Glucose-Regulated Glucose Uptake by Transplanted Muscle Cells Expressing Glucokinase Counteracts Diabetic Hyperglycemia

Otaegui, Pedro J.; Ontiveros, Maria; Ferré, Tura; Riu, Efrén; Jimenez, Rocio; Bosch, Fátima

doi:10.1089/104303402320987824

Cited by 9 publications

(3 citation statements)

References 47 publications

(51 reference statements)

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“…This should help prevent hypoglycaemia by acting as a classical "gluco-sensor". This approach was first demonstrated in a double transgenic mouse model and subsequently after viral transduction [242,246]. Using this approach, we observed normal blood glucose levels in fasted diabetic mice without hypoglycemia after AAV-treatment [242].…”

Section: Gene Therapy Strategies For the Treatment Of Type 1 Diabetesmentioning

confidence: 86%

Skeletal Muscle Metabolism in the Pathology and Treatment of Type 1 Diabetes

Mann

Ayuso²,

Anguela³

et al. 2010

CPD

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Type 1 diabetes is characterised by the absence of circulating insulin due to the autoimmune destruction of beta-cells in the pancreas. Patients are traditionally treated with multiple daily injections of exogenous insulin analogues. However, although these therapies improve quality of life, they are associated with the risk of hypoglycemic episodes and do not prevent the development of debilitating secondary complications. For these reasons, there is increasing demand for new therapies and preventions. One approach is the use of viral or non-viral gene therapy to modify skeletal muscle to produce and secrete insulin into the circulation and/or to increase muscle glucose uptake. Skeletal muscle is a desirable target tissue for the treatment of diabetes not only for its central role in whole body metabolism and glucose homeostasis, but also for its accessibility and amenability to many potential gene therapy technologies. Here, we review the basic metabolic principles of skeletal muscle in the absorptive and post-absorptive states at rest and during exercise and discuss how these processes are affected in type 1 diabetes. Finally, current viral and non-viral strategies for modification of skeletal muscle and their application to the treatment of type 1 diabetes are also presented.

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Section: Gene Therapy Strategies For the Treatment Of Type 1 Diabetesmentioning

confidence: 86%

Skeletal Muscle Metabolism in the Pathology and Treatment of Type 1 Diabetes

Mann

Ayuso²,

Anguela³

et al. 2010

CPD

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“…These features allow glucose to be taken up only when it is at high concentrations, as previously reported in pancreatic ␤-cells (18). Expression of glucokinase in skeletal muscle increases glucose disposal and reduces diabetic hyperglycemia (17,19,20). However, expression of glucokinase alone cannot normalize glycemia in type 1 diabetes because of the lack of insulin-mediated glucose transport.…”

mentioning

confidence: 85%

Reversal of Type 1 Diabetes by Engineering a Glucose Sensor in Skeletal Muscle

Mas

Montané²,

Anguela³

et al. 2006

Diabetes

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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. Diabetes 55: 1546 -1553, 2006

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“…In an effort to mimic the physiological conditions of insulin secretion, attempts have been made by various means to control insulin secretion in response to blood glucose levels. Strategies used for transcriptional control of insulin secretion include the utilization of glucoseresponsive elements (GREs) of the rat L-pyruvate kinase (L-PK) gene, inserted into the insulin-sensitive element of rat insulin-like growth factor binding protein-1 (IGFBP-1) promoter (1,2); employment of genetically engineered cells to over-express key regulatory genes such as glucokinase (GK) in skeletal muscle (3,4); the use of phosphoenolpyruvate carboxykinase (PEPCK) promoter (5)(6)(7); and expression of the GLUT2 glucose transporter (8), etc. A combination of constructs with modified insulin gene and suitable gene delivery vectors has demonstrated partial success in the generation of glucose-modulated insulin secretion.…”

Section: Introductionmentioning

confidence: 99%