GLUT4-Overexpressing Engineered Muscle Tissue Implants as a Potential Novel Therapy for Type 2 Diabetes: Lessons from Diabetic Mice

In spite of current therapy protocols many T2DM patients fail to achieve blood glucose homeostasis goals. Insulin resistance in T2DM is associated with impaired GLUT4 function and cellular content. Thus, our aim was to improve overall glucose homeostasis by constructing engineered muscle tissue, using genetically modified skeletal muscle cells that over-express the GLUT4 transporter (OEG4). The OEG4 cells were grafted on biodegradable scaffolds and cultured to allow the formation of engineered muscle tissue constructs (EMC). Using an in-vitro 2-deoxyglucos (DOG) uptake assay, the OEG4-EMCs showed a 1.8-fold increase in DOG uptake with insulin stimulation, compared to unmodified controls. For in-vivo efficacy evaluation OEG4-EMCs and empty constructs, not seeded with cells, as control were implanted in the abdominal wall of immunodeficient recombination-activating gene 1 (Rag1)/MKR mice model of T2DM. Following i.p glucose tolerance test mice implanted with OEG4-EMCs had significantly (p<0.05) reduced maximal blood glucose levels (185+/-14.8 mg/dL), compared to diabetic controls group (294+/-23 mg/dL) and similar to nondiabetic mice (188+/-8.1 mg/dL). In addition, glucose levels returned to basal levels faster than in the control group. Since, EMC implants improved diabetic mice overall glucose homeostasis our data support the potential of such implants as novel therapeutic mode for T2DM therapy. Disclosure M. Beckerman: None. E. Karnieli: None. C. Harel: None. A. Klip: None. P.J. Bilan: None. E. Gallagher: None. D. LeRoith: Advisory Panel; Self; AstraZeneca, MannKind Corporation. S. Levenberg: None. Funding Rina and Avner Schneur Charitable Giving Fund