WS Insulin-associated and insulin-independent impacts of β adrenergic agonists and pro-inflammatory cytokines on glucose metabolism in primary rat soleus muscle

Abstract Text: Recent studies show that catecholamines and pro-inflammatory cytokines may help regulate skeletal muscle growth and metabolism even at sub-stress levels. The objective of this study was to determine the acute effects of β1 and β2-specific adrenergic agonists as well as TNFα and IL-6 on muscle glucose uptake and oxidation under basal and insulin-stimulated conditions. Primary soleus muscle was collected from adult Sprague-Dawley rats, separated tendon-to-tendon into 25-45 mg strips, and incubated in KHB spiked with or without insulin, and/or ractopamine HCl (β1 agonist), zilpaterol HCl (β2 agonist), TNFα, and IL-6. Glucose uptake was determined from cellular content of [³H]-2-deoxyglucose after 20 min. Glucose oxidation of [¹⁴C-U] glucose was determined after 2 h. Phospho-Akt/total Akt (p-Akt/Akt) was determined from protein isolated after 1 h. Compared to muscle incubated in un-spiked (basal) media, incubation with insulin increased (P < 0.05) glucose uptake by ~47%, glucose oxidation by ~32%, and p-Akt/Akt by ~238%. Muscle incubated with β2 agonist exhibited ~20% less (P < 0.05) glucose uptake but ~32% greater (P < 0.05) glucose oxidation than basal. Moreover, incubation with β2 agonist+insulin increased (P < 0.05) glucose oxidation and p-Akt/Akt over insulin alone. Muscle incubated with β1 agonist did not differ from basal for any output. Likewise, β1 agonist+insulin incubations did not differ from insulin alone. Glucose oxidation was ~23% and ~33% greater (P< 0.05), respectively, in muscle incubated with TNFα and IL-6 compared to basal, yet glucose uptake and p-Akt/Akt did not differ. Glucose uptake, glucose oxidation, and p-Akt/Akt were similar among muscle incubated with TNFα+insulin, IL-6+insulin, and insulin alone. In addition, glucose oxidation in muscle incubated with TNFα+insulin and IL-6+insulin did not differ from TNFα alone or IL-6 alone. These results show that acute β2 stimulation had opposite effects on glucose uptake and glucose oxidation in muscle, and that acute β1 stimulation had no evident impact on muscle metabolism. Moreover, β2 stimulation was synergistic with insulin, as glucose oxidation and Akt phosphorylation were greater with the two products together than with either individually. Lastly, acute stimulation with TNFα or IL-6 increased glucose oxidation rates independently of insulin or Akt phosphorylation. Together, our findings demonstrate that adrenergic and inflammatory mediators can have insulin-associated or insulin-independent effects on glucose metabolism and that these effects may differ for glucose uptake and oxidation.

Keywords: β-agonist, glucose metabolism, stress hormones