Beta2-agonist impairs muscle insulin sensitivity in persons with insulin resistance

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

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

CONTEXT: Given the promising effects of prolonged treatment with beta2-agonist on insulin sensitivity in animals and non-diabetic 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 cross-over design, we assessed the effect of beta2-agonist on insulin-stimulated muscle glucose uptake during a 3-h 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, two 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. While 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.

CONCLUSIONS: Our findings suggest that beta2-agonist inhibits glycogenesis while intralipid inhibits glycolysis in skeletal muscle of insulin-resistant individuals. These results should be addressed in future treatment of insulin resistance with beta2-agonist.

Original languageEnglish
Article numberdgae381
JournalThe Journal of Clinical Endocrinology & Metabolism
Volume110
Issue number1
Pages (from-to)275-288
ISSN0021-972X
DOIs
Publication statusPublished - 18. Dec 2024

Keywords

  • Adrenergic beta-2 Receptor Agonists/pharmacology
  • Adult
  • Blood Glucose/metabolism
  • Cross-Over Studies
  • Emulsions
  • Female
  • Glucose Clamp Technique
  • Glucose/metabolism
  • Humans
  • Insulin Resistance
  • Insulin/metabolism
  • Male
  • Middle Aged
  • Muscle, Skeletal/metabolism
  • Overweight/metabolism
  • Phospholipids/metabolism
  • Soybean Oil/pharmacology
  • muscle glucose uptake
  • beta2-adrenergic agonists
  • intralipid
  • glycogenesis
  • glucose-6-phosphate
  • insulin resistance

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