Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin molecules were covalently attached to detergent-solubilized Sendai virus envelope glycoproteins (HN and F polypeptides) by the use of the crosslinking reagent succinimidyl 4-(p-maleimidophenyl)butyrate (SMPB). Reconstitution of modified viral glycoproteins (carrying covalently attached insulin) together with unmodified viral glycoproteins resulted in the formation of "fusogenic" viral envelopes bearing insulin molecules. Reconstitution of such fusogenic viral envelopes in the presence of ricin A or simian virus 40 (SV40) DNA resulted in the formation of viral envelopes bearing insulin molecules and loaded with ricin A or SV40 DNA. Such viral envelopes were able to bind to hepatoma tissue culture cells (HTCC) from which Sendai virus receptors were removed by treatment with neuraminidase. Incubation of viral envelopes loaded with ricin A with virus receptor-depleted HTCC resulted in fusion-mediated injection of the toxin, as inferred from inhibition of protein synthesis and decrease in cell viability of the microinjected cells. Fusion-mediated injection of SV40 DNA was inferred from the appearance of SV40 tumor antigen in microinjected cells. Binding and fusion of the loaded viral envelopes to neuraminidase-treated HTCC was mediated solely by the virus-associated insulin molecules. Addition of free insulin molecules inhibited binding of the viral envelopes and, consequently, the microinjection of ricin A and SV40 DNA.
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PMID:Targeting of loaded Sendai virus envelopes by covalently attached insulin molecules to virus receptor-depleted cells: fusion-mediated microinjection of ricin A and simian virus 40 DNA. 299 83

Insulin-secreting tumor of the pancreas was diagnosed in 55 dogs. Diagnosis was based mainly on the increase of serum insulin concentrations in the presence of hypoglycemia. The use of the amended insulin/glucose ratio to diagnose the tumor, although providing less false-negative results than did increased serum insulin concentrations alone, appeared less specific and gave false-positive results in dogs without insulin-secreting tumors. Management of the disease included surgical intervention alone (26 dogs), surgery plus medical management with diazoxide (14 dogs), and medical management with diazoxide alone (4 dogs). Eleven dogs were euthanatized at the time of diagnosis. Diazoxide therapy controlled hypoglycemia in about 70% of the dogs.
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PMID:Insulin-secreting tumor: diagnosis and medical and surgical management in 55 dogs. 300 16

Hypoglycemia secondary to organic hyperinsulinism in children can be caused by diffuse or localized pancreatic lesions. Differentiation between these two types of lesions is of utmost importance since the surgical approach will be different. Some tumors escape detection by all preoperative investigations including ultrasound, scintiscan, arteriography, and computerized tomography. We are reporting on a 12-year-old boy with organic hyperinsulinism in whom we were unable to localize a tumor preoperatively. Peroperative determination of insulin levels from a number of sites on the pancreas enabled us to localize an insulin-producing pancreatic adenoma. This technique can be done easily by catheterizing the splenic and portal vein through a branch of the splenic vein and by serial sampling at 2 cm intervals along the portal and splenic veins. Insulin levels at these sites were determined by quick double-antibody radioimmunoassay, which allows the determination of the insulin levels within 50 minutes after sampling. There was a perfect biochemic and anatomic correlation allowing us to perform a precise distal pancreatectomy. The technique can be used to localize pancreatic adenomas and to decide how much pancreas to remove in diffuse lesions avoiding "blind" pancreatectomies.
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PMID:The occult insulinoma operative localization by quick insulin radioimmunoassay. 300 24

The differential tissue-specific regulation of glucokinase activity in liver and pancreatic islet cells was investigated in the insulinoma-bearing rat. A transplantable insulinoma caused hyperinsulinemia and hypoglycemia in the host by 2-3 months after implantation. Suppression of the pancreatic B-cells by the high insulin and/or low glucose manifested itself by a decrease of insulin in islet tissue. Removal of the tumor initiated transient insulin deficiency and hyperglycemia with extremes of these changes at 24 h after tumor resection. These conditions markedly affected glucose phosphorylation in the islet cells: glucokinase activity was reduced 71% in islet samples from insulinoma-bearing rats, and the enzyme fully recovered within 24 h after tumor resection. Hexokinase activity, by contrast, was not affected by these manipulations. To evaluate the relative contributions of hypoglycemia and hyperinsulinemia in islet glucokinase adaptation, glucose was intravenously infused to insulinoma-bearing rats; glycemia in excess of 150 mg/100 ml combined with excessive hyperinsulinemia resulted in a partial recovery of islet glucokinase activity, first apparent after 9 h of glucose infusion and with doubling of the activity after 24 h after glucose loading. In contrast, liver glucokinase was increased nearly 4-fold at the time of extreme hypoglycemia and hyperinsulinemia and rapidly fell to control rates following tumor removal. Intravenous infusion of glucose for 24 h into the tumor-bearing rat (i.e. hyperglycemia combined with excessive plasma insulin) had no influence on liver glucokinase activity. Liver hexokinase was not influenced by any of these experimental manipulations. The data indicate that the activities of pancreatic islet and liver glucokinase are regulated in a differential manner. Insulin is apparently the primary determinant of liver glucokinase and glucose seems to control islet glucokinase. Biochemical mechanisms for differential organ-specific regulation of glucokinase activity seem to have evolved such that this enzyme may play a dual role in glucose homeostasis, namely to serve as insulin-dependent glucose sensor in the B-cells and as insulin-sensitive determinant of hepatic glucose use.
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PMID:Differential regulation of glucokinase activity in pancreatic islets and liver of the rat. 301 39

