RESUMEN
Vanadium-based drugs lower glucose by enhancing the effects of insulin. Oral vanadium drugs are being tested for the treatment of diabetes. Vanadium accumulates in bone, though it is not known if incorporated vanadium affects bone quality. Nine- to 12-month-old control and streptozotocin-induced diabetic female Wistar rats were given bis(ethylmaltolato)oxovanadium(IV) (BEOV), a vanadium-based anti-diabetic drug, in drinking water for 12 weeks. Non-diabetic rats received 0, 0.25 or 0.75 mg/ml BEOV. Groups of diabetic rats were either untreated or treated with 0.25-0.75 mg/ml BEOV as necessary to lower blood glucose in each rat. In diabetic rats, this resulted in a Controlled Glucose group, simulating relatively well-managed diabetes, and an Uncontrolled Glucose group, simulating poorly managed diabetes. Plasma insulin, glucose and triglyceride assays assessed the diabetic state. Bone mineral density (BMD), mechanical testing, mineral assessment and histomorphometry measured the effects of diabetes on bone and the effects of BEOV on non-diabetic and diabetic bone. Diabetes decreased plasma insulin and increased plasma glucose and triglycerides. In bone, diabetes decreased BMD, strength, mineralization, bone crystal length, and bone volume and connectivity. Treatment was effective in incorporating vanadium into bone. In all treated groups, BEOV increased osteoid volume. In non-diabetic bone, BEOV increased cortical bone toughness, mineralization and bone formation. In controlled glucose rats, BEOV lowered plasma glucose and improved BMD, mechanical strength, mineralization, bone crystal length and bone formation rate. In poorly controlled rats, BEOV treatment slightly lowered plasma glucose but did not improve bone properties. These results suggest that BEOV improves diabetes-related bone dysfunction primarily by improving the diabetic state. BEOV also appeared to increase bone formation. Our study found no negative effects of vanadium accumulation in bone in either diabetic or non-diabetic rats at the dose given.
Asunto(s)
Huesos/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Vanadatos/administración & dosificación , Vanadatos/farmacología , Absorciometría de Fotón , Administración Oral , Animales , Fenómenos Biomecánicos , Glucemia/metabolismo , Peso Corporal , Densidad Ósea , Huesos/efectos de los fármacos , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/fisiopatología , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Insulina/sangre , Radioinmunoensayo , Distribución Aleatoria , Ratas , Ratas Wistar , Triglicéridos/sangre , Vanadatos/farmacocinética , Vanadatos/uso terapéutico , Difracción de Rayos XRESUMEN
This is a preliminary study in which both acute and chronic oral administration of bis(maltolato)oxovanadium (IV) (BMOV) was examined in the Zucker diabetic fatty (ZDF) rat, an animal model that develops overt hyperglycemia in the presence of hyperinsulinemia followed by beta-cell depletion. At 9-10 weeks of age, in the presence of hyperglycemia, hyperinsulinemia and hyperlipidemia, an acute oral gavage dose response was conducted to determine glucose-lowering properties of BMOV, time of response and effect of BMOV on plasma insulin levels. Doses of BMOV greater than 0.2 mmol/kg resulted in plasma glucose levels of less than 9 mmol/l. The highest dose administered (0.8 mmol/kg) significantly reduced plasma insulin (initial: 2.83+/-0.2, final: 1.23+/-0.09 nmol/l, P<0.05) and plasma triglyceride (initial: 4.94+/-0.33, final: 1.55+/-0.07 mmol/l, P<0.05) levels. At 15 weeks of age, in the presence of hyperglycemia, hyperlipidemia and normal insulin levels, BMOV was administered orally in the drinking water for a 10-week period to determine the effect of treatment on glucose, insulin and lipid levels. BMOV treatment significantly reduced plasma glucose levels (final BMOV-treated: 13.25+/-1.43, untreated: 28.71+/-0.6 mmol/l, P<0.05) and effectively preserved pancreatic beta-cell function. These data suggest a role for BMOV as a therapeutic agent in non-insulin-dependent diabetes mellitus through improvement in glucose homeostasis and preservation of insulin reserves.
Asunto(s)
Diabetes Mellitus/sangre , Hipoglucemiantes/administración & dosificación , Obesidad , Pironas/administración & dosificación , Ratas Zucker/sangre , Vanadatos/administración & dosificación , Administración Oral , Animales , Glucemia/análisis , Glucemia/efectos de los fármacos , Diabetes Mellitus/genética , Relación Dosis-Respuesta a Droga , Hipoglucemiantes/farmacología , Insulina/sangre , Masculino , Pironas/farmacología , Ratas , Ratas Zucker/genética , Factores de Tiempo , Triglicéridos/sangre , Vanadatos/farmacologíaRESUMEN
Sodium selenate, administered intraperitoneally (i.p.), resulted in an improvement in glucose tolerance in treated diabetic rats. Fed rat plasma glucose levels were reduced by selenate treatment in streptozotocin diabetic rats. The lowest values of blood glucose were reached within 3 weeks of beginning the treatment. Food and fluid consumption was reduced in treated compared to untreated diabetic rats. Diabetic treated rats did not release insulin in response to a glucose challenge and insulin release in response to a challenge was markedly reduced in control treated rats. Assessment of heart function using a working heart apparatus showed that treated diabetic rats with improved blood glucose levels had normal heart function at 8 weeks of diabetes in contrast to hearts from non-treated diabetics. This study extends previous observations on the in vivo insulin-like effects of sodium selenate.
