The β3-Adrenergic Receptor Agonist Mirabegron Improves Glucose Homeostasis in Obese Humans

Authors

Brian S. Finlin, University of KentuckyFollow
Hasiyet Memetimin, University of KentuckyFollow
Beibei Zhu, University of KentuckyFollow
Amy L. Confides, University of KentuckyFollow
Hemendra J. Vekaria, University of KentuckyFollow
Riham H. El Khouli, University of KentuckyFollow
Zachary R. Johnson, University of KentuckyFollow
Philip M. Westgate, University of KentuckyFollow
Jianzhong Chen, University of KentuckyFollow
Andrew J. Morris, University of KentuckyFollow
Patrick G. Sullivan, University of KentuckyFollow
Esther E. Dupont-Versteegden, University of KentuckyFollow
Philip A. Kern, University of KentuckyFollow

Abstract

BACKGROUND. Beige adipose tissue is associated with improved glucose homeostasis in mice. Adipose tissue contains β3-adrenergic receptors (β3-ARs), and this study was intended to determine whether the treatment of obese, insulin-resistant humans with the β3-AR agonist mirabegron, which stimulates beige adipose formation in subcutaneous white adipose tissue (SC WAT), would induce other beneficial changes in fat and muscle and improve metabolic homeostasis.

METHODS. Before and after β3-AR agonist treatment, oral glucose tolerance tests and euglycemic clamps were performed, and histochemical analysis and gene expression profiling were performed on fat and muscle biopsies. PET-CT scans quantified brown adipose tissue volume and activity, and we conducted in vitro studies with primary cultures of differentiated human adipocytes and muscle.

RESULTS. The clinical effects of mirabegron treatment included improved oral glucose tolerance (P < 0.01), reduced hemoglobin A1c levels (P = 0.01), and improved insulin sensitivity (P = 0.03) and β cell function (P = 0.01). In SC WAT, mirabegron treatment stimulated lipolysis, reduced fibrotic gene expression, and increased alternatively activated macrophages. Subjects with the most SC WAT beiging showed the greatest improvement in β cell function. In skeletal muscle, mirabegron reduced triglycerides, increased the expression of PPARγ coactivator 1 α (PGC1A) (P < 0.05), and increased type I fibers (P < 0.01). Conditioned media from adipocytes treated with mirabegron stimulated muscle fiber PGC1A expression in vitro (P < 0.001).

CONCLUSION. Mirabegron treatment substantially improved multiple measures of glucose homeostasis in obese, insulin-resistant humans. Since β cells and skeletal muscle do not express β3-ARs, these data suggest that the beiging of SC WAT by mirabegron reduces adipose tissue dysfunction, which enhances muscle oxidative capacity and improves β cell function.

TRIAL REGISTRATION. Clinicaltrials.gov NCT02919176.

FUNDING. NIH: DK112282, P30GM127211, DK 71349, and Clinical and Translational science Awards (CTSA) grant UL1TR001998.

Document Type

Article

Publication Date

5-1-2020

Notes/Citation Information

Published in The Journal of Clinical Investigation, v. 130, no. 5.

Copyright © 2020 American Society for Clinical Investigation

The copyright holder has granted the permission for posting the article here.

Digital Object Identifier (DOI)

https://doi.org/10.1172/JCI134892

Funding Information

This study was funded by NIH grants DK112282, P30GM127211, and DK 71349 and by CTSA, NIH grant UL1TR001998.

Repository Citation

Finlin, Brian S.; Memetimin, Hasiyet; Zhu, Beibei; Confides, Amy L.; Vekaria, Hemendra J.; El Khouli, Riham H.; Johnson, Zachary R.; Westgate, Philip M.; Chen, Jianzhong; Morris, Andrew J.; Sullivan, Patrick G.; Dupont-Versteegden, Esther E.; and Kern, Philip A., "The β3-Adrenergic Receptor Agonist Mirabegron Improves Glucose Homeostasis in Obese Humans" (2020). Internal Medicine Faculty Publications. 242.
https://uknowledge.uky.edu/internalmedicine_facpub/242