Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Arsenic (As) contamination of drinking water is considered a serious worldwide environmental health threat that is associated with increased disease risks including skin, lung, bladder, and other cancers; type 2 diabetes; vascular and cardiovascular diseases; reproductive and developmental effects; and neurological and cognitive effects. Increased health risks may occur at as low as 10-50 ppb, while biological effects have been observed in experimental animal and cell culture systems at much lower levels. We previously reported that As is a potent endocrine disruptor, altering gene regulation by the closely related glucocorticoid, mineralocorticoid, progesterone, and androgen steroid receptors (SRs) at concentrations as low as 0.01 microM ( approximately 0.7 ppb). Very low doses enhanced hormone-mediated gene transcription, whereas slightly higher but still noncytotoxic doses were suppressive. We report here that As also disrupts the more distally related estrogen receptor (ER) both in vivo and in cell culture. At noncytotoxic doses (1-50 micromol/kg arsenite) As strongly suppressed ER-dependent gene transcription of the 17beta-estradiol (E2)-inducible vitellogenin II gene in chick embryo liver in vivo. In cell culture, noncytotoxic levels (0.25-3 microM, approximately 20-225 ppb) of As significantly inhibited E2-mediated gene activation of an ER-regulated reporter gene and the native ER-regulated GREB1 gene in human breast cancer MCF-7 cells. While the effects of As on ER-dependent gene regulation were generally similar to As effects on the other SRs, there were specific differences, particularly the lack of significant enhancement at the lowest doses, that may provide insights into possible mechanisms.
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PMID:Arsenic as an endocrine disruptor: effects of arsenic on estrogen receptor-mediated gene expression in vivo and in cell culture. 1728 78

Insulin resistance, defined as an attenuated or inadequate response to a given amount of insulin, is associated with a wide variety of conditions including obesity, type 2 diabetes, essential hypertension, cardiovascular disease, polycystic ovary syndrome, non-alcoholic fatty liver, breast cancer, and acquired immune deficiency syndrome. Although pharmacological options for the management of insulin resistance and type 2 diabetes have been increasing, not all patients benefit, as the cost of prescription medications is often beyond the financial capacity of many patients. A potential new approach is the use of antioxidants. The objectives of this review are to discuss the scientific rationale for proposing the evaluation of antioxidants for insulin resistance, and to provide an update of intervention studies, with an emphasis on clinical trials, in which antioxidants have been tested. Briefly, this approach capitalizes on emerging data implicating lipid oversupply, chronic, lowgrade inflammation, and oxidative stress as root causes in the development and exacerbation of insulin resistance.
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PMID:Antioxidants: do they have a role in the treatment of insulin resistance? 1749 61

Breast cancer-associated mutations affecting the highly-conserved C-terminal BRCT domains of the tumor suppressor gene breast cancer susceptibility gene 1 (BRCA1) fully disrupt the ability of BRCA1 to interact with acetyl coenzyme A carboxylase alpha (ACCA), the rate-limiting enzyme catalyzing de novo fatty acid biogenesis. Specifically, BRCA1 interacts solely with the phosphorylated (inactive) form of ACCA (P-ACCA), and the formation of the BRCA1/P-ACCA complex interferes with ACCA activity by preventing P-ACCA dephosphorylation. One of the hallmarks of aggressive cancer cells is a high rate of energy-consuming anabolic processes driving the synthesis of lipids, proteins, and DNA (all of which are regulated by the energy status of the cell). The ability of BRCA1 to stabilize the phosphorylated/inactive form of ACCA strongly suggests that the tumor suppressive function of BRCA1 closely depends on its ability to mimic a cellular-low-energy status, which is known to block tumor cell anabolism and suppress the malignant phenotype. Interestingly, physical exercise and lack of obesity in adolescence have been associated with significantly delayed breast cancer onset for Ashkenazi Jewish women carrying BRCA1 gene mutations. Further clinical work may explore a chemopreventative role of "low-energy-mimickers" deactivating the ACCA-driven "lipogenic phenotype" in women with inherited mutations in BRCA1. This goal might be obtained with current therapeutic approaches useful in treating the metabolic syndrome and associated disorders in humans (e.g., type 2 diabetes and obesity), including metformin, thiazolidinediones (TZDs), calorie deprivation, and exercise. Alternatively, new forthcoming ACCA inhibitors may be relevant in the management of BRCA1-dependent breast cancer susceptibility and development.
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PMID:BRCA1 and acetyl-CoA carboxylase: the metabolic syndrome of breast cancer. 1762 Mar 10

