RESUMEN
Propionic acid derivative 8, which was designed and synthesized based on putative pharmacophores of known PPARgamma- and PPARalpha-selective compounds, exhibits potent dual PPARalpha/gamma agonist activity as demonstrated by in vitro binding and dose overlap in the newly introduced EOB mouse model for glucose lowering and lipid/cholesterol homeostasis.
Asunto(s)
Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacología , Propionatos/síntesis química , Propionatos/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Factores de Transcripción/agonistas , Animales , Glucemia/metabolismo , HDL-Colesterol/sangre , Diabetes Mellitus/sangre , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/genética , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diseño de Fármacos , Ratones , Ratones Endogámicos , Receptores Citoplasmáticos y Nucleares/genética , Factores de Transcripción/genética , Triglicéridos/sangreRESUMEN
An in vivo adenoviral gene delivery system was utilized to assess the effect of overexpressing protein kinase C (PKC)-zeta on rat skeletal muscle glucose transport activity. Female lean Zucker rats were injected with adenoviral/human PKC-zeta (hPKC-zeta) and adenoviral/LacZ in opposing tibialis anterior muscles. One week subsequent to adenoviral/gene delivery rats were subjected to hind limb perfusion. The hPKC-zeta protein was expressed at the same level (fast-twitch white) or at approximately 80% of the level (fast-twitch red) of endogenous PKC-zeta, thus approximately doubling the amount of PKC-zeta in tibialis anterior. Basal glucose transport activity was elevated approximately 3.4- and 2-fold, respectively, in fast-twitch white and red hPKC-zeta muscle relative to control. Submaximal insulin-stimulated glucose transport activity, corrected for basal transport, was approximately 90 and 40% over control values, respectively, in fast-twitch white and red hPKC-zeta muscle. The enhancement of glucose transport activity in muscle expressing hPKC-zeta occurred in the absence of any change in GLUT1 or GLUT4 protein levels, suggesting a redistribution of existing transporters to the cell surface. These results demonstrate that an adenoviral vector can be used to deliver expressible hPKC-zeta to adult rat skeletal muscle in vivo and also affirm a role for PKC-zeta in the regulation of glucose transport activity.
Asunto(s)
Adenoviridae/genética , Glucosa/metabolismo , Proteínas Musculares , Músculo Esquelético/efectos de los fármacos , Proteína Quinasa C/farmacología , Animales , Transporte Biológico/efectos de los fármacos , Desoxiglucosa/metabolismo , Femenino , Técnicas de Transferencia de Gen , Vectores Genéticos , Transportador de Glucosa de Tipo 1 , Transportador de Glucosa de Tipo 4 , Humanos , Inyecciones Intramusculares , Insulina/farmacología , Proteínas de Transporte de Monosacáridos/análisis , Fibras Musculares de Contracción Rápida/enzimología , Músculo Esquelético/enzimología , Proteína Quinasa C/genética , Ratas , Ratas Zucker , Proteínas Recombinantes/farmacologíaRESUMEN
Amylin, an islet amyloid peptide secreted by the pancreatic beta cell, has been proposed as a humoral regulator of islet insulin secretion. Four separate preparations of amylin were tested for effects on hormone secretion in both freshly isolated and cultured rat islets and in HIT-T15, hamster insulinoma cells. With all three experimental models, exposure to human amylin acid and human and rat amylin at concentrations as high as 100 nM had no significant effect on rates of insulin or glucagon secretion. These observations suggest that amylin, even at concentrations appreciably higher than those measured in peripheral plasma, is not a significant humoral regulator of islet hormone secretion.
