The β3-adrenergic receptor agonist mirabegron improves glucose homeostasis in obese humans
Brian S. Finlin, … , Esther E. Dupont-Versteegden, Philip A. Kern
Brian S. Finlin, … , Esther E. Dupont-Versteegden, Philip A. Kern
Published January 21, 2020
Citation Information: J Clin Invest. 2020;130(5):2319-2331. https://doi.org/10.1172/JCI134892.
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Clinical Research and Public Health Metabolism

The β3-adrenergic receptor agonist mirabegron improves glucose homeostasis in obese humans

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.

Authors

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

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Figure 2

Mirabegron treatment improves glucose homeostasis in obese, insulin-resistant subjects.

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Mirabegron treatment improves glucose homeostasis in obese, insulin-resi...
Subjects were treated with mirabegron (50 mg/day) for 12 weeks. OGTTs and euglycemic clamps were performed at baseline and after treatment. (A) OGTT results and AUC for all subjects (n = 12). Data indicate the mean ± SEM. OGTT data were analyzed by a 2-way, repeated-measures ANOVA (***P < 0.001 and ****P < 0.0001); AUC data were analyzed by a paired, 2-tailed Student’s t test (**P < 0.01). (B) Euglycemic clamping was performed at an insulin infusion rate of 1.0 mU/kg/min, and the GIR was determined before and after treatment. Data indicate the mean ± SEM (n = 13) and were analyzed by a paired, 2-tailed Student’s t test (*P < 0.05). (C) The insulinogenic index was determined from the results of the oral glucose tolerance test. Data indicate the mean ± SEM (n = 12) and were analyzed by a paired, 2-tailed Student’s t test (*P < 0.05). (D) The disposition index is the product of (C) insulin sensitivity and (D) the insulinogenic index. Data indicate the mean ± SEM (n = 12). **P < 0.01, by paired, 2-tailed Student’s t test. (E) BAT volume was quantified by PET-CT scans before and after treatment. Eight subjects had no BAT at baseline, and BAT did not increase after treatment of these subjects. (F) The change in SC WAT beiging was calculated as the difference in UCP1 protein expression before and after treatment. The change in the disposition index (D) and the change in UCP1 in SC WAT were analyzed by regression analysis. The Spearman’s correlation coefficient and P value are indicated in F.