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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Selective estrogen receptor modulators (SERMs) have been used successfully in the treatment of breast cancer and osteoporosis while Tibolone has been used extensively in Europe for the treatment of menopausal symptoms. Limited data is available on the effect of these agents on the cardiovascular system. Traditional and novel lipid markers are valuable in determining patients at increased cardiovascular risk. The purpose of this article is to discuss the mechanism of action of Tamoxifen, Raloxifene and Tibolone and their effects on lipid metabolism.
Diabetes Obes Metab 2005 Sep
PMID:Effects of oestrogen receptor-active compounds on lipid metabolism. 1605 Sep 39

Osteoporosis and osteopenia are frequent complications of thalassemia major (TM) and intermedia (TI). Osteoporosis was found in 23/25 patients with TI and in 115/239 patients with TM. In TM, no association was found with specific polymorphisms in candidate genes (vitamin D receptor, estrogen receptor, calcitonin receptor, and collagen type 1 alpha 1). Osteoporosis in TM female was strongly associated with primary amenorrhea (P < .0001), while in male patients with TM hypogonadism was not significantly related to BMD (P = .0001). Low BMD was also associated with cardiomiopathy (P = .01), diabetes mellitus (P = .0001), chronic hepatitis (P = .0029), and increased ALT (P = .01).
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PMID:Evaluation of ICL670, a once-daily oral iron chelator in a phase III clinical trial of beta-thalassemia patients with transfusional iron overload. 1633 64

Osteoporosis and osteopenia are frequent complications of thalassemia major (TM) and intermedia (TI). Osteoporosis was found in 23/25 patients with TI and in 115/239 patients with TM. In TM, no association was found with specific polymorphisms in candidate genes (vitamin D receptor, estrogen receptor, calcitonin receptor, and collagen type 1 alpha 1). Osteoporosis in female patients with TM was strongly associated with primary amenorrhea (P < .0001), while in male patients with TM, hypogonadism was not significantly related to bone mineral density (BMD) (P = .0001). Low BMD was also associated with cardiomiopathy (P = .01), diabetes mellitus (P = .0001), chronic hepatitis (P = .0029), and increased ALT (P = .01).
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PMID:Osteoporosis in beta-thalassemia: Clinical and genetic aspects. 1633 96

The etiology of obesity is multifactorial and still unclear. Genetic factors play a significant role and include several gene candidates: polymorphisms of genes for ss(2)-adrenoreceptor, resistin, estrogen receptor-a and peroxisome proliferator-activated receptor-gamma. Moreover, peptides regulating hunger and satiety, e.g. leptin, galanin, cholecystokinin and neuropeptide Y, and altered nutritional patterns have been implicated. Also, factors associated with aging, e.g. decreased levels of growth hormone and dehydroepiandrosterone, and the activity of the sympathetic nervous system (resting metabolism and thermogenesis) cannot be disregarded. Participation of the sex steroids and inflammatory factors has also been postulated in the etiology of obesity. Three phenotypes of obesity are postulated; however, the visceral (abdominal) phenotype is typical of postmenopausal women and is characterized by several metabolic disorders with high risks of diabetes mellitus type 2 and cardiovascular disease. On the basis of personal experience and data from evidence-based medicine, diagnostic-therapeutic algorithms of climacteric obesity are presented.
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PMID:Climacteric obesity: from genesis to clinic. 1652 29

Although genistein, a soy isoflavone, has beneficial effects on various tissues, it is unclear whether it plays a role in physiological insulin secretion. Here, we present evidence that genistein increases rapid glucose-stimulated insulin secretion (GSIS) in both insulin-secreting cell lines (INS-1 and MIN6) and mouse pancreatic islets. Genistein elicited a significant effect at a concentration as low as 10 nmol/l with a maximal effect at 5 micromol/l. The effect of genistein on GSIS was not dependent on estrogen receptor and also not related to an inhibition of protein tyrosine kinase (PTK). Consistent with its effect on GSIS, genistein increases intracellular cAMP and activates protein kinase A (PKA) in both cell lines and the islets by a mechanism that does not involve estrogen receptor or PTK. The induced cAMP by genistein, at physiological concentrations, may result primarily from enhanced adenylate cyclase activity. Pharmacological or molecular intervention of PKA activation indicated that the insulinotropic effect of genistein is primarily mediated through PKA. These findings demonstrated that genistein directly acts on pancreatic beta-cells, leading to activation of the cAMP/PKA signaling cascade to exert an insulinotropic effect, thereby providing a novel role of soy isoflavones in the regulation of insulin secretion.
Diabetes 2006 Apr
PMID:Genistein acutely stimulates insulin secretion in pancreatic beta-cells through a cAMP-dependent protein kinase pathway. 1656 27

