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

A study begun by a drug company and taken over by the FDA (Food and Drug Administration) in 1970 attempted to assess the role of oral contraceptives in tumorigenesis and clotting abnormalities in animals. The study used ethynerone (MK 665) + mestranol; chloroethynyl norgestrel (Wy-4355) + mestranol; anagestone acetate + mestranol; ethynerone, and; mestranol administered at levels up to 25 times the human use level to female beagle dogs and 50 times the human use level to female rhesus monkeys. No behavioral changes related to compound or dose were observed in either species. Both species exhibited pharmacologic effects of hormone administration. Inhibition of the estrous cycle and vulvar enlargement were seen in all dosed dogs. Both species exhibited a dose-dependent, nonprogressive decrease in hemoglobin and hematocrits, with the anagestone acetate-mestranol combination showing the greatest effect. More nodules developed in the mammary glands of dogs who received the progestogen-mestranol combinations and who received ethynerone alone than control dogs. The 3 progestogen-mestranol combination showed the greatest tumorigenic effect as expressed by the number of dogs affected and by numbers of mammary nodules. This effect was dose-dependent for the ethynerone-mestranol and chloroethynyl norgestrel-mestranol combinations, but for the anagestone acetate-mestranol combination was maximal at the lower dose. A small number of dogs that received each progestogen-mestranol combination developed clinically malignant tumors; control dogs or dogs that received only mestranol or ethynerone were unaffected. In contrast, none of the drugs was associated with an increased incidence of mammary nodules in the monkeys. Some monkeys that received each drug showed ductal epithelial hyperplasia in mammary gland biopsies. Diabetes mellitus occurred in 10 dogs from the chloroethynyl norgestrel-mestranol and anagestone acetate-mestranol groups and in 3 monkeys from the ethynerone-mestranol high dose and anagestone acetate-mestranol high dose groups. Generalized cystic hyperplasia of the gallbladder mucosa was seen in a small number of dogs from the anagestone acetate-mestranol group. The suitability of the dog as test species for the tumorigenic and carcinogenic study of oral contraceptives is indicated.
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PMID:FDA studies of estrogen, progestogens, and estrogen/progestogen combinations in the dog and monkey. 41 41

Homozygosity for the severe combined immunodeficiency (scid) mutation results in a block in T- and B-lymphocyte development. An unusually high incidence of spontaneous thymic lymphoma development was observed after transfer of this mutation from the C.B-17 congenic strain background onto the diabetes-susceptible nonobese diabetic (NOD) background. Thymomagenesis in the NOD-scid/scid mouse was associated with expression of an NOD mouse-unique endogenous ecotropic murine leukemia provirus locus (Emv-30, mapped to proximal region of chromosome 11) not expressed in the standard substrain NOD/Lt thymus. All tumors exhibited insertions of ecotropic proviruses, whereas only a subset also exhibited proviral integrations of mink cell focus-forming retrovirus. Neither class of retrovirus was associated with consistent integration into genes previously associated with activation of oncogenesis. We propose that the unusual features of T-cell ontogeny characteristic of the NOD inbred strain synergize with the scid-imparted block in thymocyte development, leading to activation of the NOD-unique Emv-30 to initiate thymomagenesis.
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PMID:The nonobese diabetic scid mouse: model for spontaneous thymomagenesis associated with immunodeficiency. 137 93

Transgenic mice have been used for analyses of cis-acting elements which are involved in the tissue-specific and developmental-specific expression, for analyses of physiological function of genes, or for the production of a human disease model. This approach is especially successful in the fields of immunology and oncology. Several years ago it was shown that the major histocompatibility complex (MHC) class II gene is identical to the immune response gene by demonstrating that the immune response can be restored by the new expression of class II molecules on immunocompetent cells. Recent evidence suggests that the class II molecule is involved in the generation of autoimmune disease, such as insulin-dependent diabetes mellitus (IDDM). The NOD (non-obese diabetic) mouse is shown to be a mouse model for human IDDM. Concerning the class II genes, the NOD mouse has two characteristic features, the lack of I-E and the presence of unique I-A. It is discussed how the role of class II molecules in the development of IDDM in the NOD mouse can be analyzed. In addition, the transgenic technique can be applied to the study of differentiation and oncogenesis of lymphoid cells. Factors or molecules that affect these processes will also be discussed.
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PMID:Transgenic mouse as a tool for the study of autoimmune disease: insulin-dependent diabetes mellitus. 161 97