Breastfeeding is associated with decreased risk for many early-life diseases and conditions, including otitis media, respiratory tract infections, atopic dermatitis, gastroenteritis, type 2 diabetes, sudden infant death syndrome, and obesity. Breastfeeding also is associated with health benefits to women, including decreased risk for type 2 diabetes, ovarian cancer, and breast cancer. Exclusive breastfeeding is defined as an infant receiving only breast milk and no other liquids or solids except for drops or syrups consisting of vitamins, minerals, or medicines. In 2007, Healthy People 2010 (HP2010) objectives for breastfeeding initiation and duration were updated to include two new objectives on exclusive breastfeeding (i.e., to increase the proportion of mothers who exclusively breastfeed their infants through age 3 months to 60% and through age 6 months to 25% [objectives 16-19d and 16-19e]). To monitor progress toward achieving HP2010 breastfeeding objectives, CDC analyzed data from the National Immunization Survey (NIS). This report describes the results of that analysis, which indicated that rates for breastfeeding initiation and duration increased among infants born during 2000-2004. Rates for exclusive breastfeeding through ages 3 months and 6 months among infants born in 2004 were 30.5% and 11.3%, respectively, below targets set by HP2010. Rates of exclusive breastfeeding were significantly lower among black infants (compared with white infants) and infants born to unmarried mothers (compared with married mothers). Additionally, older age, urban residence, higher education, and higher income of mothers all were positively associated with exclusive breastfeeding. Further research is needed to identify successful programs and policies to support exclusive breastfeeding, especially among subgroups with the lowest rates.
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PMID:Breastfeeding trends and updated national health objectives for exclusive breastfeeding--United States, birth years 2000-2004. 1767 96

Upper body obesity and the related metabolic disorder type 2 diabetes have been identified as risk factors for breast cancer, and associated with late-stage disease and a poor prognosis. Components of the metabolic syndrome, including visceral adiposity, insulin resistance, hyperglycemia and hyperinsulinemia, with or without clinically manifest diabetes mellitus, low serum high-density lipoprotein cholesterol and hypertension have all been related to increased breast cancer risk. The biochemical mechanisms include extraglandular oestrogen production, reduced sex hormone-binding globulin with consequent elevation of the bioactive plasma free oestradiol and increased insulin biosynthesis, all of which exert mitogenic effects on both untransformed and neoplastic breast epithelial cells. Obesity, type 2 diabetes and the metabolic syndrome also have in common an increased production of leptin and a decreased production of adiponectin by adipose tissue, with consequent elevations and reductions, respectively, in the circulating levels of these two adipokines. These changes in plasma leptin and adiponectin, acting through endocrine and paracrine mechanisms, have been associated in several studies with an increase in breast cancer risk and, perhaps, to more aggressive tumours; studies in vitro showed that leptin stimulates, and adiponectin inhibits, tumour cell proliferation and the microvessel angiogenesis which is essential for breast cancer development and progression.
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PMID:Adiposity, type 2 diabetes and the metabolic syndrome in breast cancer. 1771 97

Breast cancer, the second most common cause of cancer-related deaths in American women, varies substantially in incidence and mortality according to race and ethnicity in the United States. Although the overall incidence of breast cancer among African-American (AA) women is lower than in white American women, this cancer is more common in young premenopausal AA women, and AA breast cancer patients of all ages are more likely to have advanced disease at diagnosis, higher risk of recurrence, and poorer overall prognosis. Epidemiological studies indicate that these differences may be attributable in part to variation in obesity and body fat distribution. Additionally, AA women more frequently exhibit breast cancer with an aggressive and metastatic phenotype that may also be attributable to the endocrine and metabolic changes associated with upper body obesity. These changes include both elevated estrogen and androgen bioactivity, hyperinsulinemia, and perturbations of the adipokines. Type 2 diabetes and the metabolic syndrome, which are more common in AA women, have also been associated with breast cancer risk. Moreover, each of the individual components of the syndrome has been associated with increased breast cancer risk, including low levels of the adipocytokine, adiponectin. This review explores the specific roles of obesity, body fat distribution (particularly visceral and sc adipose tissue), type 2 diabetes, metabolic syndrome, and adipocytokines in explaining the differential patterns of breast cancer risk and prognosis between AA and white American women.
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PMID:Adiposity, the metabolic syndrome, and breast cancer in African-American and white American women. 1798 90

Metformin is used for the treatment of type 2 diabetes because of its ability to lower blood glucose. The effects of metformin are explained by the activation of AMP-activated protein kinase (AMPK), which regulates cellular energy metabolism. Recently, we showed that metformin inhibits the growth of breast cancer cells through the activation of AMPK. Here, we show that metformin inhibits translation initiation. In MCF-7 breast cancer cells, metformin treatment led to a 30% decrease in global protein synthesis. Metformin caused a dose-dependent specific decrease in cap-dependent translation, with a maximal inhibition of 40%. Polysome profile analysis showed an inhibition of translation initiation as metformin treatment of MCF-7 cells led to a shift of mRNAs from heavy to light polysomes and a concomitant increase in the amount of 80S ribosomes. The decrease in translation caused by metformin was associated with mammalian target of rapamycin (mTOR) inhibition, and a decrease in the phosphorylation of S6 kinase, ribosomal protein S6, and eIF4E-binding protein 1. The effects of metformin on translation were mediated by AMPK, as treatment of cells with the AMPK inhibitor compound C prevented the inhibition of translation. Furthermore, translation in MDA-MB-231 cells, which lack the AMPK kinase LKB1, and in tuberous sclerosis complex 2 null (TSC2(-/-)) mouse embryonic fibroblasts was unaffected by metformin, indicating that LKB1 and TSC2 are involved in the mechanism of action of metformin. These results show that metformin-mediated AMPK activation leads to inhibition of mTOR and a reduction in translation initiation, thus providing a possible mechanism of action of metformin in the inhibition of cancer cell growth.
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PMID:Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. 1800 25

