The Potential for Exercise-Induced Myokines as a Therapeutic for Types 2 Diabetes
Introduction: Type 2 Diabetes a chronic and debilitating disease on the rise and is estimated to effect more than 34 million people in the United States1. Nearly 88 million Americans can be classified as prediabetic as well, and the prevalence is roughly the same across all age demographics1. The hallmark of Type 2 Diabetes (T2D) is insulin insensitivity and hyperglycemia, which can lead to systemic effects including cataracts, kidney failure, and retinopathy, as well as increase risk for cancer and fatty-liver disease2-3. Although exercise has already been identified as an effective method to combat diseases related to metabolic dysfunction like T2D, recent studies have identified several molecules or myokines that are released upon skeletal muscle stimulation5. Many of the identified myokines have key regulatory roles in inflammation and cell migration, but the myokine CX3CL1, commonly known as fractalkine has been shown to specifically modulate pancreatic ß-cell function and hepatocyte insulin responses in the glucose-stimulation insulin secretion (GSIS) system5-7. Additional studies show that Fractalkine plays a key role in exercise-invoked changes that are needed for proper glucose mobilization and metabolism8. Together, these studies suggest that exercise has benefits beyond weight loss and fat reduction and may have a role as a therapeutic for T2D. Methods: Genetic knockout (KO) mice for the gene coding CX3CR1 (fractalkine receptor) were engineered to analyze loss-of-function of fractalkine in vivo6. A synthetic fractalkine antibody (FKN-Fc) was used to test the impact chronic administration of fractalkine on glucose metabolism function5. Effects of exercise were stimulated in gnawing model with mice, and in vivo fluorescence using α-sarcoglycan staining to monitor GLUT4 translocation in muscle tissue8. A synthetic fractalkine antagonist AZD8797 was administered to highlight fractalkine’s role in molecular responses to exercise8. Results: KO mice displayed elevated blood glucose levels after glucose tolerance tests via reduced insulin release compared to control groups. KO mice also had genetic downregulation of PDX1, GLUT2, and insulin6. Administration of FKN-Fc increased insulin release and decreased hepatic-glucose release via glucagon5. Exercise evoked increased GLUT2 translocation in muscle tissue, which was wiped out upon AZD8797 administration8. Discussion: Fractalkine is a key mediator of exercise-induced changes in glucose metabolism including modulating pancreatic ß-cell function and gene expression, hepatocyte insulin response, and skeletal muscle GLUT translocation. Further research is needed to optimize administration of this molecule and maximize its release via skeletal muscle activation. Fractalkine represents a novel therapeutic strategy utilizing physical exercise as a potential mode of delivery for the treatment of Type II Diabetes.
- Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2020. Atlanta, GA: Centers for Disease Control and Prevention, U.S. Dept of Health and Human Services; 2020.
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- Riopel M, Seo JB, Bandyopadhyay GK, et al. Chronic fractalkine administration improves glucose tolerance and pancreatic endocrine function. J Clin Invest. 2018;128(4):1458–1470.
- Lee YS, Morinaga H, Kim JJ, et al. The fractalkine/CX3CR1 system regulates β cell function and insulin secretion. Cell. 2013;153(2):413–425.
- Umehara, H., Bloom, E.T., Okazaki, T., Nagano, Y., Yoshie, O., & Imai, T. (2004). Fractalkine in vascular biology: from basic research to clinical disease. Arteriosclerosis, thrombosis, and vascular biology, 24 1, 34-40 .
- Chaweewannakorn, C., Nyasha, M.R., Chen, W., Sekiai, S., Tsuchiya, M., Hagiwara, Y., Bouzakri, K., Sasaki, K. and Kanzaki, M. (2020), Exercise‐evoked intramuscular neutrophil‐endothelial interactions support muscle performance and GLUT4 translocation: a mouse gnawing model study. J Physiol, 598: 101-122.