We stably expressed human complement receptor 2 ([CR2] CD21 C3d/Epstein-Barr virus [EBV] receptor) on the rat insulinoma cell line RINm5F with a recombinant retroviral vector. CR2-expressing RINm5F cells secreted 78-33% less insulin than parental cells or cells transduced with an antisense vector and could be infected with high-titer EBV. We tested whether human CR2 expression on RINm5F cells would affect tumorigenesis after transplantation to syngeneic New England Deaconess Hospital rats. Non-CR2-expressing antisense-transduced RINm5F cells rapidly grew tumors and caused hypoglycemia, hyperinsulinemia, and the death of the animals after 15.7 +/- 0.7 days. CR2-expressing RINm5F cells were infiltrated by mononuclear cells at an early stage and eventually caused noninfiltrated tumors and the death of the animals after 33.0 +/- 0.4 days. These tumors were CR2- and are believed to have arisen from a minor CR2- population of tumor cells. The pancreatic islets were histologically normal at all time points. We conclude that expression of a xenoantigen on a rat insulinoma cell line induces an immune response in syngeneic rats but does not result in breakage of tolerance to parental or revertant cells.
Diabetes 1991 Jul
PMID:Expression of functional human Epstein-Barr virus/C3d receptor ([CR2] CD21) on insulinoma cell line. Induction of tumor rejection but not diabetes in syngeneic rats. 164 92

Gangliocytomas are benign, slow growing neuronal tumors and are found for the most part in children and young adults. They are most often localized in either the spinal cord or the cerebral hemispheres. Gangliocytomas in the sellar region are extremely rare and only 43 such tumors (including 4 own cases) have ever been described in the literature. Although these tumors are genuine rarities without any epidemiological importance, they do provide some interesting information on tumorigenesis of pituitary adenomas: 65% of the sellar gangliocytomas are associated with a pituitary adenoma. 74% of patients with these tumors suffered hormonal oversecretion of at least one of the pituitary hormones (mostly growth hormone). With only one exception, the hypothalamic releasing hormone corresponding to the hormonal oversecretion syndrome could be demonstrated in the gangliocytoma immunohistochemically. Ultrastructural studies could demonstrate close cell to cell contacts between adenoma and gangliocytome cells. All these data support the hypothesis that chronic overstimulation by hypothalamic releasing hormones play a role in the development of hormone secreting pituitary adenomas. However, in contrast to sellar gangliocytemas, extrahypothalamic tumors secreting excessive hypothalamic hypophysiotropic hormones have never been associated with a pituitary adenoma. They have only been associated with pituitary cell hyperplasia. Therefore, the hypothesis can be made that hypothalamic releasing hormones only promote but do not initiate tumorigenesis of pituitary adenomas.
Exp Clin Endocrinol Diabetes 1995
PMID:Gangliocytomas of the sellar region--a review. 758 15

Conditional oncogene expression in transgenic mice is of interest for studying the oncoprotein requirements during tumorigenesis and for deriving cell lines that can be induced to undergo growth arrest and enhance their differentiated functions. We utilized the bacterial tetracycline (Tet)-resistance operon regulatory system (tet) from Tn10 of Escherichia coli to control simian virus 40 (SV40) large tumor (T) antigen (TAg) gene expression and to generate conditionally transformed pancreatic beta cells in transgenic mice. A fusion protein containing the tet repressor (tetR) and the activating domain of the herpes simplex virus protein VP16, which converts the repressor into a transcription activator, was produced in beta cells of transgenic mice under control of the insulin promoter. In a separate lineage of transgenic mice, the TAg gene was introduced under control of a tandem array of tet operator sequences and a minimal promoter, which by itself is not sufficient for gene expression. Mice from the two lineages were then crossed to generate double-transgenic mice. Expression of the tetR fusion protein in beta cells activated TAg transcription, resulting in the development of beta-cell tumors. Tumors arising in the absence of Tet were cultured to derive a stable beta-cell line. Cell incubation in the presence of Tet led to inhibition of proliferation, as shown by decreased BrdUrd and [3H]thymidine incorporation. The Tet derivative anhydrotetracycline showed a 100-fold stronger inhibition compared with Tet. When administered in vivo, Tet efficiently inhibited beta-cell proliferation. These findings indicate that transformed beta cells selected for growth during a tumorigenesis process in vivo maintain a dependence on the continuous presence of the TAg oncoprotein for their proliferation. This system provides an approach for generation of beta-cell lines for cell therapy of diabetes as well as conditionally transformed cell lines from other cell types of interest.
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PMID:Conditional transformation of a pancreatic beta-cell line derived from transgenic mice expressing a tetracycline-regulated oncogene. 772 1

The effects of two synthetic progestins, medroxyprogesterone acetate (MPA) and proligestone (PROL), on the release of growth hormone (GH) and glucose metabolism were studied in two groups of eight ovariohysterectomized dogs. Eight injections of long-acting progestins were administered at 3-week intervals. Recovery was studied in four dogs of each treatment group in the 6 months following cessation of progestin administration. Treatment with both MPA and PROL resulted in similar increases in plasma levels of GH and insulin-like growth factor I (IGF-I). The GH responses to both clonidine and growth hormone-releasing hormone became impaired. In neither treatment group did the elevated plasma GH levels decrease after administration of the synthetic somatostatin analogue SMS 201-995. The size and shape of the pituitary gland were not changed by progestin treatment. After cessation of progestin administration, basal plasma levels of GH and IGF-I did not return to pretreatment values. The GH response to growth hormone-releasing hormone remained impaired for at least 6 months after the last progestin administration. In both treatment groups, glucose homeostasis was sustained initially by increased insulin production. Prolonged treatment with MPA and PROL resulted in glucose intolerance. No amelioration was observed during the recovery period in either group. A small number of dogs developed diabetes mellitus. In more than 50% of the dogs in both treatment groups small mammary tumours developed. The recently discovered local production of GH probably played a role in mammary tumorigenesis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Progestin treatment in the dog. I. Effects on growth hormone, insulin-like growth factor I and glucose homeostasis. 792 Dec 31

