RESUMEN
To assess the dominance between hypoinsulinemia and hypoleptinemia as factors in the development of hyperphagia in streptozotocin (STZ)-induced diabetes mellitus (STZ-DM) rodents with respect to hormone-neuropeptide interactions, changes in gene expression of agouti gene-related protein (AGRP) in the arcuate nucleus of the hypothalamus were investigated using STZ-DM rats, fasting Zucker fa/fa rats and STZ-DM agouti (STZ-DM A(y)/a) mice. AGRP mRNA and neuropeptide Y mRNA were both significantly up-regulated in STZ-DM rats, which are associated with body weight loss, hyperglycemia, hypoinsulinemia and hypoleptinemia. We proceeded to analyze whether insulin or leptin played the greater role in the regulation of AGRP using Zucker fa/fa rats. The AGRP mRNA did not differ significantly between fasted fa/fa rats, which have both leptin-insensitivity and hypoinsulinemia, and fed Zuckers, which have leptin-insensitivity and hyperinsulinemia. We further found that up-regulation of AGRP expression was normalized by infusion of leptin into the third cerebroventricle (i3vt), but not by i3vt infusion of insulin, although up-regulation of AGRP was partially corrected by systemic insulin infusion. The latter finding supports hypoleptinemia as a key-modulator of STZ-DM-induced hyperphagia because systemic insulin infusion, at least partially, restored hypoleptinemia through its acceleration of fat deposition, as demonstrated by the partial recovery of lost body weight. After STZ-DM induction, A(y)/a mice whose melanocortin-4 receptor (MC4-R) was blocked by ectopic expression of agouti protein additionally accelerated hyperphagia and up-regulated AGRP mRNA, implying that the mechanism is triggered by a leptin deficit rather than by the main action of the message through MC4-R. Hypoleptinemia, but not hypoinsulinemia per se, thus develops hyperphagia in STZ-DM rodents. These results are very much in line with evidence that hypothalamic neuropeptides are potently regulated by leptin as downstream targets of its actions.
Asunto(s)
Diabetes Mellitus Experimental/fisiopatología , Hiperfagia/fisiopatología , Insulina/sangre , Insulina/farmacología , Péptidos y Proteínas de Señalización Intercelular , Leptina/sangre , Leptina/farmacología , Neuropéptido Y/genética , Proteínas/genética , Proteína de Señalización Agouti , Animales , Glucemia/metabolismo , Ventrículos Cerebrales , Diabetes Mellitus Experimental/sangre , Conducta Alimentaria/efectos de los fármacos , Privación de Alimentos , Regulación de la Expresión Génica , Hiperfagia/genética , Hipotálamo/metabolismo , Infusiones Parenterales , Insulina/administración & dosificación , Leptina/administración & dosificación , Masculino , Precursores de Proteínas/genética , ARN Mensajero/genética , Ratas , Ratas Wistar , Ratas Zucker , Transcripción Genética , Pérdida de PesoRESUMEN
The diabetic heart has an abnormal intracellular calcium ([Ca(2+)]i) metabolism. However, the responsible molecular mechanisms are unclear. The present study aimed to investigate mRNAs expressed in the proteins which regulate heart [Ca(2+)]i metabolism in streptozotocin (STZ)-induced diabetic rats. Expression of sarcoplasmic reticulum Ca(2+)-adenosine triphosphatase (SR Ca(2+)-ATPase) mRNA was significantly less in the heart 3 weeks after STZ injection than that in the age-matched controls. Together with the down-regulation of SR Ca(2+)-ATPase, expression of ryanodine sensitive Ca(2+)channel (RYR) mRNA was also decreased 12 weeks after STZ injection. Insulin supplementation fully restored the decreased mRNAs expression of SR Ca(2+)-ATPase and RYR. The diminished expression and restoration with insulin supplementation of SR Ca(2+)-ATPase was further confirmed at the protein level. In contrast, expression of mRNAs coding the L-type Ca(2+)channel, Na(+)-Ca(2+)exchanger, or phospholamban were not affected 3 or 12 weeks after STZ injection. These results can be taken to indicate that the down-regulation of SR Ca(2+)-ATPase and RYR mRNAs is a possible underlying cause of cardiac dysfunction in STZ-induced diabetic rats.
Asunto(s)
ATPasas Transportadoras de Calcio/genética , Miocardio/enzimología , ARN Mensajero , Canal Liberador de Calcio Receptor de Rianodina/genética , Retículo Sarcoplasmático/enzimología , Animales , Glucemia/análisis , Peso Corporal , Calcio/metabolismo , Diabetes Mellitus Experimental , Regulación de la Expresión Génica , Insulina/administración & dosificación , Insulina/sangre , Masculino , Ratas , Ratas Wistar , EstreptozocinaRESUMEN
Intra-arterial digital subtraction angiography using CO2 (CO2-IA-DSA) is effective for detecting arteriovenous and arterioportal shunts in the liver. We carried out CO2-IA-DSA in addition to selective arteriography using a iodinated contrast medium in 31 patients with unresectable hepatocellular carcinoma (HCC). As a result, CO2-IA-DSA detected an AV shunt in 4/31 patients and an AP shunt in 16/31 patients for a total of 20 cases of shunt, whereas conventional hepatic IA-DSA detected only AP (AV shunt) shunts in 3/31 patients. For HCC without any shunt, Gelfoam embolization was carried out after injection of Lipiodol and Farmorubicin (FARM). In patients with an AP shunt, injection of Lipiodol and FARM was performed after the shunt had been embolized with Gelfoam. In patients with an AV shunt, Lipiodol and FARM were injected after the shunt had been embolized with a metallic coil. In conclusion, detection of shunts by CO2-IA-DSA is useful for determining the optimal approach for transcatheter arterial injection.