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

Abstract

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

Altered REDD1, myostatin, and Akt/mTOR/FoxO/MAPK signaling in streptozotocin-induced diabetic muscle atrophy

“…The atrophic effect of STZ on skeletal muscle seems to be comparable with that of mice with a mutation in the insulin gene (26). In STZ animals, the diabetic phenotype can be mostly prevented with artificial insulin expression in muscle, including decreases in body weight (8,40) and skeletal muscle mass (30). Moreover, many but not all of the other effects of STZ-induced diabetes are normalized with insulin implant (8).…”

High AAV vector purity results in serotype- and tissue-independent enhancement of transduction efficiency

“…It is possible that the more abundant impurities in vectors prepared by the standard process coat the surface of vector particles, and thereby inhibit target cell binding. The use of AAV vector with increased transduction efficiency in liver and muscle is relevant because these tissues are important targets of gene transfer studies for inherited and metabolic diseases 9,12,[19][20][21] as well as the need for high levels of transgene expression for some applications to achieve therapeutic efficacy. 20,22 Increasing vector purity and potency is predicted to reduce the risk of deleterious, efficacy-limiting immune responses after administration of recombinant AAV to human subjects, a critical consideration for an inherently immunogenic (that is viral) biologic product that will depend on avoidance of certain immune responses to achieve long-term efficacy.…”

Immunity to adeno-associated virus vectors in animals and humans: a continued challenge

“…Furthermore several cures have been reported in animal models of human diseases. [13][14][15][16][17][18] However, complications of treatment related to immune responses against the vectors have emerged as serious obstacles for successful translations to humans.…”