Asunto(s)
Amiloide/farmacología , Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Amiloide/síntesis química , Animales , Línea Celular , Células Cultivadas , Cricetinae , Glucagón/metabolismo , Glucosa/farmacología , Humanos , Técnicas In Vitro , Secreción de Insulina , Insulinoma , Polipéptido Amiloide de los Islotes Pancreáticos , Islotes Pancreáticos/efectos de los fármacos , Cinética , Masculino , Neoplasias Pancreáticas , Ratas , Ratas EndogámicasRESUMEN
Compound M & B 39890A [N-(3-imidazol-1-ylpropyl)-2- (3-trifluoromethylbenzenesulphonamido)benzamide hydrochloride] had no effect on cellular cAMP and cGMP levels but significantly inhibited insulin and glucagon secretion from freshly isolated normal rat islets stimulated with 10 mM glucose and 20 mM arginine. Daily gavage of the compound for three days lowered the elevated blood glucose and plasma insulin levels in fed, male viable yellow obese-diabetic mice; the minimum effective dose was 25 mg/kg. However, M & B 39890A did not affect the blood glucose level of fasted diabetic mice. In addition, it had no effect on blood glucose levels of normal mice and streptozotocin-diabetic rats. M & B 39890A, fed in the diet at the concentration of 1 mg/g for 42 days, reversed the hyperglycemia of the fed diabetic mice without causing tachyphylaxis and improved the sensitivity to exogenous insulin as demonstrated by the lowering of blood glucose. When M & B 39890A was fed to young male mice destined to become diabetic, the development of hyperglycemia was prevented. Thus, M & B 39890A represents a new class of pharmacological agents that may prove to be effective for the chronic treatment of type II diabetics without the risk of hypoglycemia.
Asunto(s)
Arginina/antagonistas & inhibidores , Diabetes Mellitus Experimental/fisiopatología , Glucagón/metabolismo , Hipoglucemiantes/farmacología , Imidazoles/farmacología , Insulina/metabolismo , Animales , Glucemia/metabolismo , Colforsina/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Ingestión de Alimentos/efectos de los fármacos , Hipoglucemiantes/uso terapéutico , Técnicas In Vitro , Insulina/sangre , Insulina/farmacología , Secreción de Insulina , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Masculino , Ratones , Ratones Obesos , Ratas , Ratas EndogámicasRESUMEN
MTP-3115 is a newly-synthesized thiopyranopyrimidine compound with a structure similar to that of MTP-1403 and MTP-1307. However, the biological profile of MTP-3115 is different from that of MTP-1403 and MTP-1307 (previously reported). Similar to MTP-1403 and MTP-1307, MTP-3115 improves glucose tolerance in both normal and obese-diabetic viable yellow mice with equal potency. However, unlike MTP-1403 and MTP-1307, MTP-3115 also lowers blood glucose of fed and fasted normal and obese-diabetic viable yellow mice. Although the mechanisms of action of MTP-3115 are not elucidated, it is unlikely that its mode of action is similar to that of sulfonylureas because tolbutamide neither improves glucose tolerance nor lowers blood glucose in obese-diabetic viable yellow mice.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Hipoglucemiantes/farmacología , Pirazinas/farmacología , Pirimidinas/farmacología , Animales , Glucemia/metabolismo , Diabetes Mellitus Experimental/sangre , Prueba de Tolerancia a la Glucosa , Masculino , Ratones , Ratones Obesos , Tolbutamida/farmacologíaRESUMEN
ONO-2235 [(E)-3-carboxymethyl-5-[(2E)-2-methyl-3-phenyl-propenylidene]rhodanine], an ARI, was reported to prevent significantly the decrease of norepinephrine (NE) turnover in three tissues of streptozotocin (STZ)-diabetic rats (1). To examine whether the partial restoration of NE turnover by ONO-2235 is related to its ARI activity, the effect of another ARI, AL-1576 [spiro(2,7-difluoro-9H-fluoren-9, 4'-imidazoline)-2'5'-dione], on NE turnover in STZ rats was investigated. STZ caused an accumulation of sorbitol in the lens and decreased NE turnover in interscapular brown adipose tissue (IBAT), heart and pancreas. AL-1576 totally prevented the accumulation of sorbitol in the lens but had no effect on the decreased NE turnover in all three tissues. These results suggest that the partial prevention of NE turnover decrease by ONO-2235 may not have been mediated by its ARI activity.