GLUT4-overexpressing engineered muscle constructs as a therapeutic platform to normalize glycemia in diabetic mice

Margarita Beckerman; Chava Harel; Inbal Michael; Amira Klip; Philip J Bilan; Emily J Gallagher; Derek LeRoith; Eli C Lewis; Eddy Karnieli; Shulamit Levenberg

doi:https://doi.org/10.1126/sciadv.abg3947

GLUT4-overexpressing engineered muscle constructs as a therapeutic platform to normalize glycemia in diabetic mice

Margarita Beckerman, Chava Harel, Inbal Michael, Amira Klip, Philip J Bilan, Emily J Gallagher, Derek LeRoith, Eli C Lewis, Eddy Karnieli, Shulamit Levenberg

Ben-Gurion University of the Negev, Technion - Israel Institute of Technology

Research output: Contribution to journal › Article › peer-review

Abstract

Skeletal muscle insulin resistance is a main defect in type 2 diabetes (T2D), which is associated with impaired function and content of glucose transporter type 4 (GLUT4). GLUT4 overexpression in skeletal muscle tissue can improve glucose homeostasis. Therefore, we created an engineered muscle construct (EMC) composed of GLUT4-overexpressing (OEG4) cells. The ability of the engineered implants to reduce fasting glucose levels was tested in diet-induced obesity mice. Decrease and stabilization of basal glucose levels were apparent up to 4 months after implantation. Analysis of the retrieved constructs showed elevated expression of myokines and proteins related to metabolic processes. In addition, we validated the efficiency of OEG4-EMCs in insulin-resistant mice. Following high glucose load administration, mice showed improved glucose tolerance. Our data indicate that OEG4-EMC implant is an efficient mode for restoring insulin sensitivity and improving glucose homeostasis in diabetic mice. Such procedure is a potential innovative modality for T2D therapy.

Original language	American English
Article number	eabg3947
Pages (from-to)	eabg3947
Number of pages	13
Journal	Science Advances
Volume	7
Issue number	42
DOIs	https://doi.org/10.1126/sciadv.abg3947
State	Published - 13 Oct 2021

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title = "GLUT4-overexpressing engineered muscle constructs as a therapeutic platform to normalize glycemia in diabetic mice",

abstract = "Skeletal muscle insulin resistance is a main defect in type 2 diabetes (T2D), which is associated with impaired function and content of glucose transporter type 4 (GLUT4). GLUT4 overexpression in skeletal muscle tissue can improve glucose homeostasis. Therefore, we created an engineered muscle construct (EMC) composed of GLUT4-overexpressing (OEG4) cells. The ability of the engineered implants to reduce fasting glucose levels was tested in diet-induced obesity mice. Decrease and stabilization of basal glucose levels were apparent up to 4 months after implantation. Analysis of the retrieved constructs showed elevated expression of myokines and proteins related to metabolic processes. In addition, we validated the efficiency of OEG4-EMCs in insulin-resistant mice. Following high glucose load administration, mice showed improved glucose tolerance. Our data indicate that OEG4-EMC implant is an efficient mode for restoring insulin sensitivity and improving glucose homeostasis in diabetic mice. Such procedure is a potential innovative modality for T2D therapy.",

author = "Margarita Beckerman and Chava Harel and Inbal Michael and Amira Klip and Bilan, {Philip J} and Gallagher, {Emily J} and Derek LeRoith and Lewis, {Eli C} and Eddy Karnieli and Shulamit Levenberg",

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AU - Beckerman, Margarita

AU - Harel, Chava

AU - Michael, Inbal

AU - Klip, Amira

AU - Bilan, Philip J

AU - Gallagher, Emily J

AU - LeRoith, Derek

AU - Lewis, Eli C

AU - Karnieli, Eddy

AU - Levenberg, Shulamit

N1 - Publisher Copyright: Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

PY - 2021/10/13

Y1 - 2021/10/13

N2 - Skeletal muscle insulin resistance is a main defect in type 2 diabetes (T2D), which is associated with impaired function and content of glucose transporter type 4 (GLUT4). GLUT4 overexpression in skeletal muscle tissue can improve glucose homeostasis. Therefore, we created an engineered muscle construct (EMC) composed of GLUT4-overexpressing (OEG4) cells. The ability of the engineered implants to reduce fasting glucose levels was tested in diet-induced obesity mice. Decrease and stabilization of basal glucose levels were apparent up to 4 months after implantation. Analysis of the retrieved constructs showed elevated expression of myokines and proteins related to metabolic processes. In addition, we validated the efficiency of OEG4-EMCs in insulin-resistant mice. Following high glucose load administration, mice showed improved glucose tolerance. Our data indicate that OEG4-EMC implant is an efficient mode for restoring insulin sensitivity and improving glucose homeostasis in diabetic mice. Such procedure is a potential innovative modality for T2D therapy.

AB - Skeletal muscle insulin resistance is a main defect in type 2 diabetes (T2D), which is associated with impaired function and content of glucose transporter type 4 (GLUT4). GLUT4 overexpression in skeletal muscle tissue can improve glucose homeostasis. Therefore, we created an engineered muscle construct (EMC) composed of GLUT4-overexpressing (OEG4) cells. The ability of the engineered implants to reduce fasting glucose levels was tested in diet-induced obesity mice. Decrease and stabilization of basal glucose levels were apparent up to 4 months after implantation. Analysis of the retrieved constructs showed elevated expression of myokines and proteins related to metabolic processes. In addition, we validated the efficiency of OEG4-EMCs in insulin-resistant mice. Following high glucose load administration, mice showed improved glucose tolerance. Our data indicate that OEG4-EMC implant is an efficient mode for restoring insulin sensitivity and improving glucose homeostasis in diabetic mice. Such procedure is a potential innovative modality for T2D therapy.

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GLUT4-overexpressing engineered muscle constructs as a therapeutic platform to normalize glycemia in diabetic mice

Abstract

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