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Impaired regulation of hepatic glucose production in mice lacking the forkhead transcription factor Foxo1 in liver

Michihiro Matsumoto1, Alessandro Pocai, Luciano Rossetti

  • 1Naomi Berrie Diabetes Center, Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.

Cell Metabolism
|September 5, 2007
PubMed

Insights

Forkhead protein Foxo1 inactivation in mouse liver significantly reduces glucose levels by impairing key production pathways. This finding offers a unifying mechanism for hepatic glucose regulation by insulin and cAMP.

Area of Science:

  • Metabolism
  • Endocrinology
  • Molecular Biology

Background:

  • Type 2 diabetes is characterized by excessive hepatic glucose production, a process regulated by various factors in cultured cells.
  • In vivo identification of key mediators of hepatic glucose production has been challenging.

Purpose of the Study:

  • To investigate the role of forkhead protein Foxo1 in regulating hepatic glucose production in vivo.
  • To elucidate the mechanism by which Foxo1 influences gluconeogenesis and glycogenolysis.

Main Methods:

  • Gene ablation of Foxo1 in mouse liver.
  • Gene expression analysis.
  • Glucose clamp studies.
  • Analysis of insulin receptor knockout mice.

Main Results:

  • Foxo1 inactivation in mouse liver reduced glucose levels at birth and after fasting.
  • Foxo1 ablation impaired fasting- and cAMP-induced glycogenolysis and gluconeogenesis.
  • Foxo1 deletion prevented neonatal diabetes and hepatosteatosis in insulin receptor knockout mice.

Conclusions:

  • Foxo1 is a critical regulator of hepatic glucose production in vivo.
  • Foxo1 mediates the effects of cAMP and insulin on glucose metabolism.
  • Targeting Foxo1 may offer a therapeutic strategy for type 2 diabetes.

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