Acute AKT signaling increases glucose phosphorylation and contribution to glycogen in hepatocytes.

Authors

Megan Stefkovich, Won Dong Lee, Talia Coopersmith, Joseph A Baur, Joshua D Rabinowitz, Paul M Titchenell

Published in

iScience. Volume 29. Issue 8. Pages 116956. Aug 21, 2026. Epub Jul 30, 2026.

Abstract

Insulin's regulation of hepatic glucose production and glycogen is critical for postprandial glucose disposal. AKT, a serine-threonine kinase and insulin signaling intermediate, regulates liver glucose metabolism through transcriptional and posttranslational mechanisms. However, current knowledge largely stems from genetic loss-of-function models, precluding observation of AKT's non-transcriptional effects. To measure rapid changes to glucose and glycogen metabolism, isotope tracing using [U-¹³C]-glucose and [U-¹⁴C]-glucose was coupled with the AKT inhibitor MK-2206 in primary rat hepatocytes. MK-2206 treatment decreased AKT phosphorylation and glucose contribution to glucose 6-phosphate and uridine diphosphate glucose within minutes without affecting metabolite pool sizes or protein levels of glucokinase, glucose 6-phosphatase, or phosphoenolpyruvate carboxykinase. MK-2206 also decreased glucose contribution to glycogen, independent of glycogen breakdown or glycogen synthase phosphorylation. These results demonstrate that AKT acutely regulates glucose contribution to glycogen and upstream precursors, suggesting a transcription-independent mechanism that is proximal to glucose 6-phosphate generation for glycogen synthesis.

PMID:
42571371
Bibliographic data and abstract were imported from PubMed on 09 Aug 2026.

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