Engineered Muscle Tissue Implants as a Potential Therapy for Type 2 Diabetes

Background: Type 2 Diabetes (DM2) is a complex metabolic disease, characterized by defects in insulin secretion and adipose and muscle insulin resistance. Insulin resistance in DM2 is associated with impaired function and cellular content of the skeletal muscle glucose-transporter-type4 (GLUT4). We hypothesize that overall glucose homeostasis can be improved by constructing an engineered muscle tissue, using genetically modified skeletal muscle cells overexpressing the Glut4 transporter (OEG4).

Methods: To test the hypothesis we created engineered muscle constructs (EMCs), out of wild-type (WT) and OEG4 cells. In-vitro glucose uptake was evaluated by a 2- deoxyglucose (2DOG) uptake assay. For in-vivo efficacy assessment, we implanted the WT and OEG4 EMCs and acellular constructs, into two DM2 mice models. Diet induced obesity (DIO) model and insulin resistance (Rag\MKR) model. Basal glucose levels were followed, and glucose tolerance was evaluated at different time points during this period.

Results: The OEG4-EMCs exhibited higher 2DOG uptake with insulin stimulation, compared to WT EMCs. DIO mice implanted with OEG4-EMCs showed a decrees and stabilization of the basal glucose levels compered to WT-EMCs. Following administration of high external glucose dosage, Rag\MKR mice implanted with OEG4-EMCs show significantly lower increase in their plasma glucose levels. In addition, glucose levels returned to basal levels faster than the control groups.

Conclusion: EMC implants improved diabetic mice overall glucose homeostasis and the data show the potential of such implants as a novel therapeutic modality for DM2.