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 hormonal environments require by human breast cancer cells MCF-7 to produce solid tumors in nude mice are described. A 100% take was obtained within 7 days following inoculation of 2X10(6) actively growing (log phase) MCF-7 cells into the mammary fat pads of intact, athymic BALB/c nude mice. Tumors failed to develop, even with an inoculum of 20X10(6) cells/mouse, in ovariectomized mice or in mice made diabetic with streptozotocin and observed for 90 days after cell inoculation. A 100% incidence of tumors was obtained in mice that were either hypophysectomized or made diabetic but received injections of 0.2 IU insulin/day/mouse. A 100% incidence of tumors was also obtained in ovariectomized mice that received 17 beta-estradiol in the form of a pellet placed subcutaneously in the interscapular region at the time of cell inoculation. Palpable tumors also developed in ovariectomized mice treated with prolactin, perphenazine, estrone, or estriol, but no takes were observed in ovariectomized mice treated with progesterone, 5 alpha-dihydrotestosterone, or hydrocortisone. Growth of the MCF-7 tumor was stimulated five- to sixfold in both intact and hypophysectomized mice that each received a 17 beta-estradiol pellet. Removal of the 17 beta-estradiol pellets form tumor-bearing ovariectomized mice failed to induce tumor regression. Tumors that continued to grow in ovariectomized mice deprived of 17 beta-estradiol regressed by 50% or more of their initial volume when tamoxifen was injected for 7 days at 5 micrograms/mouse/day) +/- theophyline (1 mg/mouse/day), tumor growth arrest was observed during the 2-to 3-week treatment period. Streptozotocin-induced diabetes in tumor-bearing mice always resulted in complete tumor regression following a 3-week treatment period.
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PMID:Role of hormones in the growth and regression of human breast cancer cells (MCF-7) transplanted into athymic nude mice. 626 82

We evaluated the effect of metformin (N,N-dimethylbiguanide), a biguanide known to be less toxic than phenformin, on insulin binding to its receptors, both in vitro and in vivo. Specific 125I-insulin binding to cultured IM-9 human lymphocytes and MCF-7 human breast cancer cells was determined after preincubation with metformin. Specific 125I-insulin binding to circulating monocytes was also evaluated in six controls, eight obese subjects, and six obese type II diabetic patients before and after a short-term treatment with metformin (850 mg orally, b.i.d., for 4 days). Plasma insulin levels and blood glucose were also measured on both occasions. Metformin significantly increased insulin binding in vitro to both IM-9 lymphocytes and MCF-7 cells; the maximum increment was 47.1% and 38.0%, respectively. Metformin treatment significantly increased insulin binding in vivo to monocytes of obese subjects (+ 31%, P less than 0.05) and diabetic patients (+ 63%, P less than 0.01). Scatchard analysis indicated that the increased binding was mainly due to an increase in receptor capacity. Insulin binding to monocytes of normal controls was unchanged after metformin as were insulin levels in all groups; blood glucose was significantly reduced after metformin only in diabetic patients. These data indicate that metformin increases insulin binding to its receptors in vitro and in vivo. The effect in vivo is observed in obese subjects and in obese type II diabetic patients, paralleling the clinical effectiveness of this antidiabetic agent, and is not due to receptor regulation by circulating insulin, since no variation in insulin levels was recorded. By this mechanism, therefore, metformin may contribute to restoring insulin effectiveness in subjects with impaired insulin responsiveness.
Diabetes Care
PMID:Metformin and insulin receptors. 637 23

MCF-7 cells, a human breast carcinoma line, forms tumors when injected into athymic nude mice. These tumors are able to metastasize to lungs, liver and spleen. 17 beta-estradiol treatment increases both the growth rate and frequency of metastases. Castration or diabetes prevents metastasis formation, but treatment with estrogen or insulin restores the metastasizing capacity. MCF-7 cells secrete into the culture media collagenases able to lyse types I and IV collagens. Estrogen or insulin addition to the culture enhances collagenase production. Attention is called to the coexistence of enhancement in collagenase production and metastasis formation.
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PMID:Formation of metastasis by human breast carcinoma cells (MCF-7) in nude mice. 645 Jun 36

The effects of the two groups of oral agents on insulin receptors were studied in several types of cells in tissue culture: MCF-7 human breast cancer cells, IM-9 human lymphocytes, human fibroblasts, and H-35 rat hepatoma cells. In none of these cells did the four sulfonylureas tested, tolbutamide, glibenclamide (glyburide), gliclazide, and glisolamide, have any significant effects on insulin binding to its receptor. In contrast the two biguanides tested, phenformin and metformin, increased insulin binding in all cell types by 44 to 101%. These studies raise the possibility, therefore, that biguanides may have a direct effect on insulin receptors and this effect may account for the known effects of biguanides to lower elevated blood sugar levels in diabetic patients.
Diabetes Care
PMID:Effects of biguanides and sulfonylureas on insulin receptors in cultured cells. 673 5

