Clenbuterol exerts antidiabetic activity through metabolic reprogramming of skeletal muscle cells

Systemic treatment with beta2-adrenergic (b2-AR) agonists results in multiple beneficial metabolic effects, including improved glucose homeostasis. To elucidate the underlying cellular and molecular mechanisms, we chronically treated wild-type mice and several novel mutant mouse strains with clenbuterol, a selective b2-AR agonist. Clenbuterol administration caused pronounced improvements in glucose homeostasis and prevented the metabolic deficits in mouse models of beta-cell dysfunction and insulin resistance. Studies with skeletal muscle (SKM)-specific mutant mice demonstrated that these metabolic improvements required activation of SKM b2-ARs and the stimulatory G protein, Gs. Unbiased transcriptomic and metabolomic analyses showed that chronic b2-AR stimulation caused metabolic reprogramming of SKM characterized by enhanced glucose utilization. These new data strongly suggest that agents targeting SKM metabolism by modulating b2-AR-dependent signaling pathways may prove highly beneficial as novel antidiabetic drugs.