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)

Approximately 70% of primary 7,12-dimethylbenz(alpha)-anthracene-induced mammary tumors regressed when (tumor-bearing) rats were made diabetic after treatment with streptozotocin. In the intact animal, cyclic adenosine 3':5"-monophosphate (cAMP) levels of tumors that regressed following the induction of diabetes were initially 4-fold lower than in unresponsive tumors but increased 4-fold during regression. The insulin-independent tumors showed no statistically significant changes. cAMP binding in cytosol of regressing tumors was about 80% above the initial values at 36 hr after therapy but decreased to about 45% 1 week later. On the contrary, the binding capacity of the nuclei showed a 56% increase at 36 hr and increased gradually to about 3-fold 1 week later. Within 36 hr after treatment, total histone kinase activity increased 127% in the cytosol and 153% in the nuclei of regressing tumors. The increment of histone kinase activity was almost totally in the cAMP-dependent component of the enzyme. These changes were not apparent in insulin-independent tumors. The results are interpreted to indicate that mammary tumor regression due to diabetes involves the cAMP system and occurs through a sequence of events similar to those observed during regression induced by either ovariectomy or dibutyryl cAMP (cyclic adenosine 3':5'-monophosphate) treatment.
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PMID:Cyclic adenosine 3':5'-monophosphate and protein kinase activity in insulin-dependent and -independent mammary tumors. 22 Nov 6

Insulin is a potent mitogen for many cell types in vitro. During tissue culture, supraphysiological concentrations of insulin are necessary to promote cell replication in connective or musculoskeletal tissues. Insulin promotes the growth of these cells by binding, with low affinity, to the type I insulin-like growth factor (IGF) receptor, not through the high affinity insulin receptor. In other cell types, such as hepatocytes, embryonal carcinoma cells, or mammary tumor cells, the type I IGF receptor is virtually absent, and insulin stimulates the growth of these cells at physiological concentrations by binding to the high affinity insulin receptor. Both receptor systems activate phosphorylation reactions within the cell which extend to ribosomal proteins. Insulin acts synergistically with other factors, such as platelet-derived growth factor and epidermal growth factor, to stimulate the progression of cells through the cycle of proliferation. Abnormal insulin secretion or action, before or after birth, often is associated with disordered growth suggesting that insulin may function as a growth factor in vivo. Poor growth follows impaired insulin secretion in diabetes mellitus. This is associated with reduced circulating levels of IGF's which may be partly responsible for the growth failure. Insulin has a direct action on release of IGF's from the liver in vitro, but during experimental diabetes there is a reduced number of hepatic somatotropic receptors which could limit the ability of growth hormone to regulate IGF release. Diabetic children, treated conventionally, have normal circulating IGF levels, but both growth rate and serum IGF concentration may increase dramatically when diabetic control is optimized.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Insulin as a growth factor. 241 20

Phosphatidylinositol (PI) kinase was characterized, its activity was measured in plasma membrane-enriched fractions of R3230AC rat mammary tumors, and these results were compared to enzyme activity in normal mammary glands at various stages of differentiation. PI kinase activity was found to be highest in mammary adenocarcinomas, whereas the mammary gland displayed the following order of decreasing activity: late lactation greater than early lactation greater than late pregnancy. Although diabetes only slightly increased tumor membrane PI kinase activity, insulin treatment of tumor-bearing diabetic rats, which reduced R3230AC tumor growth, caused a significant reduction (30 to 40%) in PI kinase activity. These results imply that PI kinase activity may be correlatable with normal mammary gland differentiation and with mammary tumor growth behavior. Formation of phosphatidylinositol-4-phosphate in tumor membranes was inhibited by low concentrations of calcium (microM range), suggesting the presence of calcium-sensitive polyphosphoinositide metabolism in the R3230AC carcinoma.
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PMID:Membrane-associated phosphatidylinositol kinase of R3230AC mammary tumors and normal mammary glands and effects of insulin on tumor enzyme activity. 284 58