Fatty acid metabolism in the hypothalamus has recently been shown to regulate feeding. The selective estrogen receptor modulator tamoxifen (TMX) exerts a potent anorectic effect. Here, we show that the anorectic effect of TMX is associated with the accumulation of malonyl-CoA in the hypothalamus and inhibition of fatty acid synthase (FAS) expression specifically in the ventromedial nucleus of the hypothalamus (VMN). Furthermore, we demonstrate that FAS mRNA expression is physiologically regulated by fasting and refeeding in the VMN but not in other hypothalamic nuclei. Thus, the VMN appears to be the hypothalamic site where regulation of FAS and feeding converge. Supporting the potential clinical relevance of these observations, reanalysis of a primary breast cancer prevention study showed that obese women treated with TMX gained significantly less body weight over a 6-year period than obese women given placebo. The finding that TMX can modulate appetite through alterations in FAS expression and malonyl-CoA levels suggests a link between hypothalamic sex steroid receptors, fatty acid metabolism, and feeding behavior.
Diabetes 2006 May
PMID:Tamoxifen-induced anorexia is associated with fatty acid synthase inhibition in the ventromedial nucleus of the hypothalamus and accumulation of malonyl-CoA. 1664 89

In diabetes, the death of insulin-producing beta-cells by apoptosis leads to insulin deficiency. The lower prevalence of diabetes in females suggests that female sex steroids protect from beta-cell injury. Consistent with this hypothesis, 17beta-estradiol (estradiol) manifests antidiabetic actions in humans and rodents. In addition, estradiol has antiapoptotic actions in cells that are mediated by the estrogen receptor-a (ERalpha), raising the prospect that estradiol antidiabetic function may be due, in part, to a protection of beta-cell apoptosis via ERalpha. To address this question, we have used mice that were rendered estradiol-deficient or estradiol-resistant by targeted disruption of aromatase (ArKO) or ERalpha (alphaERKO) respectively. We show here that in both genders, ArKO(-/-) mice are vulnerable to beta-cell apoptosis and prone to insulin-deficient diabetes after exposure to acute oxidative stress with streptozotocin. In these mice, estradiol treatment rescues streptozotocin-induced beta-cell apoptosis, helps sustain insulin production, and prevents diabetes. In vitro, in mouse pancreatic islets and beta-cells exposed to oxidative stress, estradiol prevents apoptosis and protects insulin secretion. Estradiol protection is partially lost in beta-cells and islets treated with an ERalpha antagonist and in alphaERKO islets. Accordingly, alphaERKO mice are no longer protected by estradiol and display a gender nonspecific susceptibility to oxidative injury, precipitating beta-cell apoptosis and insulin-deficient diabetes. Finally, the predisposition to insulin deficiency can be mimicked in WT mice by pharmacological inhibition of ERalpha by using the antagonist tamoxifen. This study demonstrates that estradiol, acting, at least in part, through ERalpha, protects beta-cells from oxidative injury and prevents diabetes in mice of both genders.
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PMID:Estrogens protect pancreatic beta-cells from apoptosis and prevent insulin-deficient diabetes mellitus in mice. 1675 60

