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 protein tyrosine phosphatase PTP1B, previously recognized for its role in downregulating insulin and leptin signaling, has now been shown to function as a positive regulator of signaling events associated with breast tumorigenesis. Inhibitors of PTP1B that have been developed as drug candidates for treatment of diabetes and obesity may offer new avenues for the treatment of breast cancer.
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PMID:A brake becomes an accelerator: PTP1B--a new therapeutic target for breast cancer. 1734 79

Increased glycogen synthase kinase-3 (GSK-3) activity is believed to contribute to the etiology of chronic disorders like Alzheimer's disease and diabetes, thus supporting therapeutic potential of GSK-3 inhibitors. However, sustained GSK-3 inhibition might induce tumorigenesis through beta-catenin-APC dysregulation. Besides, sustained in vivo inhibition by genetic means (constitutive knock-out mice) revealed unexpected embryonic lethality due to massive hepatocyte apoptosis. Here, we have generated transgenic mice with conditional (tetracycline system) expression of dominant-negative-GSK-3 as an alternative genetic approach to predict the outcome of chronic GSK-3 inhibition, either per se, or in combination with mouse models of disease. By choosing a postnatal neuron-specific promoter, here we specifically address the neurological consequences. Tet/DN-GSK-3 mice showed increased neuronal apoptosis and impaired motor coordination. Interestingly, DN-GSK-3 expression shut-down restored normal GSK-3 activity and re-established normal incidence of apoptosis and motor coordination. These results reveal the importance of intact GSK-3 activity for adult neuron viability and physiology and warn of potential neurological toxicity of GSK-3 pharmacological inhibition beyond physiological levels. Interestingly, the reversibility data also suggest that unwanted side effects are likely to revert if excessive GSK-3 inhibition is halted.
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PMID:Neuronal apoptosis and reversible motor deficit in dominant-negative GSK-3 conditional transgenic mice. 1751 Jun 31

Apoptosis has been accepted as a fundamental component in the pathogenesis of cancer, in addition to other human diseases including neurodegeneration, coronary disease and diabetes. The origin of cancer involves deregulated cellular proliferation and the suppression of apoptotic processes, ultimately leading to tumor establishment and growth. Several lines of evidence point toward the IAP family of proteins playing a role in oncogenesis, via their effective suppression of apoptosis. The central mechanisms of IAP apoptotic suppression appear to be through direct caspase and pro-caspase inhibition (primarily caspase 3 and 7) and modulation of, and by, the transcription factor NF-kappaB. Thus, when the IAPs are over-expressed or over-active, as is the case in many cancers, cells are no longer able to die in a physiologically programmed fashion and become increasingly resistant to standard chemo- and radiation therapies. To date several approaches have been taken to target and eliminate IAP function in an attempt to re-establish sensitivity, reduce toxicity, and improve efficacy of cancer treatment. In this review, we address IAP proteins as therapeutic targets for the treatment of cancer and emphasize the importance of novel therapeutic approaches for cancer therapy. Novel targets of IAP function are being identified and include gene therapy strategies and small molecule inhibitors that are based on endogenous IAP antagonists. As well, molecular mechanistic approaches, such as RNAi to deplete IAP expression, are in development.
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PMID:The inhibitors of apoptosis (IAPs) as cancer targets. 1757 56

It has been estimated that up to 1 in 10 adults has at least one adrenocortical nodule up to 1 cm on autopsy; these benign tumors may contribute to metabolic syndrome, hypertension, obesity and abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis that can be linked to other serious disorders such as osteoporosis, depression and late-onset diabetes mellitus. In addition, up to 1 in 1500 of these adrenal "incidentalomas" may hide a carcinoma, which, if diagnosed late or left untreated, is associated with significant morbidity and mortality. Consistent with the theme of this symposium, in the present report, we review the efforts undertaken at the National Institutes of Health (NIH) in the last quarter century to unravel the complex clinical genetics and molecular mechanisms involved in adrenal tumorigenesis. We first proposed that adrenocortical tumors form in a molecular sequence of events similar to that in other organs: as the pathology of the tumor increases towards malignancy, genetic changes accumulate. For example, known genetic associations, like TP53 gene changes, occur during the latest stages of adrenocortical tumorigenesis. At the NIH, significant progress has been made in the understanding of the genetics of primary pigmented adrenocortical disease (PPNAD) and other forms of bilateral adrenocortical hyperplasias. This recently led to the identification of phosphodiesterase 11A ( PDE11A) mutations as a low-penetrance predisposing factor to adrenocortical hyperplasias of both the pigmented and non-pigmented variants.
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PMID:Adrenocortical tumors, primary pigmented adrenocortical disease (PPNAD)/Carney complex, and other bilateral hyperplasias: the NIH studies. 1757 66

