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

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.