The estrogen receptor-alpha gene (ESR1) was selected as a positional candidate under a type 2 diabetes linkage peak at 6q24-27. A total of 42 ESR1 single nucleotide polymorphisms (SNPs) were genotyped in 380 African-American type 2 diabetic case subjects with end-stage renal disease (ESRD) and 276 African-American control subjects. A total of 22 ancestry informative markers were also genotyped, and the program Admixmap was used to adjust allelic and haplotypic association tests for individual estimates of admixture. The most significant association with type 2 diabetes-ESRD was with rs1033182 in intron 2 (P = 0.013, admixture-adjusted P(a) = 0.021). Genotyping 17 SNPs across a region of ESR1 intron 1-intron 2 in an expanded population of 851 case and 635 control subjects supported association with rs1033182 (P = 0.004, P(a) = 0.027) and with an independent six-SNP haplotype of high linkage disequilibrium spanning 6.4 kb (P < 0.0001, P(a) < 0.0001). The same 17 ESR1 SNPs were genotyped in 300 European-American type 2 diabetes-ESRD case subjects and 310 European-American control subjects. Two intron 2 SNPs, rs2431260 (P = 0.015) and rs1709183 (P = 0.019), and a four-SNP haplotype containing these SNPs (P = 0.033) were associated with type 2 diabetes and/or ESRD. Results suggest that intron 1 and intron 2 of the ESR1 gene may contain functionally important regions related to type 2 diabetes or ESRD risk.
Diabetes 2007 Mar
PMID:Investigation of the estrogen receptor-alpha gene with type 2 diabetes and/or nephropathy in African-American and European-American populations. 1732 35

Diabetic rats have characteristic reproductive deficits. Peripheral and central (intra-cerebro-ventricular [ICV]) insulin restores the reproductive phenotype to control levels. In this experiment, we evaluated a possible defect in steroid feedback by evaluating hypothalamic estrogen receptor (ER) alpha availability using ERalpha immunocytochemistry. Animals were ovariectomised and given estradiol and progesterone. Diabetic and control animals were given ICV insulin or saline. Nuclear and/or cytoplasmic ERalpha immunoreactivity was evaluated in the paraventricular nucleus (PVN) and the organum vasculosum laminae terminalis (OVLT). In the PVN, nuclear immunoreactivity was increased among diabetic, ICV insulin-treated animals. Diabetic saline-treated and nondiabetic animals had similar ERalpha immunoreactivity. The OVLT had lower numbers of immunoreactive neurons compared to the PVN; no differences among the treatment groups were found in the OVLT. Central insulin treatment increased the number of PVN nuclear ERalpha immunoreactive neurons among diabetic animals. However, there was no reduction in ERalpha when comparing saline-treated diabetic animals to non-diabetic rats, suggesting that decreases in hypothalamic ERalpha in the regions studied do not account for diabetes-induced reproductive deficits.
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PMID:The effect of diabetes and centrally administered insulin on anterior hypothalamic estrogen receptor alpha immunoreactivity. 1735 85

Estrogens are essential for fertility and also have important effects on regulation of adiposity and the euglycemic state. We report here that lipin1, a candidate gene for lipodystrophy and obesity that is a phosphatidic acid phosphatase critical in regulation of cellular levels of diacylglycerol and triacylglycerol and a key regulator of lipid utilization, is rapidly and robustly down-regulated in the uterus by estradiol via the estrogen receptor. Lipin1 is expressed predominantly in the uterine luminal and glandular epithelium, and during the estrous cycle, lipin1 is lowest when blood levels of estrogen are highest. Lipin1 is expressed throughout all cells in the liver of ovariectomized female mice, and a sustained down-regulation is observed at the mRNA, protein and immunohistochemical levels after estrogen administration. Because the coupling of proper energy use and availability is central to reproduction, we also investigated expression of lipin1 in the uterus and liver of several mouse models of diabetes. Nonobese diabetic (NOD) mice, which have high blood levels of estrogen and impaired fertility, were severely deficient in lipin1 in the uterus and liver, which, interestingly, could be restored by insulin treatment. By contrast, nonobese diabetic/severe combined immunodeficient (NOD-SCID) mice, which do not develop diabetes, showed normal levels of lipin1. Our findings of lipin1 regulation by estrogen in two key target organs suggest a new role for this lipid-regulating phosphatase not only in central metabolic regulation but also in uterine function and reproductive biology. Estrogen regulation of lipin1 may provide a mechanistic link between estrogens, lipid metabolism, and lipid signaling.
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PMID:Lipin1 regulation by estrogen in uterus and liver: implications for diabetes and fertility. 1746 59


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