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The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression

J Nakae1, T Kitamura, D L Silver

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

The Journal of Clinical Investigation
|November 7, 2001
PubMed

Insights

In type 2 diabetes, insulin fails to suppress glucose production due to reduced Forkhead box protein 1 (Foxo1). Restoring Foxo1 enables insulin to inhibit key glucose-producing enzymes in kidney and liver cells.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Metabolic Diseases

Background:

  • Type 2 diabetes is marked by impaired insulin suppression of hepatic and renal glucose production.
  • Insulin normally inhibits gluconeogenesis and glycogenolysis via transcriptional suppression of key enzymes like phosphoenolpyruvate carboxykinase (Pepck) and glucose-6-phosphatase (G6p).
  • The transcription factors mediating insulin's direct effects on glucose production are not fully understood.

Purpose of the Study:

  • To investigate the role of transcription factors in insulin's regulation of glucose production, particularly in the context of impaired insulin signaling.
  • To determine if the forkhead transcription factor Foxo1 mediates insulin's ability to suppress gluconeogenic enzymes.

Main Methods:

  • Utilized kidney epithelial cells and primary mouse hepatocytes.
  • Investigated the effects of dexamethasone (dex) and cAMP induction on Pepck and G6p expression.
  • Examined insulin response in the presence and absence of Foxo1 manipulation (adenoviral transduction, dominant-negative mutants).

Main Results:

  • Kidney cells resistant to insulin's suppression of Pepck and G6p showed reduced Foxo1 expression.
  • Restoring Foxo1 expression in kidney cells restored insulin's ability to inhibit dex/cAMP-induced G6p expression.
  • Dominant-negative Foxo1 mutants partially inhibited dex/cAMP-induced G6p and Pepck expression in hepatocytes and kidney cells.

Conclusions:

  • Foxo1 is implicated in mediating insulin's regulation of glucose production.
  • Foxo1 appears to be crucial for insulin to reduce the glucocorticoid/cAMP-driven expression of G6p.
  • These findings suggest Foxo1 is a key player in the molecular mechanisms underlying insulin resistance in type 2 diabetes.

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