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 af dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer 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.

OriginalsprogEngelsk
TidsskriftThe Journal of clinical endocrinology and metabolism
ISSN0021-972X
DOI
StatusAccepteret/In press - 2024

Bibliografisk note

© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact [email protected] for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact [email protected]. See the journal About page for additional terms.

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