Reversal of type 1 diabetes by engineering a glucose sensor in skeletal muscle

Alex Mas, Joel Montané, Xavier M. Anguela, Sergio Muñoz, Anne M. Douar, Efren Riu, Pedro Otaegui, Fatima Bosch*

*Autor correspondiente de este trabajo

Producción científica: Artículo en revista indizadaArtículorevisión exhaustiva

50 Citas (Scopus)

Resumen

Type 1 diabetic patients develop severe secondary complications because insulin treatment does not guarantee normoglycemia. Thus, efficient regulation of glucose homeostasis is a major challenge in diabetes therapy. Skeletal muscle is the most important tissue for glucose disposal after a meal. However, the lack of insulin during diabetes impairs glucose uptake. To increase glucose removal from blood, skeletal muscle of transgenic mice was engineered both to produce basal levels of insulin and to express the liver enzyme glucokinase. After streptozotozin (STZ) administration of double-transgenic mice, a synergic action in skeletal muscle between the insulin produced and the increased glucose phosphorylation by glucokinase was established, preventing hyperglycemia and metabolic alterations. These findings suggested that insulin and glucokinase might be expressed in skeletal muscle, using adeno-associated viral 1 (AAV1) vectors as a new gene therapy approach for diabetes. AAV1-Ins+GK-treated diabetic mice restored and maintained normoglycemia in fed and fasted conditions for >4 months after STZ administration. Furthermore, these mice showed normalization of metabolic parameters, glucose tolerance, and food and fluid intake. Therefore, the joint action of basal insulin production and glucokinase activity may generate a "glucose sensor" in skeletal muscle that allows proper regulation of glycemia in diabetic animals and thus prevents secondary complications.

Idioma originalInglés
Páginas (desde-hasta)1546-1553
Número de páginas8
PublicaciónDiabetes
Volumen55
N.º6
DOI
EstadoPublicada - 2006

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