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Diabetologia ; 46(9): 1234-44, 2003 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-12898011


AIM/HYPOTHESIS: Increased expression of haeme-oxygenase 1 (HO1) and other antioxidant enzymes could improve pancreatic beta-cell survival under stressful conditions, including hyperglycaemia. However, how hyperglycaemia increases islet HO1 expression is not known. METHODS: Rat islets were pre-cultured for 1 week in RPMI medium containing 10 mmol x l(-1) glucose (G10), and further cultured overnight in G5-G30 plus various test substances. Islet HO1 mRNA and protein expression was measured by semiquantitative RT-PCR, western blot, and immunohistochemistry. RESULTS: Islet HO1 mRNA expression was minimal after overnight culture in G10, slightly increased in G5, and increased by five- to ten-fold in G30 in parallel with a heterogeneous increase in beta-cell HO1 protein expression. The effect of G30 was fully inhibited by agents decreasing cytosolic Ca2+ (diazoxide, nimodipine), but was only slightly reproduced by agents raising Ca2+ (tolbutamide, 30 mmol x l(-1) potassium). It was also suppressed by the alpha2-adrenoceptor agonist clonidine, whereas dibutyryl-cyclic-AMP largely increased beta-cell HO1 expression. The induction of HO1 mRNA expression by G30 was independent from changes in medium insulin concentration, but was completely inhibited by a cocktail of antioxidants. In contrast to HO1, islet mRNA expression of glutathione peroxidase and constitutive haeme-oxygenase 2 were not affected by G30, nor by dibutyryl-cyclic-AMP. CONCLUSION/INTERPRETATION: High glucose and dibutyryl-cyclic-AMP stimulate expression of HO1 in rat pancreatic beta cells. The inhibition of HO1 expression in G30 by nimodipine, clonidine, and antioxidants, suggests that Ca2+ influx and cyclic-AMP are necessary for the generation of oxidative stress by G30, or for the stimulation of beta-cell HO1 expression by increased oxidative stress.

AMP Cíclico/farmacología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Glucosa/farmacología , Hemo Oxigenasa (Desciclizante)/genética , Islotes Pancreáticos/enzimología , Animales , Secuencia de Bases , Calcio/metabolismo , AMP Cíclico/metabolismo , Cartilla de ADN , ADN Complementario/genética , Semivida , Hemo-Oxigenasa 1 , Islotes Pancreáticos/efectos de los fármacos , Cinética , Masculino , ARN Mensajero/genética , Ratas , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos
Diabetologia ; 39(1): 3-11, 1996 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-8720597


Selenium is a trace element that exerts certain insulin-like actions in vitro. In this study, we evaluated its in vivo effects on the glucose homeostasis of rats made diabetic and insulin-deficient by streptozotocin. Na2SeO4 was administered ad libitum in drinking water and/or food for 10 weeks. The elevated plasma glucose levels (approximately 25 mmol/l) and glucosuria (approximately 85 mmol/day) of untreated rats were decreased by 50 and 80%, respectively, by selenate treatment. The beneficial effect of selenate was also evident during oral and intravenous glucose tolerance tests: the integrated glucose responses were decreased by 40-50% as compared to those in untreated rats. These effects were not due to an increase in plasma insulin levels. Compared to non-diabetic rats, pancreatic insulin reserves were reduced by more than 90% in treated and untreated diabetic rats. The hepatic activities and mRNA levels of two key glycolytic enzymes, glucokinase and L-type pyruvate kinase were blunted in diabetic rats. They increased approximately two- to threefold after selenate treatment, to reach 40-75% of the values in non-diabetic rats. In contrast, elevated activity and mRNA levels of the gluconeogenic enzyme, phosphoenolpyruvate carboxykinase, were reduced by 40-65% after selenate administration. Since selenate induced a moderate decrease in body weight due to an anorexigenic effect, we checked that there was no improvement of glucose homeostasis or hepatic glucose metabolism in an additional group of calorie-restricted diabetic rats, which was weight-matched with the selenate group. In addition, no obvious toxic side-effects on the kidney or liver were observed in the rats receiving selenate. In conclusion, selenate induces a sustained improvement of glucose homeostasis in streptozotocin-diabetic rats by an insulin-like action, which involves partial correction of altered pretranslational regulatory mechanisms in liver metabolism.

Glucemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Glucosa/metabolismo , Hígado/enzimología , Compuestos de Selenio/farmacología , Administración Oral , Animales , Glucemia/efectos de los fármacos , Northern Blotting , Peso Corporal/efectos de los fármacos , Sondas de ADN , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/tratamiento farmacológico , Expresión Génica/efectos de los fármacos , Glucoquinasa/biosíntesis , Gluconeogénesis , Prueba de Tolerancia a la Glucosa , Glucólisis , Homeostasis/efectos de los fármacos , Insulina/sangre , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/fisiología , Islotes Pancreáticos/fisiopatología , Hígado/efectos de los fármacos , Masculino , Fosfoenolpiruvato Carboxiquinasa (GTP)/biosíntesis , Piruvato Quinasa/biosíntesis , Ratas , Ratas Wistar , Ácido Selénico , Selenio/metabolismo , Compuestos de Selenio/administración & dosificación
Mol Cell Endocrinol ; 78(3): 179-86, 1991 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-1663876


Catecholamines inhibit adenylate cyclase in pancreatic B-cells, but the importance of the resulting fall in cAMP concentration for the decrease in insulin release remains controversial. Adrenaline caused a dose-dependent inhibition (EC50 = 5.7 nM) of insulin release by mouse islets incubated in a medium containing 15 mM glucose. Supplementation of the medium with 500 microM dibutyryl-cAMP or 1 microM forskolin potentiated the effect of glucose on release and attenuated the inhibition by 1 and 10 nM adrenaline; the EC50 value was increased 2-fold. The inhibitory action of 100 nM or 1 microM adrenaline was, however, not affected. This apparent change in adrenaline potency was not simply due to the larger rate of release since it was not observed when the effect of glucose was potentiated by cytochalasin-B. However, when the same rate of insulin release as that produced by 15 mM glucose alone was achieved by combining 10 mM glucose and 250 microM dibutyryl-cAMP, the inhibitory potency of adrenaline was unaffected. Intracellular microelectrodes were used to determine whether the changes in B-cell membrane potential brought about by adrenaline are mediated by a fall in cAMP levels. Addition of dibutyryl-cAMP or forskolin to a medium containing 10 or 15 mM glucose increased the Ca(2+)-dependent electrical activity triggered by the sugar. However, this did not prevent adrenaline from hyperpolarizing the membrane transiently and causing a steady-state decrease in the intensity of the electrical activity.(ABSTRACT TRUNCATED AT 250 WORDS)

AMP Cíclico/metabolismo , Epinefrina/farmacología , Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Inhibidores de Adenilato Ciclasa , Animales , Glucemia/metabolismo , Bucladesina/farmacología , Calcio/metabolismo , Colforsina/farmacología , Citocalasina B/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Islotes Pancreáticos/efectos de los fármacos , Potenciales de la Membrana/efectos de los fármacos , Ratones , Ratones Endogámicos
Arch Int Pharmacodyn Ther ; 271(2): 324-34, 1984 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-6391402


Glucose homeostasis of normal rats was studied after chronic or acute administration of chloroquine. Male rats received, in drinking water, a daily dose of 5-20 mg chloroquine/kg, for 20 weeks. The high dose caused a slight decrease in food intake and weight gain. In these animals, plasma glucose levels were somewhat lower than in controls after an overnight fast and after oral administration of glucose or intravenous administration of insulin, but not after intravenous administration of glucose. Their insulin response to oral or intravenous glucose was normal. The insulin content of their pancreas was decreased by about 15%. Electron microscopy revealed the presence of myeloid bodies and numerous lysosomes in B cells. Acute intraperitoneal administration of chloroquine was without effect on glucose tolerance and insulin release. This study shows that chloroquine, at plasma concentrations similar to those reached in treated patients, does not impair glucose homeostasis in normal rats.

Glucemia/metabolismo , Cloroquina/farmacología , Homeostasis/efectos de los fármacos , Animales , Ingestión de Alimentos/efectos de los fármacos , Prueba de Tolerancia a la Glucosa , Insulina/sangre , Masculino , Ratas