independent mechanism(s), increased IGFR expression, IGFR and insulin receptor substrate phosphorylation, and extracellular signal-regulated kinase activation in db/db MC. In contrast, ER expression was decreased in MC and glomeruli of db/db mice. Treatment with a neutralizing antibody to IGF-I or the MAPK inhibitor PD98059 increased ER expression and transcriptional activity. This suggests that the local prosclerotic IGF-I system is activated in type 2 diabetes and diminishes ER-mediated protection against GS. Although estrogens may stimulate protective ER signaling, they also activate the IGF-I system via ER-independent mechanisms in db/db MC. The later estrogen effects appear to outweigh the antisclerotic effects of ER activation. This may in part account for loss of estrogen protection against the progression of diabetic GS in women with type 2 diabetes.
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PMID:Autocrine activation of the local insulin-like growth factor I system is up-regulated by estrogen receptor (ER)-independent estrogen actions and accounts for decreased ER expression in type 2 diabetic mesangial cells. 1555 May 5

Gender influences mediated by 17 beta-estradiol (E2) have been associated with susceptibility to and severity of autoimmune diseases such as diabetes, arthritis, and multiple sclerosis. In this regard, we have shown that estrogen receptor-alpha (Esr1) is crucial for the protective effect of 17 beta-estradiol (E2) in murine experimental autoimmune encephalitis (EAE), an animal model of multiple sclerosis. The expression of estrogen receptors among various immune cells (eg, T and B lymphocytes, antigen-presenting cells) suggests that the therapeutic effect of E2 is likely mediated directly through specific receptor binding. However, the target immune cell populations responsive to E2 treatment have not been identified. In the current study, we induced EAE in T-cell-deficient, severe combined immunodeficient mice or in immunocompetent mice with encephalitogenic T cells from wild-type Esr1+/+ or Esr1 knockout (Esr1-/-) donors and compared the protective E2 responses. The results showed that E2-responsive, Esr1+/+ disease-inducing encephalitogenic T cells were neither necessary nor sufficient for E2-mediated protection from EAE. Instead, the therapeutic response appeared to be mediated through direct effects on nonlymphocytic, E2-responsive cells and down-regulation of the inflammatory response in the central nervous system. These results provide the first demonstration that the protective effect of E2 on EAE is not mediated directly through E2-responsive T cells and raise the alternative possibility that nonlymphocytic cells such as macrophages, dendritic cells, or other nonlymphocytic cells are primarily responsive to E2 treatment in EAE.
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PMID:T lymphocytes do not directly mediate the protective effect of estrogen on experimental autoimmune encephalomyelitis. 1557 49


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