Publication: Estudio del mecanismo de translocación núcleo-citoplasma de la glucokinasa mediante la caracterización funcional de mutaciones asociadas a hiperglucemia familiar MODY2
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2018-04-06
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Universidad Complutense de Madrid
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Abstract
La forma más común de diabetes mellitus es la diabetes tipo 2, donde la hiperglucemia está causada por una combinación de defectos en la secreción y en la acción de insulina. Esta enfermedad supone actualmente un gran problema de salud pública a nivel mundial y se prevé un fuerte incremento de su prevalencia en los próximos años. Por ello es de gran importancia la disponibilidad de terapias antidiabéticas efectivas. En las últimas décadas, la enzima glucokinasa (GCK) está siendo considerada como una potencial diana terapéutica debido a su papel central en la homeostasis de glucosa, lo que ha resultado en el descubrimiento de moléculas activadoras de esta enzima (GKAs). La glucokinasa es una de las cuatro isoformas de hexokinasa que cataliza el primer paso limitante en el metabolismo de la glucosa convirtiéndola en glucosa 6‐fosfato (G6P) y utilizando ATP como segundo sustrato. Esta enzima se expresa en una restringida variedad de tipos celulares. En la célula β pancreática la GCK actúa como sensor de glucosa al integrar las variaciones de glucosa en sangre y su metabolismo con la secreción de insulina. En el hepatocito, a través de la producción de G6P, la actividad GCK regula el ritmo de acumulación de glucógeno a partir de glucosa, la glicolisis y la gluconeogénesis. El papel central de la actividad GCK en la homeostasis de glucosa lo corroboran las casi 700 mutaciones asociadas a distintos síndromes glucémicos. Mutaciones que incrementan la actividad GCK producen hipoglucemia por hiperinsulinismo. Por el contrario, mutaciones que hacen disminuir la actividad enzimática producen hipoinsulinismo e hiperglucemia. En heterocigosis las mutaciones inactivantes dan lugar a una forma de hiperglucemia familiar denominada maturity onset diabetes of the young 2 (MODY2) y en homocigosis producen diabetes neonatal permanente...
Type 2 diabetes mellitus (T2DM), the most common form of diabetes caused by impairment of insulin secretion and action, is an increasing worldwide health problem. Effective antidiabetic drugs are necessary and many new agents are currently under development. The metabolic enzyme glucokinase (GCK) plays a central role in glucose homeostasis, thus it has been considered as a potential target in T2DM treatment. Research efforts during the last two decades have discovered molecules that act as glucokinase activators (GKAs). However, despite the antidiabetic potential of these GKAs, the development of reliable new therapeutic agents has not yet been successful. Glucokinase catalyzes the first limiting step of glucose utilization. Like other hexokinases, GCK transfers a phosphate group from ATP to glucose forming glucose 6phosphate (G6P). GCK expression is restricted to cells with important roles in glucose homeostasis. In pancreatic β cells, glucokinase acts as a glucosensor by integrating blood glucose levels and its metabolism with insulin secretion. More than 99% of total glucokinase content is expressed in the liver, where its activity controls glycogen accumulation, glycolysis and gluconeogenesis rates. The importance of glucokinase in glucose homeostasis is illustrated by the fact that nearly 700 mutations in GCK are associated with human monogenic glycemic disorders. Activating mutations are associated with hyperinsulinemic hypoglycemia (HH). Heterozygous inactivating mutations cause maturity‐onset diabetes of the young subtype 2 (MODY2) and homozygous inactivating mutations result in permanent neonatal diabetes mellitus (PNDM)...
Type 2 diabetes mellitus (T2DM), the most common form of diabetes caused by impairment of insulin secretion and action, is an increasing worldwide health problem. Effective antidiabetic drugs are necessary and many new agents are currently under development. The metabolic enzyme glucokinase (GCK) plays a central role in glucose homeostasis, thus it has been considered as a potential target in T2DM treatment. Research efforts during the last two decades have discovered molecules that act as glucokinase activators (GKAs). However, despite the antidiabetic potential of these GKAs, the development of reliable new therapeutic agents has not yet been successful. Glucokinase catalyzes the first limiting step of glucose utilization. Like other hexokinases, GCK transfers a phosphate group from ATP to glucose forming glucose 6phosphate (G6P). GCK expression is restricted to cells with important roles in glucose homeostasis. In pancreatic β cells, glucokinase acts as a glucosensor by integrating blood glucose levels and its metabolism with insulin secretion. More than 99% of total glucokinase content is expressed in the liver, where its activity controls glycogen accumulation, glycolysis and gluconeogenesis rates. The importance of glucokinase in glucose homeostasis is illustrated by the fact that nearly 700 mutations in GCK are associated with human monogenic glycemic disorders. Activating mutations are associated with hyperinsulinemic hypoglycemia (HH). Heterozygous inactivating mutations cause maturity‐onset diabetes of the young subtype 2 (MODY2) and homozygous inactivating mutations result in permanent neonatal diabetes mellitus (PNDM)...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, Departamento de Bioquímica y Biología Molecular, leída el 07/03/2017