The effect of the hypoglycemic biguanide, phenformin, on the binding of insulin to MCF-7 cells, an in vitro line derived from a human breast cancer, has been investigated. Cells incubated for 24 h in the presence of 1.0 micrograms/ml of phenformin bound 62.2 +/- 8.1% (mean +/- SE) more 125I-insulin than did controls. The phenformin effect was dose-dependent over the concentration range of 0.1 micrograms/ml to 10.0 micrograms/ml. The increased binding was due to an increase in receptor number without a change in binding affinity. This demonstration of increased receptor number in response to phenformin exposure provides support for the hypothesis that one action of phenformin is to enhance tissue sensitivity to insulin.
Diabetes 1980 Apr
PMID:Phenformin increases insulin binding to human cultured breast cancer cells. 698 25

We previously demonstrated that activation of the insulin-receptor promoter occurs between Xho I and HindIII restriction enzyme sites located 877 and 578 bp upstream, respectively, from the translational initiation site. Deletion mutants 5' of this promoter region were constructed with the reporter gene, CAT, and transiently transfected into HepG2 and MCF-7 cells. This study demonstrated that most of the promoter activity could be localized to a 40-bp region between -618 and -578. When attached to a heterologous SV40 early promoter, this 40-bp insulin-receptor regulatory region, in either orientation, stimulated the SV40 early promoter by approximately two- to threefold after transfection into HepG2 cells. EMSA demonstrated that the purified transcription factor, Sp1, binds to this transcription activator. DNA binding of protein obtained from crude HepG2 nuclear extracts demonstrated electrophoretically retarded bands that competed for the consensus Sp1 element; these bands were not observed in a similar analysis with crude MCF-7 nuclear extracts. However, in both HepG2 and MCF-7 cells, a protein was identified that specifically binds to this important insulin-receptor promoter region, but does not bind to the Sp1 consensus element. We conclude that activation of insulin-receptor gene transcription occurs in a 40 bp region 578 bp upstream from the translational initiation site, and that Sp1 and another nuclear factor other than Sp1 may be important in regulating transcription in HepG2 cells.
Diabetes 1993 Jan
PMID:Nuclear protein-binding analysis of a GC-rich insulin-receptor promoter regulatory region. 838 May 64

MDA-MB231 human breast cancer cells are unresponsive to insulin and contain a glycoprotein inhibitor of insulin-stimulated insulin receptor (IR) tyrosine kinase activity. Prior studies in both fibroblasts from insulin- resistant non-insulin-dependent diabetes mellitus patients and transfected cells indicate that overexpression of membrane glycoprotein PC-1 reduces IR tyrosine kinase activity. In the present study, we measured PC-1 content and activity in MDA-MB231 and four other human breast cancer cell lines. We observed that PC-1 expression was 3- to 30-fold higher in MDA-MB231 cells when compared with the other breast cell lines. Wheat germ agglutinin extracts of MDA-MB231 cells inhibited IR tyrosine kinase activity. Treatment of these extracts with an antibody to PC-1 significantly reduced their ability to inhibit insulin-stimulated IR tyrosine kinase activity. In addition, when cell clones with different PC-1 activity were selected from MDA-MB231 cells, we found an inverse correlation (r = -0.741, P = 0.006) between the PC-1 activity and the insulin-stimulated IR autophosphorylation. A similar inverse correlation was observed in cell clones derived from the insulin-responsive breast cancer cell line MCF-7. By both immunoprecipitation and cross-linking studies we found PC-1 to be associated with IR. These studies indicate, therefore, that overexpression of PC-1 in MDA-MB231 cells may account, at least in part, for the reduced IR tyrosine kinase activity and suggest that PC-1 is a specific modulator of the IR activity in breast cancer cells.
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PMID:Overexpression of membrane glycoprotein PC-1 in MDA-MB231 breast cancer cells is associated with inhibition of insulin receptor tyrosine kinase activity. 892 58

