Asunto(s)
Acondroplasia/tratamiento farmacológico , Acondroplasia/patología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/deficiencia , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Displasia Tanatofórica/tratamiento farmacológico , Displasia Tanatofórica/patología , Animales , Femenino , MasculinoRESUMEN
Glycogen synthase kinase 3 ß (GSK-3ß) is an essential negative regulator or "brake" on many anabolic-signaling pathways including Wnt and insulin. Global deletion of GSK-3ß results in perinatal lethality and various skeletal defects. The goal of our research was to determine GSK-3ß cell-autonomous effects and postnatal roles in the skeleton. We used the 3.6-kb Col1a1 promoter to inactivate the Gsk3b gene (Col1a1-Gsk3b knockout) in skeletal cells. Mutant mice exhibit decreased body fat and postnatal bone growth, as well as delayed development of several skeletal elements. Surprisingly, the mutant mice display decreased circulating glucose and insulin levels despite normal expression of GSK-3ß in metabolic tissues. We showed that these effects are due to an increase in global insulin sensitivity. Most of the male mutant mice died after weaning. Prior to death, blood glucose changed from low to high, suggesting a possible switch from insulin sensitivity to resistance. These male mice die with extremely large bladders that are preceded by damage to the urogenital tract, defects that are also seen type 2 diabetes. Our data suggest that skeletal-specific deletion of GSK-3ß affects global metabolism and sensitizes male mice to developing type 2 diabetes.
Asunto(s)
Desarrollo Óseo , Huesos/enzimología , Diabetes Mellitus Tipo 2/complicaciones , Metabolismo Energético , Glucógeno Sintasa Quinasa 3/metabolismo , Resistencia a la Insulina , Enfermedades Urogenitales Masculinas/complicaciones , Animales , Huesos/metabolismo , Huesos/patología , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Cadena alfa 1 del Colágeno Tipo I , Cruzamientos Genéticos , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Susceptibilidad a Enfermedades , Femenino , Glucógeno Sintasa Quinasa 3/genética , Glucógeno Sintasa Quinasa 3 beta , Masculino , Ratones , Ratones Noqueados , Ratones Mutantes , Ratones Transgénicos , Regiones Promotoras Genéticas , Caracteres Sexuales , Análisis de Supervivencia , Sistema Urogenital/patología , DesteteRESUMEN
Eighty-seven patients who underwent a late secretory phase endometrial biopsy while taking clomiphene citrate (CC) for ovulation induction were studied. Of the endometrial biopsies, 21 (24%) showed an endometrium greater than 2 days out of phase (OOP) with respect to the subsequent menstrual cycle. All 87 patients were categorized by age, weight, CC dosage, and underlying disease entity. The patients then were evaluated by these categories in relation to the incidence of an OOP biopsy while taking CC. Patients with a diagnosis of hypothalamic amenorrhea were statistically more likely to have an OOP endometrium. No other subgroup showed an increased or decreased incidence of OOP biopsies. Conception and spontaneous abortion rates were similar among patients with in-phase biopsies and those with out-of-phase biopsies, which subsequently were corrected with further medical therapy. An aggressive approach to the diagnosis and treatment of luteal phase insufficiency in patients who receive CC for ovulation induction is recommended.