Glucagon increases hepatic glucose production by activating both glycogenolysis and gluconeogenesis. Its effect on gluconeogenesis is traditionally attributed to increased expression of gluconeogenic enzyme genes. However, whether glucagon’s transcription-independent actions are sufficient to acutely stimulate hepatic glucose output remains uncertain. To investigate this, we examined the acute effects of glucagon on hepatic gluconeogenesis using an in situ perfused mouse liver model. Livers from male, freely fed C57BL/6JRj mice (11–16 weeks) were perfused via the portal vein with oxygenated Krebs–Henseleit bicarbonate buffer. Hepatic glucose output was measured every three minutes. Glucagon (10 nM) added to the perfusate rapidly increased hepatic glucose production, with a 3.6-fold rise observed within minutes. This effect was absent in overnight-fasted mice. When gluconeogenic substrates (6 mM lactate, pyruvate, or both) were added to the perfusate, acute glucose production was stimulated. Co-administration of glucagon (10 nM) further enhanced glucose output by 36–43 % (p ≤ 0.044). Repeated stimulation experiments confirmed the reproducibility and reversibility of the response. These findings demonstrate that glucagon acutely and reversibly enhances hepatic gluconeogenesis, independent of transcriptional regulation and in the absence of hepatic glycogen. Our data redefine glucagon as a rapid metabolic modulator capable of minute-to-minute control of hepatic glucose output in the fasted state. This has important implications for our understanding of glucose homeostasis during fasting, stress, and disease, and challenges conventional textbook views of glucagon’s role as solely a transcriptional regulator of gluconeogenic genes.
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