Pip M.G. van Lier1, Tineke van de Weijer1,2, Froukje Vanweert1, Kim Brouwers2, Kevin M.R. Nijssen1, Gert Schaart1, Esther Moonen-Kornips3, Sten M.M. van Beek1, Sam Springer2, Roel Wierts2, Peter J. Joris1, Vera B. Schrauwen-Hinderling2,6,7, Esther Phielix1, Tore Bengtsson5, Patrick Schrauwen4,6,7, Joris Hoeks1
1Department of Nutrition and Movement Sciences, NUTRIM Institute of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands; 2Department of Radiology and Nuclear Medicine, MUMC+, Maastricht, the Netherlands; 3Department of Human Biology, NUTRIM Institute of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands; 4Clinical Epidemiology, Leiden University Medical Center, The Netherlands; 5Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden; 6Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany; 7German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany.
Introduction: Impaired post-prandial skeletal muscle glucose uptake plays a pivotal role in the development of type 2 diabetes (T2DM), yet effective pharmacological strategies to enhance muscle glucose uptake are limited. Interestingly, previous (pre)clinical research in various rodent models, as well as in healthy volunteers, revealed that β2-adrenergic receptor (β2-AR) stimulation robustly enhances muscle glucose uptake. Although highly promising, the clinical relevance of these findings in individuals with obesity- who are more prone to develop T2DM- is currently unknown.
Methods: In a double-blinded, placebo-controlled, randomized cross-over study, we investigated the effects of a 4-week treatment with the β2-adrenergic agonist clenbuterol (40 μg/day) on insulin-stimulated glucose uptake, as reflected by metabolic rate of glucose (MRgluc), in skeletal muscle (primary outcome) and brown adipose tissue glucose uptake (secondary outcome) using hyperinsulinemic-euglycemic clamp combined with a 18F-FDG PET-MRI in fourteen individuals with overweight or obesity. PET-MRI also allowed the assessment of insulin-stimulated MRgluc in liver and heart. Nocturnal energy expenditure and substrate utilization were investigated by whole-room calorimetry.
Results: Clenbuterol treatment tended to improve insulin-stimulated MRgluc in the vastus lateralis by ~15% (p=0.072), while in the hamstring muscle MRgluc was significantly increased by ~13% (p=0.037) compared to placebo. Glucose uptake in brown adipose tissue and MRgluc in liver and heart remained unaffected. Although no effects were observed on nocturnal energy expenditure, protein oxidation was significantly reduced by 7.9% during the night after clenbuterol treatment (p=0.029).
Conclusion: Prolonged stimulation of β2-ARs augments skeletal muscle MRgluc, even in individuals with obesity, highlighting the potential clinical relevance of the β2-AR pathway in the prevention or treatment of T2DM.