Jeremiah Ling

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 disease^2-3. 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) system^5-7. 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.

1.  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.
2. Cowie CC, Casagrande SS, Geiss LS. Prevalence and incidence of type 2 diabetes and prediabetes. In Diabetes in America. 3rd ed. Cowie CC, Casagrande SS, Menke A, et al., Eds. Bethesda, MD, National Institutes of Health, 2018, pp. 3.1– 3.32
3. Deepthi, B., Sowjanya, K., Lidiya, B., Bhargavi, R. S., & Babu, P. S. (2017). A modern review of diabetes mellitus: an annihilatory metabolic disorder. J In Silico In Vitro Pharmacol, 3(1).
4. Eckardt, Kristin & Görgens, Sven & Raschke, Silja & Eckel, Jürgen. (2014). Myokines in insulin resistance and type 2 diabetes. Diabetologia. 57.
5. 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.
6. 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.
7. 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 .
8. 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.