Insulin (INS) stimulates, and diabetes inhibits, low Km cAMP phosphodiesterase (PDE). This mechanism, at least in part, accounts for the lowering of cyclic AMP levels in plasma and tissue of diabetic patients and animals. Phorbol, a tumor-promoting agent known to act through protein kinase C and calcium translocation, exhibits a powerful effect stimulating PDE in rat adipose tissue. Nifedipine, a calcium channel blocker, inhibits insulin, but not phorbol stimulated PDE. These data demonstrate new effects of inositide diacylglycerol-Ca++ pathway components on PDE and suggest some common pathways of activation of low Km cAMP PDE through insulin and phorbol esters.
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PMID:Activation of cyclic AMP phosphodiesterase by phorbol and protein kinase C pathway. 301 37

The mechanisms by which glyburide and tolbutamide signal insulin secretion were examined using a beta cell line (Hamster insulin-secreting tumor (HIT) cells). Insulin secretion was measured in static incubations, free cytosolic Ca2+ concentration ([Ca2+]i) was monitored in quin 2-loaded cells, and cAMP quantitated by radioimmunoassay. Insulin secretory dose-response curves utilizing static incubations fit a single binding site model and established that glyburide (ED50 = 112 +/- 18 nM) is a more potent secretagogue than tolbutamide (ED50 = 15 +/- 3 microM). Basal HIT cell [Ca2+]i was 76 +/- 7 nM (mean +/- S.E., n = 141) and increased in a dose-dependent manner with both glyburide and tolbutamide with ED50 values of 525 +/- 75 nM and 67 +/- 9 microM, respectively. The less active tolbutamide metabolite, carboxytolbutamide, had no effect on [Ca2+]i or insulin secretion. Chelation of extracellular Ca2+ with 4 mM EGTA completely inhibited the sulfonylurea-induced changes in [Ca2+]i and insulin release and established that the rise in [Ca2+]i came from an extracellular Ca2+ pool. The Ca2+ channel blocker, verapamil, inhibited glyburide- or tolbutamide-stimulated insulin release and the rise in [Ca2+]i at similar concentrations with IC50 values of 3 and 2.5 microM, respectively. At all concentrations tested, the sulfonylureas did not alter HIT cell cAMP content. These findings provide direct experimental evidence that glyburide and tolbutamide allow extracellular Ca2+ to enter the beta cell through verapamil-sensitive, voltage-dependent Ca2+ channels, causing a rise in [Ca2+]i which is the second messenger that stimulates insulin release.
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PMID:Increased cytosolic calcium. A signal for sulfonylurea-stimulated insulin release from beta cells. 302 89

The diagnosis of insulinoma on the basis of persistent hypoglycemia requires further confirmation. The insulin suppression test has been used to support this diagnosis prior to surgical intervention. In this study the euglycemic clamp technique was used to compare five control volunteers with four hypoglycemic patients with suspected insulinoma. Insulin was infused over successive two-hour periods at 2, 4, and 8 mU/kg/min. Plasma glucose levels were clamped at 80 mg/dL (4.4 mmol/L) using an artificial pancreas. High insulin levels were measured in all subjects, ranging from 225 +/- 30 microU/mL (1614 +/- 215 pmol/L) to 1018 +/- 239 microU/mL (7304 +/- 1714 pmol/L). Levels of C peptide fell to 0.1 ng/mL (0.028 nmol/L) in control subjects but remained at high levels in the patients. Insulinoma was confirmed on laparotomy in all four patients. In two patients tested after removal of the tumor the results were found to have returned to normal.
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PMID:Use of the glucose clamp technique for confirmation of insulinoma autonomous hyperinsulinism. 303 80

