RESUMEN
Tribbles 3 (TRB3) is a recently recognized atypical inactive kinase that negatively regulates Akt activity in hepatocytes, resulting in insulin resistance. Recent reports link TRB3 to nutrient sensing and regulation of cell survival under stressful conditions. We studied the regulation of TRB3 by glucose, insulin, dexamethasone (Dex), and the unfolded protein response (UPR) in 3T3-L1 adipocytes and in L6 myotubes. In 3T3-L1 adipocytes, incubation in high glucose with insulin did not increase TRB3 mRNA expression. Rather, TRB3 mRNA increased fourfold with glucose deprivation and two- to threefold after incubation with tunicamcyin (an inducer of the UPR). Incubation of cells in no glucose or in tunicamcyin stimulated the expression of CCAAT/enhancer-binding protein homologous protein. In L6 myotubes, absent or low glucose induced TRB3 mRNA expression by six- and twofold, respectively. The addition of Dex to 5 mM glucose increased TRB3 mRNA expression twofold in 3T3-L1 adipocytes but decreased it 16% in L6 cells. In conclusion, TRB3 is not the mediator of high glucose or glucocorticoid-induced insulin resistance in 3T3-L1 adipocytes or L6 myotubes. TRB3 is induced by glucose deprivation in both cell types as a part of the UPR, where it may be involved in regulation of cell survival in response to glucose depletion.
Asunto(s)
Adipocitos/metabolismo , Proteínas de Ciclo Celular/biosíntesis , Proteínas de Ciclo Celular/genética , Dexametasona/farmacología , Glucosa/farmacología , Fibras Musculares Esqueléticas/metabolismo , Células 3T3-L1 , Adipocitos/efectos de los fármacos , Animales , Transporte Biológico Activo , Western Blotting , Medios de Cultivo , Regulación de la Expresión Génica/efectos de los fármacos , Glucosa/deficiencia , Glucosa/toxicidad , Ratones , Fibras Musculares Esqueléticas/efectos de los fármacos , Fosforilación , Pliegue de Proteína , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción CHOP/biosíntesisRESUMEN
The newer, atypical antipsychotic drugs have improved the treatment of schizophrenia and are widely used. A disadvantage is that they increase food intake, promote weight gain and may facilitate development of diabetes. The mechanism of the latter effect is controversial. A possible interaction of these drugs with glucose transporters has been proposed: peripheral insulin resistance may develop if these drugs inhibited glucose transport in cells which express the insulin responsive glucose transporter, GLUT4, i.e., muscle and adipocytes. To test this hypothesis, we incubated 3T3-L1 adipocytes, which express GLUT1 and GLUT4, with the atypical antipsychotic drug olanzapine for 1 or 20 h and then measured basal and insulin-stimulated glucose transport. The doses of olanzapine tested (70 nM and 350 nM) encompass and exceed maximal steady-state concentrations of the drug in plasma of patients maintained on maximal recommended doses (20 mg QD) of olanzapine. A maximally stimulating insulin concentration (100 nM) accelerated glucose transport 10- to 15-fold in 3T3-L1 adipocytes, and the half-maximally stimulating insulin dose was 0.4 nM. Olanzapine (70 or 350 nM) did not affect basal or insulin-stimulated glucose transport following 1 or 20 h drug treatment at any insulin concentration tested. The data do not support the hypothesis that olanzapine at therapeutically relevant concentrations may cause peripheral insulin resistance by direct interaction with the insulin responsive glucose transport system.
Asunto(s)
Adipocitos/efectos de los fármacos , Antipsicóticos/farmacología , Glucosa/metabolismo , Hipoglucemiantes/farmacología , Insulina/farmacología , Células 3T3 , Animales , Benzodiazepinas/farmacología , Desoxiglucosa/metabolismo , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Ratones , Olanzapina , Factores de TiempoRESUMEN
BACKGROUND: Systemic lupus erythematosus (SLE) is known to be much more prevalent in females than in males, but the cause of this sexual predilection is not established. In addition, much controversy surrounds the differences in manifestations of SLE in both sexes. OBJECTIVE: This article reviews the possible etiologies of the greater prevalence of SLE in females, as well as the differences in the clinical presentation of the disease in both sexes. METHODS: Relevant studies were identified through a PubMed search for articles published between 1960 and 2001; no language restrictions were applied. Search terms included lupus, SLE, and gender differences. Books and online resources were also consulted. RESULTS: Potential causes of the female predilection for SLE included the effects of estrogen and its hydroxylation, decreased androgen levels, hyperprolactinemia, and differences in gonadotropin-releasing hormone (GnRH) signaling. Clinical manifestations of SLE included females having more frequent relapses, but the incidence of severe relapses was the same in both sexes. Raynaud phenomenon, arthritis, and leukopenia were more common in women, whereas skin manifestations, serositis, and renal involvement were more common in men. For neurologic manifestations, females with SLE experienced more psychiatric symptoms and headaches, whereas males with SLE experienced more seizures and peripheral neuropathy. Males with SLE also tended to have more severe renal disease and cardiorespiratory involvement. CONCLUSIONS: The increased frequency of SLE among women may be attributed to differences in the metabolism of sex hormones and/or GnRH. Though less common in men, when it does occur SLE tends to run a more severe course-an important consideration in the diagnosis and follow-up of male patients with SLE.