Beta₂-agonist Impairs Muscle Insulin Sensitivity in Persons With Insulin Resistance.

Onslev, Johan; Fiorenza, Matteo; Thomassen, Martin; Havelund, Jesper; Bangsbo, Jens; Færgeman, Nils; Wojtaszewski, Jørgen F P; Hostrup, Morten

Context Given the promising effects of prolonged treatment with beta2-agonist on insulin sensitivity in animals and nondiabetic individuals, the beta2-adrenergic receptor has been proposed as a target to counter peripheral insulin resistance. On the other hand, rodent studies also reveal that beta2-agonists acutely impair insulin action, posing a potential caveat for their use in treating insulin resistance. Objective To assess the impact of beta2-agonist on muscle insulin action and glucose metabolism and identify the underlying mechanism(s) in 10 insulin-resistant subjects. Methods and participants In a crossover design, we assessed the effect of beta2-agonist on insulin-stimulated muscle glucose uptake during a 3-hour hyperinsulinemic isoglycemic clamp with and without intralipid infusion in 10 insulin-resistant, overweight subjects. Two hours into the clamp, we infused beta2-agonist. We collected muscle biopsies before, 2 hours into, and by the end of the clamp and analyzed them using metabolomic and lipidomic techniques. Results We establish that beta2-agonist, independently from and additively to intralipid, impairs insulin-stimulated muscle glucose uptake via different mechanisms. In combination, beta2-agonist and intralipid nearly eliminates insulin-dependent muscle glucose uptake. Although both beta2-agonist and intralipid elevated muscle glucose-6-phosphate, only intralipid caused accumulation of downstream muscle glycolytic intermediates, whereas beta2-agonist attenuated incorporation of glucose into glycogen. Conclusion Our findings suggest that beta2-agonist inhibits glycogenesis, whereas intralipid inhibits glycolysis in skeletal muscle of insulin-resistant individuals. These results should be addressed in future treatment of insulin resistance with beta2-agonist.

INSULIN sensitivity; INSULIN resistance; INSULIN therapy; GLUCOSE metabolism; SKELETAL muscle; INSULIN; PANCREATIC beta cells; BETA adrenoceptors

Journal of Clinical Endocrinology & Metabolism, 2025, Vol 110, Issue 1, p275

0021-972X

Academic Journal

10.1210/clinem/dgae381