The purpose of this study was to determine whether the energy metabolism of an experimental rodent sarcoma was selectively depressed by the combination of inhibition of glycolysis and respiration. In vivo phosphorus-31 nuclear magnetic resonance spectroscopy was used to monitor the response of tumor or brain high-energy phosphate compounds to insulin hypoglycemia, rhodamine 123, or both agents in fasting rats with subcutaneous methylcholanthrene-induced sarcomas. Insulin or rhodamine 123 alone produced a similar 50% to 60% reduction in tumor adenosine triphosphate (ATP) concentration compared with controls injected with saline solution (p less than 0.05, one-way analysis of variance [ANOVA]). The combination of insulin plus rhodamine 123 resulted in a 90% reduction of tumor ATP concentration, which was significantly different from the effect of either agent alone (p less than 0.05, one-way ANOVA). Brain phosphocreatine and ATP concentrations were unchanged by these agents. Administration of dimethyl sulfoxide (DMSO)/glycerol, the vehicle for rhodamine, produced a 35% reduction of tumor ATP, which was similar to the effect of insulin alone but significantly different from rhodamine. The combination of DMSO/glycerol plus insulin hypoglycemia resulted in a 70% reduction in tumor ATP, which was significantly elevated compared with the combination of rhodamine plus insulin. Glucose deprivation induced by insulin, and combined with the inhibition of oxidative phosphorylation, produces an additive depression of tumor energetics. The drug vehicle DMSO/glycerol significantly depresses tumor energy metabolism, presumably because of its DMSO component, which may explain the previously reported antineoplastic efficacy of this solvent. Combinations of inhibitors directed at different points of tumor metabolism produced an enhanced depression of tumor energetics, whereas host tissue was protected.
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PMID:Inhibition of tumor high-energy phosphate metabolism by insulin combined with rhodamine 123. 304 41

Cancer cachexia is a complex syndrome that includes host tissue wasting, anorexia, asthenia, and abnormal host intermediary metabolism. It is present in approximately 50% of cancer patients during treatment and nearly 100% of treated cancer patients at death. Cachexia has a detrimental impact on cancer therapy. The central problem of cancer cachexia is that energy balance is not maintained, and the host has a relative hypophagia which results in host tissue wasting. The tumor by its nature and obligate growth can continue to consume glucose, amino acids, and lipids at the expense of the host. This produces abnormal host intermediary metabolism including elevated glucose production and recycling, decreased muscle protein synthesis, and increased muscle and fat breakdown. The exact mechanisms of cancer cachexia have been only partially elucidated. The identification of signal molecules like cachectin which mediate these changes may be on the horizon. Nutritional support can reverse some of the derangements seen with cachexia, and there is evidence that functional lean body mass or body cell mass can be restored in some (but not all) patients. However, nutritional support has not yet improved response to chemotherapy or radiation therapy, nor has it improved host tolerance of chemotherapy. It has improved operative mortality and morbidity in cachectic cancer patients undergoing major surgical procedures. Optimum host nutritional support appears to be dependent on high insulin concentrations in both humans and rats. Insulin and exercise may be methods to preserve host lean tissue and feed the host rather than the tumor. Future studies depend on better definition of tumor-bearing host metabolism, altering the relationship between neoplasm and host to preferentially feed the host, and making the neoplasm more susceptible to effective treatment.
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PMID:Cancer cachexia. 312 81

Tumour-promoting phorbol esters have insulin-like effects on glucose transport and lipogenesis in adipocytes and myocytes. It is believed that insulin activates the glucose-transport system through translocation of glucose transporters from subcellular membranes to the plasma membrane. The aim of the present study was to investigate if phorbol esters act through the same mechanism as insulin on glucose-transport activity of rat adipocytes. We compared the effects of the tumour-promoting phorbol ester tetradecanoylphorbol acetate (TPA) and of insulin on 3-O-methylglucose transport and on the distribution of D-glucose-inhibitable cytochalasin-B binding sites in isolated rat adipocytes. Insulin (100 mu units/ml) stimulated 3-O-methylglucose uptake 9-fold, whereas TPA (1 nM) stimulated the uptake only 3-fold (mean values of five experiments, given as percentage of equilibrium reached after 4 s: basal 7 +/- 1.3%, insulin 60 +/- 3.1%, TPA 22 +/- 2.3%). In contrast, both agents stimulated glucose-transporter translocation to the same extent [cytochalasin B-binding sites (pmol/mg of protein; n = 7): plasma membranes, basal 6.2 +/- 1.0, insulin 13.4 +/- 2.0, TPA 12.7 +/- 2.7; low-density membranes, basal 12.8 +/- 2.1, insulin 6.3 +/- 0.9, TPA 8.9 +/- 0.7; high-density membranes, 6.9 +/- 1.1; insulin 12.5 +/- 1.0, TPA 8.1 +/- 0.9]. We conclude from these data: (1) TPA stimulates glucose transport in fat-cells by stimulation of glucose-carrier translocation; (2) insulin and TPA stimulate the carrier translocation to the same extent, whereas the stimulation of glucose uptake is 3-fold higher with insulin, suggesting that the stimulatory effect of insulin on glucose-transport activity involves other mechanisms in addition to carrier translocation.
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PMID:Phorbol esters imitate in rat fat-cells the full effect of insulin on glucose-carrier translocation, but not on 3-O-methylglucose-transport activity. 328 56


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