GLUT4-overexpressing Engineered Muscle Tissue Implants as a Potential Novel Therapy for Type 2 Diabetes

Type 2 diabetes mellitus (DM2) is a complex metabolic disease, characterized by adipose and muscle insulin resistance accompanied by defects in insulin secretion. Muscle insulin resistance in DM2 is associated with impaired function and cellular content of glucose transporter type 4 (GLUT4). We hypothesize that overall glucose homeostasis can be improved using engineered muscle tissue, constructed from genetically modified skeletal muscle cells overexpressing the GLUT4 transporter (OEG4). To assess this possibility, wild type (WT) or OEG4 cells were seeded on biodegradable scaffolds and cultured to form engineered muscle constructs (EMC). In-vitro 2-deoxyglucose uptake assays demonstrated higher glucose uptake rates in OEG4-EMC as compared to WT controls. For in-vivo efficacy assessment, OEG4 and WT or acellular constructs, as controls, were implanted into the abdominal wall of diet-induced obesity (DIO) mice and insulin resistance (Rag/MKR) mice. Basal glucose levels were monitored for up to 15 weeks post-implantation, and glucose tolerance was evaluated at different time points during this period. DIO mice implanted with OEG4-EMC showed a decrease, followed by stabilization of basal glucose levels as compared to those implanted with WT-EMC. Following administration of a high glucose dosage, Rag/MKR mice bearing the OEG4-EMC implant experienced a significantly smaller increase in their plasma glucose levels, which returned to basal levels faster, than in the control groups. Taken together, OEG4-EMC implants improved overall glucose homeostasis in diabetic mice and suggest their potential as a novel therapeutic modality for DM2.