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Hormonal regulation of hepatic P-enolpyruvate carboxykinase (GTP) during development

R W Hanson, J Ballard

    Federation Proceedings
    |February 1, 1975
    PubMed

    Insights

    Hepatic gluconeogenesis begins at birth in rats, driven by increased cyclic adenosine monophosphate (cAMP) stimulating key enzyme synthesis. A drop in insulin levels after birth likely removes inhibition, allowing glucagon to promote this crucial metabolic process.

    Area of Science:

    • Biochemistry
    • Developmental Biology
    • Endocrinology

    Background:

    • Hepatic gluconeogenesis is a critical metabolic pathway for maintaining blood glucose levels.
    • The enzyme phosphoenolpyruvate carboxykinase (PEPCK) is the rate-limiting enzyme in gluconeogenesis and its synthesis is tightly regulated.
    • PEPCK activity is absent in fetal rat liver and initiates at birth.

    Purpose of the Study:

    • To investigate the regulatory mechanisms controlling the onset of hepatic gluconeogenesis at birth in rats.
    • To elucidate the roles of cyclic adenosine monophosphate (cAMP), insulin, and glucagon in the induction of PEPCK synthesis.
    • To understand the hormonal milieu changes at birth and their impact on gluconeogenic enzyme expression.

    Main Methods:

    • Studies in fetal and newborn rats, including in utero experiments.
    • Measurement of enzyme synthesis and degradation rates.
    • Hormonal manipulation using glucagon, insulin, and cAMP analogs (dibutyryl cAMP).
    • Analysis of hormonal changes (insulin, glucagon) in the perinatal period.

    Main Results:

    • PEPCK synthesis is initiated at birth, coinciding with its first appearance in the cytosol.
    • Increased hepatic cAMP concentration appears to be the primary trigger for PEPCK synthesis.
    • Insulin inhibits PEPCK synthesis in both fetal and adult liver models, while glucagon stimulates it.
    • Glucocorticoids do not affect PEPCK synthesis in fetal liver.
    • The insulin-to-glucagon molar ratio dramatically decreases at birth due to rising glucagon and falling insulin levels.

    Conclusions:

    • The onset of hepatic gluconeogenesis at birth is primarily regulated by the induction of PEPCK synthesis.
    • The hormonal shift at birth, characterized by a decreased insulin-to-glucagon ratio, is crucial for initiating gluconeogenesis.
    • Reduced insulin levels likely relieve the inhibition of PEPCK synthesis, allowing cAMP and glucagon to promote enzyme production, thereby enabling the liver to produce glucose postnatally.

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