Markers of cell proliferation (Ki-67 antigen) and apoptosis (Bax, Bcl-2) were studied in an experimental model of chemically induced carcinogenesis in normal and diabetic (type I) Sprague-Dawley rats. Thirteen diabetic and 12 normal rats developed cancer after 4-nitroquinoline-N-oxide treatment, while 6 diabetic and 6 normal animals were used as controls. The biopsies were classified pathologically (from oral mucosal dysplasia to moderately differentiated squamous cell carcinoma) and studied immunohistochemically using monoclonal antibodies against Bax, Bcl-2 and Ki-67 proteins. The Bcl-2/Bax ratio was almost stable during the oncogenesis process in the diabetic rats, whereas the normal rats showed an increased Bcl-2/Bax ratio during the stage of moderately differentiated carcinoma. In contrast, Ki-67 expression was higher in diabetic rats than in normal ones in almost all stages of oral oncogenesis, and it reached significantly increased levels in the stages of normal control tissue, dysplasia and moderately differentiated squamous cell carcinoma. These data suggest that diabetes results in increased cell proliferation during oral oncogenesis, but this is accomplished without affecting the Bax/Bcl-2-mediated apoptotic pathways.
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PMID:Diabetes enhances cell proliferation but not Bax/Bcl-2-mediated apoptosis during oral oncogenesis. 1782 29

Pancreatic disease is responsible for significant morbidity and mortality as a result of pancreatic carcinoma and diabetes mellitus. Regulation of endocrine cell mass is thought to have a central role in the pathogenesis of both these diseases. Islet cell proliferation, hypertrophy, neogenesis, and apoptosis are the main determinants of endocrine cell mass in the pancreas, and their understanding has been improved by new clues of their genetic and molecular basis. Beta cells have attracted most research interest because of potential implications in the treatment of diabetes mellitus and hypoglycemic disorders. The processes that operate during pancreatic adaptation to a changing hormonal milieu are important in pancreatic carcinogenesis. There is evidence that somatostatin and its receptors are fundamental regulators of endocrine cell mass and are involved in islet tumorigenesis.
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PMID:Proliferation, hyperplasia, neogenesis, and neoplasia in the islets of Langerhans. 1789 38

The development of peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) ligands for the treatment of diseases including metabolic syndrome, diabetes and obesity has been hampered due to contradictory findings on their potential safety. For example, while some reports show that ligand activation of PPARbeta/delta promotes the induction of terminal differentiation and inhibition of cell growth, other reports suggest that PPARbeta/delta ligands potentiate tumorigenesis by increasing cell proliferation. Some of the contradictory findings could be due in part to differences in the ligand examined, the presence or absence of serum in cell cultures, differences in cell lines or differences in the method used to quantify cell growth. For these reasons, this study examined the effect of ligand activation of PPARbeta/delta on cell growth of two human cancer cell lines, MCF7 (breast cancer) and UACC903 (melanoma) in the presence or absence of serum using two highly specific PPARbeta/delta ligands, GW0742 or GW501516. Culturing cells in the presence of either GW0742 or GW501516 caused upregulation of the known PPARbeta/delta target gene angiopoietin-like protein 4 (ANGPTL4). Inhibition of cell growth was observed in both cell lines cultured in the presence of either GW0742 or GW501516, and the presence or absence of serum had little influence on this inhibition. Results from the present studies demonstrate that ligand activation of PPARbeta/delta inhibits the growth of both MCF7 and UACC903 cell lines and provide further evidence that PPARbeta/delta ligands are not mitogenic in human cancer cell lines.
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PMID:Peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) ligands inhibit growth of UACC903 and MCF7 human cancer cell lines. 1805 22

