Selective Inhibition of FOXO1 Activator/Repressor Balance Modulates Hepatic Glucose Handling

Area of Science:

• Molecular biology
• Metabolic diseases
• Endocrinology

Background:

• Insulin resistance is a central feature of diabetes, presenting a significant clinical challenge.
• Insulin regulates glucose metabolism by suppressing hepatic glucose production and promoting lipogenesis via FOXO1.
• The dual action of insulin on glucose production and lipogenesis creates a therapeutic dilemma.

Purpose of the Study:

• To identify the unknown FOXO1 corepressor of glucokinase.
• To investigate therapeutic strategies for selective inhibition of hepatic glucose production.
• To develop novel insulin sensitizers with reduced lipogenic side effects.

Main Methods:

• Identified SIN3A as the insulin-sensitive FOXO1 corepressor of glucokinase through molecular screening.
• Utilized genetic ablation of SIN3A to assess its role in nutrient regulation and glucose metabolism.
• Conducted a small-molecule screen to discover selective inhibitors of FOXO1-dependent glucose production.

Main Results:

• SIN3A was identified as the FOXO1 corepressor for glucokinase, mediating insulin's effect on this enzyme.
• Genetic deletion of SIN3A disrupted nutrient regulation of glucokinase but spared other FOXO1 targets.
• SIN3A ablation lowered blood glucose levels without inducing hepatic steatosis (fatty liver).
• Selective inhibitors of FOXO1-dependent glucose production were discovered, lacking lipogenic activity in hepatocytes.

Conclusions:

• SIN3A is a critical mediator of insulin's dual action on hepatic glucose production and glucokinase regulation.
• Targeting SIN3A or related pathways offers a potential strategy for managing diabetes by lowering glucose without adverse lipogenic effects.
• Development of selective modulators for unliganded transcription factors could overcome limitations of current insulin sensitizers.