Asunto(s)
Glucemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Corazón/efectos de los fármacos , Compuestos de Selenio/farmacología , Animales , Peso Corporal/efectos de los fármacos , Cardiomiopatías/fisiopatología , Complicaciones de la Diabetes , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Glucosa/farmacología , Prueba de Tolerancia a la Glucosa , Pruebas de Función Cardíaca/efectos de los fármacos , Insulina/metabolismo , Lípidos/sangre , Ratas , Ratas Wistar , Ácido Selénico , Vanadio/farmacologíaRESUMEN
To explore the mechanism underlying the insulin-mimetic actions of vanadium and selenium we examined their effects on the mitogen activated protein/myelin basic protein kinases (MAPK) and ribosomal S6 protein kinases, which are among the best characterized of the kinases that comprise the phosphorylation cascade in insulin signal transduction. We observed a transient activation of MAPK and S6 kinases by insulin in rat adipocytes, while both sodium selenate and vanadyl sulphate produced prolonged activation of the kinases. Vanadyl sulphate stimulated the activity of MAPK and S6 kinase by as much as 6 fold and 15 fold, respectively. Pretreatment of the cells with genistein did not affect the activation of MAPK by insulin, but partially blocked the effects of sodium selenate and vanadyl sulphate. Genistein did not change the activation of S6 kinase by insulin, but blocked the activation in vanadyl sulphate- and sodium selenate-treated-cells, suggesting that a genistein sensitive tyrosine kinase may be involved in the activation by these two compounds. Rapamycin, a specific inhibitor of the p70s6k isoform of S6 kinase, partially reduced the activation of S6 kinase activity by sodium selenate, indicating a role for this kinase in the overall activity of the S6 kinase in sodium selenate-treated cells. A similar trend was noted in vanadyl sulphate-treated cells. Thus, this study supports the involvement of MAPK and S6 kinases in the insulin-mimetic actions of vanadium and selenium.
Asunto(s)
Tejido Adiposo/enzimología , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Proteínas Quinasas S6 Ribosómicas/metabolismo , Selenio/farmacología , Vanadio/farmacología , Tejido Adiposo/efectos de los fármacos , Animales , Cromatografía por Intercambio Iónico , Activación Enzimática , Técnicas In Vitro , Insulina/farmacología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Controversial reports on the efficacy and possible toxicity of vanadium obtained from various studies may be attributed to differences in the method of diabetes induction and (or) to differences in animal strains. The objective of this study was to evaluate the contribution of these two factors to the effects of vanadium in the treatment of experimental diabetes. Two methods of streptozotocin induction of diabetes in rats have been used for studying the antidiabetic effects of vanadium. One involves a single intravenous injection of 60 mg/kg streptozotocin, and the other uses two subcutaneous injections of 40 mg/kg streptozotocin, to either Wistar or Sprague-Dawley rats. In a 7-week chronic study, Sprague-Dawley rats appeared to develop a more severe diabetes (indicated by higher plasma cholesterol and higher fasting plasma glucose levels) following the single intravenous injection of streptozotocin than rats made diabetic by two subcutaneous injections of streptozotocin. Irrespective of the method of diabetes induction, the responses of all the diabetic animals to chronic vanadyl sulphate treatment were similar. In an acute study, Wistar diabetic rats were more responsive than Sprague-Dawley diabetic rats to vanadyl sulphate and to lower doses (0.6 and 0.8 mmol/kg) of a new organic vanadium compound, bis(maltolato)oxovanadium(i.v.).
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Pironas/uso terapéutico , Vanadatos/uso terapéutico , Compuestos de Vanadio/uso terapéutico , Animales , Glucemia/efectos de los fármacos , Diabetes Mellitus Experimental/sangre , Ácidos Grasos no Esterificados/sangre , Prueba de Tolerancia a la Glucosa , Insulina/sangre , Pironas/sangre , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Estreptozocina , Triglicéridos/sangre , Vanadatos/sangre , Compuestos de Vanadio/sangre , Compuestos de Vanadio/toxicidadRESUMEN
The incidence of mortality from cardiovascular disease is higher in diabetic patients. The objective of the present investigation was to test the hypothesis that the diabetes-induced depression in cardiac function may be due to hypertriglyceridemia. Hyperlipidemia and a depressed left ventricular developed pressure and rate of increase and decrease of ventricular pressure (+/- dP/dt) were produced in isolated hearts from rats made diabetic with streptozotocin compared with hearts from control animals. This depressed cardiac performance was successfully prevented by hydralazine treatment (for 3 weeks), which also lowered plasma triglyceride levels and suggested that hyperlipidemia may be important in altering cardiac function in experimental diabetic rats. The beneficial effects of clofibrate, verapamil, prazosin, enalapril, and benazepril administration were then studied in diabetic rats. The treatments (with the exception of enalapril) significantly reduced plasma triglyceride levels but did not prevent the onset of heart dysfunction in chronically diabetic rats. These studies suggest that in the chronically diabetic rat, hypertriglyceridemia may not be as important as previously suggested, in the development of cardiac dysfunction. Since acute dichloroacetate perfusion improves cardiac function in 6 week (but not 24 week) diabetic rats, it appears more likely that improving myocardial glycose utilization is more critical than triglyceride lowering, in preventing cardiac dysfunction in the diabetic rat at this time point.