To examine the effects of diabetes on the alteration of R3230AC mammary tumor growth by dietary lipids, streptozotocin-induced diabetic rats were fed diets containing either 20% corn oil (HF), 20% hydrogenated cottonseed oil (HCTO), or 0% fat (FF). Diabetes resulted in lower tumor weights and body weights compared to those of intact animals. Unlike intact animals, relative tumor weight (g tumor/100 g body wt) of diabetic animals fed HF diets were not greater than those from animals fed FF diets. However, in these diabetic animals, growth of tumors in HF-fed rats was faster than in HCTO-fed rats, a relationship similar to that seen in intact rats. A surprising result was the almost twofold greater tumor weight/100 g body wt observed in diabetic FF-fed rats compared to those fed HCTO diets. Insulin binding to tumor plasma membranes from diabetic animals was higher in rats fed HF diets than in rats fed FF or HCTO diets. The tumor plasma membrane fatty acid composition of diabetic rats fed FF and HCTO diets displayed higher proportions of the monounsaturates (C18:1 and C21:1) and decreased amounts of the polyunsaturates (C18:2 and C20:4) compared to the levels observed in membranes from HF-fed rats. These results, as well as the insulin binding data, were similar to those obtained using intact animals. The data presented here indicate that the more rapid growth of the R3230AC mammary tumor seen in intact animals fed high polyunsaturated fat vs fat-free diets did not occur in diabetic animals.
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PMID:Effects of diabetes on the dietary lipid alteration of R3230AC mammary carcinoma growth in rats. 388 14

Inbred strains of genetically diabetic (db/db) male mice with H-2b haplotype were heretofore found resistant to the diabetogenic action of the db mutation, whereas C3HeB/FeJ-db/db males with H-2k haplotype were susceptible. To determine whether the major histocompatibility complex was linked to diabetes predisposition, we mated C3H.SW/SnJ females (H-2b haplotype) with C3HeB/FeJ- +/db males, identified the +/db heterozygotes in the F1 generation (all H-2b/H-2k), and intercrossed these to produce F2 db/db male offspring that were classed and studied according to the three segregating H-2 genotypes. We found an accelerated diabetes pathogenesis in terms of early onset of severe hyperglycemia, destruction of pancreatic beta cells, and mortality that was not linked to H-2. Of 9 F2 male diabetics with H-2b/H-2b genotype, 14 with H-2b/H-2k genotype, and 5 with H-2k/H-2k genotype, all showed a more severe syndrome than did the grandparental-type C3HeB/FeJ-db/db males. We conclude that on the C3H inbred background, the major histocompatibility complex is not a major background modifier of the diabetes syndrome. The complexity of the results suggests residual non-H-2-related genetic variance between the two grandparental C3H stocks, with C3H.SW/SnJ females possessing diabetes susceptibility factors apparently lacking in C3HeB/FeJ (a stock bred to be free of the milk-borne mouse mammary tumor virus). Since C3H.SW/SnJ females transmitted to F2 males unknown diabetogenic factor(s) that did not appear to segregate, inheritance of a virus was suggested.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1984 Nov
PMID:Genetic control of pathogenesis of diabetes in C3H mice. Influence of the major histocompatibility complex. 650 Jan 86

To define the clonal diversity of autoreactive T cells associated with the induction of type 1 diabetes, we characterized TCR expression in the earliest detectable islet infiltrates of non-obese diabetic (NOD) mice. The islets of young NOD females were examined for V beta and J beta germ-line gene usage and V(D)J beta junctional sequence diversity. The results from 7-wk-old mice corroborate prior studies demonstrating that the T cell repertoire of islet infiltrates diversifies early in the inflammatory process. In contrast, examination of 4-wk-old NOD mice showed that TCR-beta expression in the peri-islet infiltrates was restricted both in V beta and J beta gene utilization and, most significantly, in V(D)J junctional sequence diversity. Islet-infiltrating T cells from young mice included V beta 3+ T cells, despite the presence of a mammary tumor virus-3-associated superantigen that deletes the majority of immature V beta 3+ thymocytes in NOD mice. Few other TCR V beta types were repeatedly detectable in early stage infiltrates. V(D)J junctional sequence diversity was evaluated in cDNA libraries made from the islets of young NOD mice. Analysis of these clones revealed limited junctional CDR3 diversity in early-infiltrating T cells, as compared with lymph node T cell libraries. Evaluation of TCR expression in individual islets revealed CDR3 sequence conservation between animals and among islets from a single animal. These results suggest that T cells bearing limited TCR-beta-chain diversity contribute to the inductive phases of autoimmune diabetes.
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PMID:Peri-islet infiltrates of young non-obese diabetic mice display restricted TCR beta-chain diversity. 753 89