The agouti gene normally confers the wild-type coat color of mice. Dominant mutations at the agouti locus result in a pleiotropic syndrome that is characterized by excessive amounts of yellow pigment in the coat, obesity, a non-insulin-dependent diabetic-like condition, and the propensity to form a variety of tumors. Here, we describe a new dominant mutation at the agouti locus in which an intracisternal A-particle (IAP) has integrated in an antisense orientation immediately 5' of the first coding exon of the gene. This mutation, which we have named Aiapy, results in the ectopic expression of the agouti gene through the utilization of a cryptic promoter within the IAP 5' long terminal repeat (LTR). The coat color of Aiapy/-mice ranges from solid yellow to a pigment pattern that is similar to wild type (pseudoagouti), and the expressivity of this mutant phenotype varies with parental inheritance. Those offspring with a yellow coat ectopically express agouti mRNA at high levels and exhibit marked obesity, whereas pseudoagouti mice express agouti mRNA at a very low level and their weights do not differ from wild-type littermates. Data are presented to show that the differential expressivity of the Aiapy allele is correlated with the methylation status of the inserted IAP 5' LTR. These data further support the hypothesis that in dominant yellow mutations at the agouti locus, it is the ubiquitous expression of the wild-type agouti coding sequence that is responsible for the yellow coat color, obesity, diabetes, and tumorigenesis.
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PMID:Differential expression of a new dominant agouti allele (Aiapy) is correlated with methylation state and is influenced by parental lineage. 792 45

Complexes made up of the kinases, hexokinase and glycerol kinase, together with the outer mitochondrial membrane voltage-dependent anion channel (VDAC) protein, porin, and the inner mitochondrial membrane protein, the adenine nucleotide translocator, are involved in tumorigenesis, diabetes mellitus, and central nervous system function. Identification of these two mitochondrial membrane proteins, along with an 18 kD protein, as components of the peripheral benzodiazepine receptor, provides independent confirmation of the interaction of porin and the adenine nucleotide translocator to form functional contact sites between the inner and outer mitochondrial membranes. We suggest that these are dynamic structures, with channel conductances altered by the presence of ATP, and that ligand-mediated conformational changes in the porin-adenine nucleotide translocator complexes may be a general mechanism in signal transduction.
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PMID:Microcompartmentation of energy metabolism at the outer mitochondrial membrane: role in diabetes mellitus and other diseases. 807 85

Culturing and comparing the discrete stages of tumorigenesis provide a route to defining important components of the cancer phenotype and, in addition, present the opportunity to establish cell cultures more representative of normal cells than the ultimate malignant cancer cells. Herein we report that preneoplastic foci in one multistep tumorigenesis pathway can be cultured in vitro and show that they preserve distinctive characteristics of the normal cells from which they arose, pancreatic beta cells. In the RIP1-Tag2 line of transgenic mice, which express the simian virus 40 T antigen in insulin-producing beta cells, pancreatic islets develop into vascularized tumors in a multistage pathway. We established conditions for reproducible derivation of beta-cell lines from individual hyperplastic islets that have not yet developed into solid tumors. Most of these cell lines, designated beta HC, release insulin at physiological concentrations of glucose. In contrast to tumor-derived lines (beta TC), which are not properly regulated, the ability of the beta HC lines to respond correctly to glucose correlated with maintenance of normally depressed levels of low-Km hexokinases. Glutamic acid decarboxylase (GAD), an early autoantigen in type I diabetes, was detected in most of the beta HC lines. The relative levels of the two forms of this enzyme (GAD65 and GAD67) varied significantly between the different cell lines, suggesting independent regulation. Class I major histocompatibility complex antigens were detected on the beta HC cells, and the levels of surface major histocompatibility complex expression correlated with their capacity to serve as targets in a cytotoxic T-cell killing assay. The beta HC lines will be of value for studies of beta-cell physiology, autoantigenicity, and tumor development. This work suggests the possibility of culturing preneoplastic stages of other cancers, both to address the mechanisms of transformation and to provide a source of cells that maintain important qualities of their normal progenitors.
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PMID:Pancreatic beta cells cultured from individual preneoplastic foci in a multistage tumorigenesis pathway: a potentially general technique for isolating physiologically representative cell lines. 839 34


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