Asunto(s)
Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/complicaciones , Cardiopatías/etiología , Corazón/efectos de los fármacos , Corazón/fisiopatología , Hipertrigliceridemia/complicaciones , Animales , Antihipertensivos/uso terapéutico , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Colesterol/sangre , Clofibrato/uso terapéutico , Diabetes Mellitus Experimental/tratamiento farmacológico , Ácido Dicloroacético/uso terapéutico , Cardiopatías/sangre , Cardiopatías/prevención & control , Hidralazina/uso terapéutico , Hipertrigliceridemia/tratamiento farmacológico , Hipertrigliceridemia/fisiopatología , Técnicas In Vitro , Insulina/sangre , Lípidos/sangre , Masculino , Palmitatos/farmacología , Prazosina/uso terapéutico , Ratas , Ratas Wistar , Triglicéridos/sangre , Verapamilo/uso terapéuticoRESUMEN
Treatment of streptozocin (STZ)-induced diabetic rats with sodium selenate (10-15 mumol.kg-1.day-1) for 7 wk resulted in a decrease in plasma glucose, food intake, and water intake to control or near control levels. Plasma insulin was reduced in control rats given sodium selenate to the level found in the diabetic and treated diabetic group. Treatment did not affect control rats with regard to the other measurements cited. Sodium selenate enhanced weight gain in responding diabetic rats to that seen in controls; sodium selenate's actions thus resembled those of insulin. Thus selenate, like vanadium, appears to have insulinlike effects when administered in vivo.
Asunto(s)
Glucemia/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Insulina/uso terapéutico , Compuestos de Selenio , Selenio/uso terapéutico , Animales , Peso Corporal/efectos de los fármacos , Diabetes Mellitus Experimental/sangre , Ingestión de Alimentos , Masculino , Ratas , Ratas Endogámicas , Valores de Referencia , Ácido SelénicoAsunto(s)
Carcinoma de Ehrlich/metabolismo , Nucleótidos de Purina/metabolismo , Adenina/metabolismo , Nucleótidos de Adenina/metabolismo , Adenosina Trifosfato/biosíntesis , Aerobiosis , Anaerobiosis , Animales , Metabolismo Energético/efectos de los fármacos , Nucleótidos de Purina/biosíntesis , Xantenos/farmacología , XantonasRESUMEN
Ethidium and isometamidium induce the breakdown of intracellular adenosine triphosphate in Ehrlich ascites tumor cells incubated in vitro. Ethidium induces appreciable adenosine triphosphate breakdown only when cells are incubated without glucose, whereas isometamidium produces this effect both in the presence and absence of glucose. In cells treated with isometamidium, purine nucleoside monophosphates accumulate, whereas these are mostly dephosphorylated when ethidium is used. Both ethidium and isometamidium inhibit purine nucleotide synthesis and incorporation of precursors into nucleic acids, although the magnitudes of these effects varied with the precursor used. Isometamidium inhibited the conversion of inosinate to adenine and guanine nucleotides, and both compounds partially inhibited the accumulation of phosphoribosyl pyrophosphate.
Asunto(s)
Adenosina Trifosfato/metabolismo , Carcinoma de Ehrlich/metabolismo , Etidio/farmacología , Fenantridinas/farmacología , Nucleótidos de Purina/biosíntesis , Adenina/metabolismo , Animales , Benzamidinas/farmacología , ADN de Neoplasias/biosíntesis , Glucosa/metabolismo , Glicina/metabolismo , Glucólisis , Hipoxantinas/metabolismo , Proteínas de Neoplasias/biosíntesis , Precursores de Ácido Nucleico/metabolismo , Fosforilación Oxidativa , Consumo de Oxígeno , Fosforribosil Pirofosfato/metabolismo , ARN Neoplásico/biosíntesisRESUMEN
Concentrations of intracellular orthophosphate were determined in Ehrlich ascites tumor cells incubated with glucose, inosine, or uridine in media of different orthophosphate concentration. The effects of orthophosphate concentration on the accumulation of lactate and of phosphoribosyl pyrophosphate and on concentrations of ribose 1-phosphate and ribose 5-phosphate in tumor cells incubated with glucose were also determined. Both the phosphorolysis of inosine and the rate of catabolism of ATP in cells incubated with 2-deoxyglucose were also influenced by the orthophosphate concentration of the medium.