Journal Article

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

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

2024

Overview

Abstract 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.

• Publisher: Oxford University Press
• Subject: Adrenergic beta-2 Receptor Agonists - pharmacology / Adrenergic receptors / Adult / Agonists / Biopsy / Blood Glucose - drug effects / Blood Glucose - metabolism / Cross-Over Studies / Emulsions / Female / Glucose / Glucose - metabolism / Glucose Clamp Technique / Glycogen / Glycolysis / Humans / Insulin - metabolism / Insulin Resistance / Intermediates / Male / Metabolomics / Middle Aged / Muscle, Skeletal - drug effects / Muscle, Skeletal - metabolism / Overweight - drug therapy / Overweight - metabolism / Phospholipids - metabolism / Skeletal muscle / Soybean Oil - administration & dosage / Soybean Oil - pharmacology