Publication: Papel de las isoformas del receptor de insulina en la regulación de la homeostasia glucídica y lipídica en un modelo de diabetes experimental
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2017-06-30
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Universidad Complutense de Madrid
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Abstract
La diabetes tipo 2 es una enfermedad metabólica compleja cuya patogénesis implica fallos tanto en la acción periférica de la insulina como en su secreción. En el estado postprandial, el hígado regula la homeostasia glucídica por medio de la captación de glucosa y su conversión a glucógeno y lípidos (von Wilamowitz- Moellendorff et al., 2013). La desregulación de los mecanismos por los cuales la glucosa y la insulina dirigen el metabolismo del glucógeno es una de las principales causas que provocan la diabetes tipo 2, la enfermedad metabólica más común entre la población mundial (Leibiger et al., 2001). El receptor de insulina pertenece a la superfamilia de receptores tirosina quinasa, concretamente a la subclase II, y juega un papel fundamental en el metabolismo de la glucosa. El receptor de insulina está estrechamente relacionado con otros miembros de la familia, como el receptor del factor de crecimiento similar a la insulina, el cual está implicado en procesos de crecimiento y desarrollo (Benyoucef et al., 2007; Ward et al., 2009). En mamíferos, el splicing alternativo del exón 11 del gen del receptor de insulina da lugar a dos isoformas: A y B. Concretamente, la isoforma B posee 12 aminoácidos extra localizados inmediatamente después del dominio de unión a ligando, aunque no afecta a su afinidad por la insulina, la cual es muy similar entre las dos isoformas (Menting et al., 2013; Whittaker et al., 2002). Sin embargo, la isoforma A del receptor de insulina tiene, aproximadamente, 10 veces más afinidad por los factores de crecimiento insulínicos tipo I y II que la isoforma B (Malaguarnera et al., 2011). Además, la isoforma A del receptor de insulina se expresa predominantemente durante el desarrollo embrionario, favoreciendo así los efectos del factor de crecimiento insulínico tipo II (Frasca et al., 2009). Por el contrario, la isoforma B del receptor de insulina se expresa de forma predominante en tejidos adultos, incluido el hígado, en los cuales dirige los efectos metabólicos de la insulina (Malaguarnera y Belfiore, 2011)...
Type 2 diabetes is a complex metabolic disease and its pathogenesis involves abnormalities in both peripheral insulin action and insulin secretion. In the postprandial state, liver regulates glucose homeostasis by glucose uptake and conversion to glycogen and lipids (von Wilamowitz-Moellendorff et al., 2013). The malfunction of these mechanisms, by which glucose and insulin regulate glycogen metabolism, is one of the major causes of type 2 diabetes, the most common metabolic disorder in the worldwide population (Leibiger et al., 2001). The insulin receptor is a member of subclass II of the tyrosine kinase receptor super-family that plays an essential role in glucose metabolism. Insulin receptor is closely related to other members of this family like the insulin-like growth factor receptor which is involved in normal growth and development (Benyoucef et al., 2007; Ward et al., 2009). In mammals, alternative splicing gives rise to two isoforms of insulin receptor: A and B. The isoform B has 12 additional amino acids encoded by the exon 11 (Whittaker et al., 2002). This sequence is located immediately downstream of the ligand binding domain but does not affect insulin binding affinity which is very similar between A and B (Menting et al., 2013; Whittaker et al., 2002). However, insulin receptor A isoform has approximately 10 fold higher affinity for insulin-like growth factor-I and II than insulin receptor B isoform (Malaguarnera et al., 2011). Moreover, insulin receptor A isoform is predominantly expressed during foetal development and embryogenesis where enhances insulin-like growth factor-II effects (Frasca et al., 1999). Conversely, insulin receptor B isoform is predominantly expressed in adult tissues, including liver, where it triggers the metabolic effects of insulin (Malaguarnera & Belfiore, 2011)...
Type 2 diabetes is a complex metabolic disease and its pathogenesis involves abnormalities in both peripheral insulin action and insulin secretion. In the postprandial state, liver regulates glucose homeostasis by glucose uptake and conversion to glycogen and lipids (von Wilamowitz-Moellendorff et al., 2013). The malfunction of these mechanisms, by which glucose and insulin regulate glycogen metabolism, is one of the major causes of type 2 diabetes, the most common metabolic disorder in the worldwide population (Leibiger et al., 2001). The insulin receptor is a member of subclass II of the tyrosine kinase receptor super-family that plays an essential role in glucose metabolism. Insulin receptor is closely related to other members of this family like the insulin-like growth factor receptor which is involved in normal growth and development (Benyoucef et al., 2007; Ward et al., 2009). In mammals, alternative splicing gives rise to two isoforms of insulin receptor: A and B. The isoform B has 12 additional amino acids encoded by the exon 11 (Whittaker et al., 2002). This sequence is located immediately downstream of the ligand binding domain but does not affect insulin binding affinity which is very similar between A and B (Menting et al., 2013; Whittaker et al., 2002). However, insulin receptor A isoform has approximately 10 fold higher affinity for insulin-like growth factor-I and II than insulin receptor B isoform (Malaguarnera et al., 2011). Moreover, insulin receptor A isoform is predominantly expressed during foetal development and embryogenesis where enhances insulin-like growth factor-II effects (Frasca et al., 1999). Conversely, insulin receptor B isoform is predominantly expressed in adult tissues, including liver, where it triggers the metabolic effects of insulin (Malaguarnera & Belfiore, 2011)...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Farmacia, Departamento de Bioquímica y Biología Molecular II, leída el 24/10/2016