Carolinas Research Day 2021

Biomedical Studies

06 Effects of Adipor1 Agonists on Insulin-Independent Glucose Transport Pathways in Skeletal Muscle Cells

Joseph Metz, OMS-III, Marwan Mahmoud, OMS-II, Patrick Ellis Fisher, PhD

Edward Via College of Osteopathic Medicine-Carolinas, Gibbs Cancer Institute

Abstract: As of 2015, the CDC estimates that nearly 30.3 million Americans were living with Diabetes mellitus and another 84.1 million Americans were classified as pre-diabetic. With such alarming up- trends over previous years, further elucidation of insulin-independent pathways for glucose metabolism is critical. Adiponectin is a protein-derived hormone that is produced and secreted from adipocytes that appears to help regulate glucose metabolism. A systematic review demonstrated that higher levels of circulating adiponectin are associated with a lower risk of developing type 2 diabetes and levels were inversely related to insulin resistance (1). Developing adiponectin receptor agonists could be an important turning point in the treatment of type 2 diabetes. We are examining the effects of treating cultured human skeletal muscle cells (myocytes and myotubes) with the plant lignan matairesinol and its gut microbial metabolites enterolactone and enterodiol. Previous work has shown the binding and activation of the

adiponectin receptor 1 (AdipoR1) by matairesinol (2). We hypothesize that matairesinol, along with its metabolites, can stimulate the AdipoR1 receptor and induce the translocation of insulin-responsive glucose transporter type 4 (GLUT4) to the plasma membrane, resulting in increased glucose uptake and a potential restoration of insulin sensitivity via downstream pathways. In the present study, we show that matairesinol treatment induces increased glucose uptake in human skeletal muscle tubes, similar to insulin and adiponectin. We have grown primary skeletal myocytes and differentiated them into polynucleated myotubes. Treating these with insulin, adiponectin, or our test compounds, we examined glucose uptake in muscle cells using a luciferase-based glucose uptake assay. We are currently working to determine the mechanism of activation, hypothesized to be via the AMP-activated Protein Kinase (AMPK) signaling pathway.

Clinically, these studies could lay a foundation for future work creating small molecule compounds or agonistic antibodies that could be used to decrease the use of insulin in type 2 diabetic patients. Our results could inspire new first-line medications for diabetic patients, due to the potential cardiovascular benefits associated with AdipoR1 activation and mechanistically solving the pathophysiological problem in type 2 diabetes, insulin insensitivity. 1. Shanshan L, Shin HJ, Ding EL, et al. Adiponectin levels and risk of type 2 diabetes: a systematic review and metanalysis. JAMA. 2009;302(2):179-188 2. Sun Y, Zang Z, Zhong L, et al. Identification of adiponectin receptor agonist utilizing a fluorescence polarization based high throughput assay. PLoS ONE. 2013;8(5):e63354

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