Microbial superantigens (SAGs) have been implicated in the pathogenesis of human autoimmune diseases. Preferential expansion of the Vveta7 T cell receptor positive T cell subset in patients suffering from acute-onset type I diabetes has indicated the presence of a surface membrane-bound SAG. Here, we have isolated a novel mouse mammary tumor virus-related human endogenous retrovirus. We further show that the N-terminal moiety of the envelope gene encodes an MHC class II-dependent SAG. We propose that expression of this SAG, induced in extrapancreatic and professional antigen-presenting cells, leads to beta-cell destruction via the systemic activation of autoreactive T cells. The SAG encoded by this novel retrovirus thus constitutes a candidate autoimmune gene in type I diabetes.
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PMID:A human endogenous retroviral superantigen as candidate autoimmune gene in type I diabetes. 924 4

Viral superantigens bind several alleles and isotypes belonging to the MHC class II and subsequently activate particular T cell families via the variable portion of the beta chain of TCR. As a result, a superantigen bridges MHC and TCR molecules, leading to activation of T and B cells. The T expansion of various TCR V beta subsets is triggered on the basis of their V beta specificity, but not on their antigenic specificity. The best known superantigens are bacterial endotoxins produced by Staphylococcus aureus. However, viruses such as mouse mammary tumor or rabies viruses encode superantigens too. The ability of superantigens to break the barriers of MHC restriction and to activate large numbers of T and B cells has led to the hypothesis that superantigens may activate autoreactive T and B cells to initiate or worsen autoimmune diseases such as diabetes, multiple sclerosis, or psoriasis.
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PMID:[Viral superantigens]. 1098 4

Type 1 diabetes in nonobese diabetic (NOD) mice is characterized by the infiltration of T and B cells into pancreatic islets. T cells bearing the TCR Vbeta3 chain are disproportionately represented in the earliest stages of islet infiltration (insulitis) despite clonal deletion of most Vbeta3(+) immature thymocytes by the mammary tumor virus-3 (Mtv-3) superantigen (SAg). In this report we showed that a high frequency of NOD Vbeta3(+) T cells that escape deletion are activated in vivo and that this phenotype is linked to the Mtv-3 locus. One potential mechanism of SAg presentation to peripheral T cells is by activated B cells. Consistent with this idea, we found that NOD mice harbor a significantly higher frequency of activated B cells than nondiabetes-prone strains. These activated NOD B cells expressed cell surface molecules consistent with APC function. At the molecular level, the IgH repertoire of activated B cells in NOD mice was equivalent to resting B cells, suggesting a polyclonal response in vivo. Genetic analysis of the activated B cell phenotype showed linkage to Idd1, the NOD MHC haplotype (H-2(g7)). Finally, Vbeta3(+) thymocyte deletion and peripheral T cell activation did not require B cells, suggesting that other APC populations are sufficient to generate both Mtv-3-linked phenotypes. These data provide insight into the genetic regulation of NOD autoreactive lymphocyte activation that may contribute to failure of peripheral tolerance and the pathogenesis of type I diabetes.
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PMID:Genetic control of T and B lymphocyte activation in nonobese diabetic mice. 1173 40

Recently, a newly identified human HERV-K18 like endogenous retrovirus (IDDMK(1,2)22) has been associated to the etiology of type I diabetes (IDDM). Although the exact mechanism remains unclear, it was postulated that the 3' end ORF product of the env gene of IDDMK(1,2)22 would trigger a V beta 7-specific human T cell expansion leading to their infiltration in the pancreas of afflicted patients and to the autoimmune destruction of the insulin-producing beta cells. Since then, such superantigen (SAg)-like activity as well as the association between the IDDMK(1,2)22 virus and IDDM pathogenesis have been challenged. To further characterize functionally the putative IDDMK(1,2)22-encoded SAg, we have cloned from human DNA the identical 462bp ORF sequence originally described. The IDDMK(1,2)22 ORF fragment was transfected in the same human B cell line (Raji) originally used as APC to demonstrate the V beta 7 specificity. The immunostimulatory potential of IDDM ORF was tested on murine T cell hybridomas and compared to the well-characterized mouse mammary tumor virus Mtv7 SAg transfected in the same conditions. A panel of 16 T cell hybridomas encompassing 14 different V betas was analyzed. We have failed to detect IDDMK(1,2)22-induced IL-2 production from any of these hybridomas, even those bearing the murine V beta 1 mV beta 1, V beta 4 or V beta 10 TcR beta chains which are most closely related to the human V beta 7 (hV beta 7). Our results suggest that IDDMK(1,2)22 ORF is devoid of superantigenic activity as defined by classical criteria.
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PMID:Human endogenous retrovirus IDDMK(1,2)22 and mouse mammary tumor virus superantigens differ in their ability to stimulate murine T cell hybridomas. 1184 50


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