The 14‐3‐3 protein YWHAB inhibits glucagon‐induced hepatic gluconeogenesis through interacting with the glucagon receptor and FOXO1

Glucagon antagonism has been reported as a new therapeutic approach to hyperglycaemia. As the 14-3-3 protein YWHAB identified regulator of glucagon receptor (GCGR) by affinity purification and mass spectrometry, we examined role in vivo. Ywhab knockout mice display impaired blood glucose homeostasis only under pyruvate stimulation. Deletion mouse primary hepatocytes (MPHs) increases hepatocyte production magnifying effect glucagon. Mechanistic analysis indicates that forms phosphorylation-dependent complex with GCGR directly interacts forkhead box O1 (FOXO1). Together, these results reveal inhibitory glucagon-mediated hepatic production, which may be potential target for control gluconeogenesis associated metabolic diseases.