Development of obesity-associated insulin resistance and diabetes mellitus type 2 has been linked to activation of proinflammatory pathways in the liver, leading to impaired insulin signal transduction. To further define the role of hepatic NF-kappaB activation in this process, we have analyzed glucose metabolism in mice with liver-specific inactivation of the NF-kappaB essential modulator gene (NEMO(L-KO) mice) exposed to a high-fat diet (HFD). These animals are protected from the development of obesity-associated insulin resistance, highlighting the importance of hepatic NF-kappaB activation in this context. However, hepatic NEMO deficiency synergizes with HFD in the development of liver steatosis as a consequence of decreased peroxisome proliferator-activated receptor (PPAR-alpha) and increased PPAR-gamma expression. Steatosis interacts with increased inflammation, causing elevated apoptosis in the livers of these mice under HFD. These changes result in liver tumorigenesis of NEMO(L-KO) mice under normal diet, a process that is largely aggravated when these mice are exposed to HFD. These data directly demonstrate the interaction of hepatic inflammation, dietary composition, and metabolism in the development of liver tumorigenesis.
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PMID:Hepatic NF-kappa B essential modulator deficiency prevents obesity-induced insulin resistance but synergizes with high-fat feeding in tumorigenesis. 1821 63

Oral squamous cell carcinoma (OSCC) is the sixth most common malignancy in humans including type I diabetic and normal rats. Tobacco and alcohol, as well as dysregulation of oncogenes and tumor suppressor genes, epigenetic changes and mitochondrial mutations have been implicated in OSCC development. Recent epidemiological studies have incriminated diabetes mellitus as a risk factor for the development of OSCC, as well as oral premalignant lesions. Recently, an animal model was employed to study the influence of diabetes on signal transduction pathways in every stage of oral cancer development, from normal mucosa to hyperplasia, dysplasia, early invasion, well differentiated OSCC and moderately differentiated OSCC. Diabetes was induced by streptozotocin and chemical carcinogenesis was induced by the carcinogen 4-nitroquinoline N-oxide. The expression of EGFR, erbB2, erbB3, FGFR-2, FGFR-3, c-myc, N-ras, ets-1, H-ras, c-fos and c-jun, the tumor suppressor genes p53 and p16, apoptosis markers Bax and Bcl-2, and the cell proliferation marker Ki-67 in the sequential stages of rat oral oncogenesis was investigated. Diabetes seems to promote the activation of the Ras/Raf/MAPK signal transduction pathway mainly by induction of erbB2 and erbB3 receptors, leading to increased cell proliferation, while there was no difference in apoptosis levels during oncogenesis.
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PMID:Diabetes and oral oncogenesis. 1822 90

An epidemic of overweight/obesity and type 2 diabetes, caused by overeating nutrient-poor energy-dense foods and a sedentary lifestyle, is spreading rapidly throughout the world. Abdominal obesity represents a serious threat to health because it increases the risk of developing many chronic diseases, including cardiovascular disease and cancer. Calorie restriction (CR) with adequate nutrition improves cardiometabolic health, prevents tumorigenesis and increases life span in experimental animals. The purpose of this review is to evaluate the metabolic and clinical implications of CR with adequate nutrition in humans, within the context of data obtained in animal models. It is unlikely that information regarding the effect of CR on maximal life span in humans will become available in the foreseeable future. In young and middle-aged healthy individuals, however, CR causes many of the same cardiometabolic adaptations that occur in long-lived CR rodents, including decreased metabolic, hormonal and inflammatory risk factors for diabetes, hypertension, cardiovascular disease and cancer. Unraveling the mechanisms that link calorie intake and body composition with metabolism and aging will be a major step in understanding the age-dependency of a wide range of human diseases and will also contribute to improve the general quality of life at old ages.
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PMID:Calorie restriction and cardiometabolic health. 1827 79


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