This review of the literature provides an update on the scientific biological and psychosocial bases for Canada's physical activity guide for healthy active living, with particular reference to the effect of physical activity on the health of adults aged 20-55 years. Existing physical activity guidelines for adults from around the world are summarized briefly and compared with the Canadian guidelines. The descriptive epidemiology of physical activity and inactivity in Canada is presented, and the strength of the relationship between physical activity and specific health outcomes is evaluated, with particular emphasis on minimal and optimal physical activity requirements. Finally, areas requiring further investigation are highlighted. Summarizing the findings, Canadian and most international physical activity guidelines advocate moderate-intensity physical activity on most days of the week. Physical activity appears to reduce the risk for over 25 chronic conditions, in particular coronary heart disease, stroke, hypertension, breast cancer, colon cancer, type 2 diabetes, and osteoporosis. Current literature suggests that if the entire Canadian population followed current physical activity guidelines, approximately one third of deaths related to coronary heart disease, one quarter of deaths related to stroke and osteoporosis, 20% of deaths related to colon cancer, hypertension, and type 2 diabetes, and 14% of deaths related to breast cancer could be prevented. It also appears that the prevention of weight gain and the maintenance of weight loss require greater physical activity levels than current recommendations.
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PMID:Evidence-informed physical activity guidelines for Canadian adults. 1821 40

Changes in puberty timing have implications for the treatment of individual children, for the risk of later adult disease, and for chemical testing and risk assessment for the population. Children with early puberty are at a risk for accelerated skeletal maturation and short adult height, early sexual debut, potential sexual abuse, and psychosocial difficulties. Altered puberty timing is also of concern for the development of reproductive tract cancers later in life. For example, an early age of menarche is a risk factor for breast cancer. A low age at male puberty is associated with an increased risk for testicular cancer according to several, but not all, epidemiologic studies. Girls and, possibly, boys who exhibit premature adrenarche are at a higher risk for developing features of metabolic syndrome, including obesity, type 2 diabetes, and cardiovascular disease later in adulthood. Altered timing of puberty also has implications for behavioral disorders. For example, an early maturation is associated with a greater incidence of conduct and behavior disorders during adolescence. Finally, altered puberty timing is considered an adverse effect in reproductive toxicity risk assessment for chemicals. Recent US legislation has mandated improved chemical testing approaches for protecting children's health and screening for endocrine-disrupting agents, which has led to changes in the US Environmental Protection Agency's risk assessment and toxicity testing guidelines to include puberty-related assessments and to the validation of pubertal male and female rat assays for endocrine screening.
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PMID:Public health implications of altered puberty timing. 1824 14

Metformin, a first line treatment for type 2 diabetes, has been implicated as a potential anti-neoplastic agent for breast cancers as well as other cancers. Metformin is known to work in part through the activation of AMP-dependent kinase (AMPK). AMPK is a key regulator of cellular energy homeostasis, especially under stress conditions where biosynthetic pathways are blocked by the phosphorylation of downstream AMPK substrates. Stimulation of AMPK by metformin resulted in a significant repression of cell proliferation and active MAPK1/2 in both estrogen receptor alpha (ERalpha) negative (MDA-MB-231, MDA-MB-435) and positive (MCF-7, T47D) human breast cancer cell lines. However, when ERalpha negative MDA-MB-435 cells were treated with metformin, they demonstrated increased expression of vascular endothelial growth factor (VEGF) in an AMPK dependent manner; while the ERalpha positive MCF-7 cells did not. Systemic therapy with metformin was tested for efficacy in an orthotopic model of ERalpha negative breast cancer performed in athymic nude mice. Surprisingly, metformin therapy significantly improved tumorigenic progression as compared to untreated controls. The metformin-treated group showed increased VEGF expression, intratumoral microvascular density and reduced necrosis. Metformin treatment was sufficient, however, to reduce systemic IGF-1 and the proliferation rate of tumor cells in vascularized regions. The data presented here suggests that, although metformin significantly represses breast cancer cell growth in vitro, the efficacy with respect to its therapeutic application for ERalpha negative breast cancer lesions in vivo may result in promotion of the angiogenic phenotype and increased tumorigenic progression.
Breast Cancer Res Treat 2009 Jan
PMID:Therapeutic metformin/AMPK activation promotes the angiogenic phenotype in the ERalpha negative MDA-MB-435 breast cancer model. 1825 28


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