A novel approach to treating type 2 diabetes is being developed at the Technion. The disease, caused by insulin resistance and reduction of cells’ ability to absorb sugar, is characterised by increased blood sugar levels.
It is currently treated by a combination of lifestyle changes, medication, and insulin injections, but ultimately is associated with a 10-year reduction in life expectancy.
Led by Professor Shulamit Levenberg, Ph.D. student Rita Beckerman from the Stem Cell and Tissue Engineering Laboratory in the Technion’s Faculty of Biomedical Engineering presents a novel treatment approach, using an autograft of muscle cells engineered to take in sugar at increased rates. Mice treated in this manner displayed normal blood sugar levels for months after a single procedure. The group’s findings were recently published in Science Advances.
Muscle cells are among the main targets of insulin, and they are supposed to absorb sugar from the blood.
These cells were then grown to form an engineered muscle tissue, and finally transported back into the abdomen of diabetic mice.
After this one treatment, the mice remained cured of diabetes for four months – the entire period they remained under observation. Their blood sugar levels remained lower, and they had reduced levels of fatty liver normally displayed in type 2 diabetes.
“By taking cells from the patient and treating them, we eliminate the risk of rejection,” Prof. Levenberg explained. These cells can easily integrate back into being part of the body and respond to the body’s signaling activity.
An effective treatment – and one that is a one-time treatment rather than daily medication – could significantly improve both quality of life and life expectancy of those who have diabetes. The same method could also be used to treat various enzyme deficiency disorders.
Skeletal muscle tissue takes part in various functions in the body. It comprises about 40% of total body weight and provides stability and movement to the skeleton (1). Skeletal muscle also plays a major role in glucose homeostasis, glycogen and lipid metabolism, and more. In recent years, the skeletal muscle tissue has been identified as a secretory organ; upon contraction, it releases muscle-specific cytokines and myokines that have local and/or systemic effects (2–4).
The skeletal muscle tissue is responsible for about 80% of infused glucose uptake (5). Skeletal muscle insulin resistance is a key defect in type 2 diabetes (T2D) and obesity (5–7). The clinical guideline for T2D treatment is to normalize glycemia and thus minimize the chronic diabetes–related complications that can lead to medical disability, reduction in life expectancy, and high health costs (8, 9).
The treatment consists of lifestyle modification and various oral and injectable pharmaceutical agents. The commonly used drugs mainly aim to stimulate insulin secretion, reduce hepatic glucose production, modulate incretin levels, and inhibit sodium-glucose co-transporter-2 activity. Specific agents for improving insulin action, such as peroxisome proliferator–activated receptor γ agonists, are scarcely used (7, 10, 11).
Despite numerous treatment options, patients often fail to achieve target glycemic values (8, 12). To improve the overall patient health, there is a need for developing long-acting, stimuli-responsive, and alternate delivery systems (13–17).
Insulin resistance is a main clinical feature of T2D; hence, enhancing insulin sensitivity is a valid therapeutic target. Upon insulin stimulation, glucose uptake is mediated through the adipose- and muscle-specific insulin-responsive glucose transporter type 4 (GLUT4) (18–20). GLUT4 has a very long half-life of over 24 hours (21) and a slow recycling rate allowing high availability upon a response to insulin stimuli (20).
One of the prominent defects detected in T2D is impaired GLUT4 translocation machinery and a reduction of GLUT4 cellular levels (20, 22–25). Studies in GLUT4 transgenic (TG) and knockout animals have provided important insights; the modified expression of GLUT4 in these animals, either systemic (26–31) or muscle tissue specific (32–35), influenced whole-body insulin action and glucose metabolism. GLUT4 knockout mice exhibited insulin resistance and glucose intolerance and developed a diabetic phenotype (30, 34, 35). Mice overexpressing GLUT4 showed improved insulin action and reduced glycemic levels at both fasting and postprandial states (26–29, 31–33).
Following these findings and the potential of GLUT4 to normalize glycemic values, we propose an alternative innovative therapeutic platform based on tissue engineering. Skeletal muscle engineering offers a potential solution for muscle regeneration following muscle loss due to trauma or diseases (36, 37).
In recent years, studies have shown the potential of engineered muscle constructs (EMCs) to improve muscle reconstruction in vivo. EMCs composed of either muscle cells alone or in combination with endothelium and connective tissue, seeded on suitable scaffolds, have shown increased integration into the host upon implantation and myogenesis (38–42).
Accordingly, we hypothesized that EMCs overexpressing GLUT4 would enhance glucose uptake and, concomitantly, will affect glucose homeostasis in diabetic animals. Thus, we constructed an EMC composed of skeletal muscle cells that were genetically modified to overexpress the GLUT4 transporter and implanted them into diabetic mice to then assess their glucose homeostasis.
More information: Margarita Beckerman et al, GLUT4-overexpressing engineered muscle constructs as a therapeutic platform to normalize glycemia in diabetic mice, Science Advances (2021). DOI: 10.1126/sciadv.abg3947
