November 25, 2013

Treatment of Diabetes and Long-Term Survival After Insulin and Glucokinase Gene Therapy

Text Box: Figure 1.Treatment with AAV1-Ins and AAV1-Gck corrects diabetes in dogs. A–D: Follow-up of glycemia, body weight, and insulinemia. Five diabetic dogs (Dog1–4 and DogDb3+Ins/Gck) were treated with AAV1-Ins and AAV1-Gck vectors at 1 × 1012 vg/kg each for Dog1 and Dog2 (A and B), at 2 × 1012 vg/kg each for Dog3 and DogDb3+Ins/Gck (C and D), or with AAV1-oIns and AAV1-oGck vectors at 1 × 1012 vg/kg each for Dog4 (E). Dogs had serum insulin levels that remained within the range of fasted healthy animals (dashed lines). Db indicates dog treatment with streptozotocin (STZ) plus alloxan. Gray bars indicate fasting normoglycemia range in dogs.
This paper explores the idea of long-term correction of diabetes in a large animal model using gene transfer.  Previous research by Mas et al., demonstrated that it is possible to generate a “glucose sensor” in skeletal muscle through coexpression of glucokinase and insulin, increasing glucose uptake and correcting hyperglycemia in diabetic mice.  This study was conducted in larger animals using viral vectors.  A one-time intramuscular administration of adeno-associated viral vectors of serotype 1 encoding for glucokinase and insulin in diabetic dogs resulted in normalization of fasting glycemia, accelerated disposal of glucose after oral challenge.  There were no episodes of hypoglycemia during exercise for more than 4 years after gene transfer.  No secondary compications were observed in these animal models.In contrast, exogenous insulin or gene transfer for insulin or glucokinase alone failed to achieve complete correction of diabetes, indicating that the synergistic action of insulin and glucokinase is needed for full therapeutic effect. This study provides the first proof-of-concept in a large animal model for a gene transfer approach to treat diabetes (Fig 1).


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