Background
Recently, we have demonstrated that skeletal muscle glucose uptake in rodents can be stimulated via an alternative, insulin-independent pathway, involving the activation of  β₂-adrenergic receptors. Thus, prolonged supplementation with the selective β₂-agonist clenbuterol robustly improved glucose homeostasis in various insulin resistant rodent models. However, whether prolonged β₂-agonist supplementation can promote skeletal muscle glucose uptake in humans is currently unknown.

Methods
In a randomized, double-blinded, placebo-controlled, cross-over design, 11 healthy young males (18-30 years, BMI: 20-25 kg/m²) received the β₂-agonist clenbuterol (2x 20µg/day) or a placebo for 14 days. On day 14, femoral artery blood flow and diameter were assessed with an Echo-Doppler, after which subjects stayed overnight in a metabolic chamber for the measurement of sleeping metabolic rate. The following morning, body composition was measured using a BodPod. Subsequently, a muscle biopsy was taken and a two-step hyperinsulinemic-euglycemic clamp was performed to assess liver insulin sensitivity and skeletal muscle glucose uptake.

Results
Body weight and composition were unaffected by clenbuterol supplementation. However, clenbuterol significantly increased sleeping- and resting metabolic rate by 10.2% and 5.3%, respectively, independent of changes in carbohydrate- or fat oxidation. After clenbuterol supplementation, both femoral artery blood flow and diameter were significantly increased (p=0.01 and p=0.007, respectively). Liver insulin sensitivity remained unaffected by clenbuterol supplementation. However, skeletal muscle glucose disposal was increased by ~13% (p=0.019), which was primarily accounted for by an increased non-oxidative glucose disposal of ~18% (p=0.033). Interestingly, skeletal muscle GLUT4 translocation was unaltered.

No correlation was found between blood flow measurements and skeletal muscle glucose uptake.

Discussion
Prolonged supplementation with the β₂-agonist clenbuterol significantly enhanced skeletal muscle glucose uptake in healthy young males, although the underlying mechanisms remain to be elucidated. These results indicate that β₂-adrenergic receptor associated signalling could potentially be used as a novel treatment target for type 2 diabetes mellitus.