Insulin receptor substrate-1 (IRS-1) is involved in insulin signal transduction distal to receptor occupation. Targeted disruption of IRS-1 leads to insulin resistance and hyperglycemia in mice, which suggests that altered IRS-1 expression could contribute to the insulin resistance seen in non-insulin-dependent diabetes mellitus. In vitro studies using phorbol esters have implicated the protein kinase C (PKC) pathway as being involved in the pathogenesis of insulin resistance. Using the MCF-7 breast cancer cell, a role for PKC in regulating IRS-1 expression was examined. In an MCF-7 cell line (MCF-7-PKC-alpha) that exhibits multiple alterations in PKC isoform expression, IRS-1 content was reduced to negligible levels relative to parental MCF-7 cells. This decrease in IRS-1 content was associated with a 30-fold reduction in IRS-1 transcription. In parental MCF-7 cells, PKC inhibitors (GF109203X (bisindolylmaleimide I) and staurosporine) reduced IRS-1 content. Chronic exposure to 12-O-tetradecanoylphorbol-13-acetate (TPA; >8 h) reduced IRS-1 content and down-regulated the novel PKC-delta isoform. Bryostatin 1 inhibited TPA-induced depletion of both IRS-1 and PKC-delta expression in MCF-7 cells. Associated with TPA-induced reduction in IRS-1 content was a reduction in IRS-1 transcription. These data demonstrate that PKC can modulate IRS-1 content and suggest a potential role for PKC-delta in positively regulating IRS-1 expression.
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PMID:Transcriptional regulation of insulin receptor substrate 1 by protein kinase C. 894 87

Plasma cell membrane glycoprotein-1 (PC-1) inhibits insulin receptor (IR) tyrosine kinase activity and subsequent cellular signaling. PC-1 content is elevated in fibroblasts, muscle, and adipose tissue from insulin-resistant subjects, and its elevation correlates with in vivo insulin resistance. In vitro, when PC-1 is transfected and overexpressed in cultured cells, it inhibits IR tyrosine kinase activity. To determine the mechanism whereby PC-1 regulates the IR, we studied how PC-1 interacts with this protein. Overexpression of PC-1 in MCF-7 cells inhibited tyrosine kinase activity of the IR, but not of the IGF-I receptor. When the IR was immunocaptured by specific IR monoclonal antibodies, PC-1 was associated with this receptor. In contrast, after specific immunocapture, PC-1 was not associated with the IGF-I receptor. We next studied HTC cells that were overexpressing an IR alpha-subunit mutant. This IR mutant binds insulin but has a deletion in the tyrosine kinase regulatory domain located in amino acids 485-599. In contrast to normal IRs, PC-1 did not associate with this mutant and did not affect tyrosine kinase activity. To determine whether decreasing PC-1 expression would reverse the inhibition of tyrosine kinase activity, we treated MCF-7 cells overexpressing PC-1 with a monoclonal antibody to PC-1. This treatment decreased PC-1 levels; concomitantly, IR tyrosine kinase activity increased. In contrast, IGF-I receptor tyrosine kinase activity was not increased. These studies indicate, therefore, that PC-1 may inhibit the IR by interacting directly with a specific region in the IR alpha-subunit. These studies also raise the possibility that monoclonal antibodies to PC-1 could be a new treatment for insulin resistance.
Diabetes 2000 Jan
PMID:Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs via direct interaction with the receptor alpha-subunit. 1061 44

When overexpressed, the membrane glycoprotein PC-1 may play a role in human insulin resistance through the inhibition of insulin receptor (IR) autophosphorylation. A PC-1 variant (K121Q, with lysine 121 replaced by glutamine) is also associated with whole-body insulin resistance when not overexpressed. To better understand the effects of the Q allele on IR function and downstream signaling, we transfected cultured cells with cDNAs for either the Q or the K alleles. In human MCF-7 cells, the Q allele was severalfold more effective (P < 0.05-0.01) than the K allele in reducing insulin stimulation of IR autophosphorylation, insulin receptor substrate-1 phosphorylation, phosphatidylinositol 3-kinase activity, glycogen synthesis, and cell proliferation. Similar data on IR autophosphorylation inhibition were also obtained in mouse R-/hIR and human HEK 293 cell lines. In transfected MCF-7 cells, 125I-labeled insulin binding and IR content were unchanged, and PC-1 overexpression did not influence IGF-1 stimulation of IGF-1 receptor autophosphorylation. Both the Q and K alleles directly interacted with the IR, as documented by coimmunoprecipitation assays. This interaction was greater for the Q allele than for the K allele (P < 0.01), suggesting that direct PC-1-IR interactions are important for the PC-1 inhibitory effect on insulin signaling. In conclusion, the Q allele has stronger inhibitory activity on IR function and insulin action than the more common K allele, and this is likely a consequence of the intrinsic characteristics of the molecule, which more strongly interacts with the IR.
Diabetes 2001 Apr
PMID:The Q allele variant (GLN121) of membrane glycoprotein PC-1 interacts with the insulin receptor and inhibits insulin signaling more effectively than the common K allele variant (LYS121). 1128 49


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