Alteration in S6K1-IRS1 signaling is uncoupled from whole body insulin sensitivity in animals treated with leucine or ketoisocaproic acid

• Published in: Physiology (Bethesda, Md.) Vol. 38; no. S1
• Main Author: Mann, Gagandeep
• Format: Journal Article
• Language: English
• Published: 01.05.2023
• ISSN: 1548-9213; 1548-9221
• DOI: 10.1152/physiol.2023.38.S1.5735101

Abstract only Introduction: Plasma levels of branched-chain amino acids and their metabolites, branched-chain ketoacids are increased in insulin resistance, a condition that can lead to type 2 diabetes mellitus. Questions remain as to whether elevated levels of these metabolites cause, or are a consequence of insulin resistance. We previously showed that leucine and its metabolite ketoisocaproic acid (KIC) suppressed insulin-stimulated glucose uptake in L6 myotubess. Leucine and KICwith an increase in e S6K1 activation and phosphorylation of an inhibitory serine IRS-1 residue. The objective of this study was to analyze the effect of KIC gavage on skeletal muscle and liver insulin signaling and how this impacts whole-body insulin sensitivity. We hypothesized that KIC gavage will reduce whole-body insulin sensitivity and in response to the activation of the S6K1-IRS-1 pathway as shown in vitro. alter skeletal muscle and liver insulin signaling. Methods: Five-week-old male Sprague-Ddawley rats were starved for 24 hours. Rats were then gavaged with 0.75ml/100g of water, leucine (22.3g/L) or KIC (30g/L) twice, ten minutes apart, and then either sacrificed at different timepoints post-gavage (0.5-3h). A different set of rats were starved for 6 hours and then or injected with insulin an hour after the first gavageleucine or KIC gavage. Basal blood glucose levels and post insulin injection (10-120min after injection) blood glucose levels were measured., where blood glucose was measured pre (basal) and post (10-120min) insulin injection. Results: Leucine or KIC gavage had no effect on whole-body insulin sensitivity. This was consistent with no effect on ph-Akt (S473) phosphorylation. However, IRS-1 (S612, p<0.0001), S6K1 (Thr389, p<0.001) and S6 (S235/6, p<0.0001) phosphorylation were increased 30 minutes after leucine gavage in skeletal muscle and liver, but this was alleviated by the 60-minute mark. KIC gavage had no effect on the activation of these proteins. Conclusion: Despite increased S6K1 threonine phosphorylation and IRS-1 serine phosphorylation in skeletal muscle and liver in response to leucine gavage, there was no effect on whole-body insulin sensitivity. Unlike in studies with myotubes, KIC did not activate S6K1-IRS-1 signaling. Thus, although insulin resistant states exhibit increased plasma leucine and KIC levels, their supplementation does not reduce insulin sensitivity, suggesting that their increased levels are a consequence of insulin resistance and not causative. s. This suggests other mechanisms and/or tissues may play a role in regulating whole-body insulin sensitivity during leucine/KIC gavage. NSerc, York University This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.