RESUMEN
Variants in the growth factor receptor-bound protein 10 (GRB10) gene were in a GWAS meta-analysis associated with reduced glucose-stimulated insulin secretion and increased risk of type 2 diabetes (T2D) if inherited from the father, but inexplicably reduced fasting glucose when inherited from the mother. GRB10 is a negative regulator of insulin signaling and imprinted in a parent-of-origin fashion in different tissues. GRB10 knock-down in human pancreatic islets showed reduced insulin and glucagon secretion, which together with changes in insulin sensitivity may explain the paradoxical reduction of glucose despite a decrease in insulin secretion. Together, these findings suggest that tissue-specific methylation and possibly imprinting of GRB10 can influence glucose metabolism and contribute to T2D pathogenesis. The data also emphasize the need in genetic studies to consider whether risk alleles are inherited from the mother or the father.
Asunto(s)
Proteína Adaptadora GRB10/genética , Proteína Adaptadora GRB10/metabolismo , Islotes Pancreáticos/metabolismo , Alelos , Diabetes Mellitus Tipo 2 , Ayuno/metabolismo , Estudio de Asociación del Genoma Completo/métodos , Glucosa/genética , Glucosa/metabolismo , Humanos , Insulina/genética , Insulina/metabolismo , Resistencia a la Insulina/genética , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Transducción de Señal/genéticaRESUMEN
Glucagon, secreted by the alpha-cells of the pancreatic islets, is the most important glucose-increasing hormone of the body. The precise regulation of glucagon release remains incompletely defined but has been proposed to involve release of inhibitory factors from neighbouring beta-cells (paracrine control). However, the observation that glucose can regulate glucagon secretion under conditions when insulin secretion does not occur argues that the alpha-cell is also equipped with its own intrinsic (exerted within the alpha-cell itself) glucose sensing. Here we consider the possible mechanisms involved with a focus on ATP-regulated K(+)-channels and changes in alpha-cell membrane potential.
Asunto(s)
Células Secretoras de Glucagón/efectos de los fármacos , Glucagón/metabolismo , Glucosa/farmacología , Canales KATP/fisiología , Animales , Diabetes Mellitus/metabolismo , Diabetes Mellitus/terapia , Células Secretoras de Glucagón/metabolismo , Células Secretoras de Glucagón/fisiología , Humanos , Hipoglucemiantes/farmacología , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Modelos Biológicos , Comunicación Paracrina/fisiología , Tolbutamida/farmacologíaRESUMEN
In vitro studies suggest that the G protein-coupled receptor (GPR) 30 is a functional estrogen receptor. However, the physiological role of GPR30 in vivo is unknown, and it remains to be determined whether GPR30 is an estrogen receptor also in vivo. To this end, we studied the effects of disrupting the GPR30 gene in female and male mice. Female GPR30((-/-)) mice had hyperglycemia and impaired glucose tolerance, reduced body growth, increased blood pressure, and reduced serum IGF-I levels. The reduced growth correlated with a proportional decrease in skeletal development. The elevated blood pressure was associated with an increased vascular resistance manifested as an increased media to lumen ratio of the resistance arteries. The hyperglycemia and impaired glucose tolerance in vivo were associated with decreased insulin expression and release in vivo and in vitro in isolated pancreatic islets. GPR30 is expressed in islets, and GPR30 deletion abolished estradiol-stimulated insulin release both in vivo in ovariectomized adult mice and in vitro in isolated islets. Our findings show that GPR30 is important for several metabolic functions in female mice, including estradiol-stimulated insulin release.