Insulin modulates gluconeogenesis by inhibition of the coactivator TORC2

Area of Science:

• Metabolism
• Molecular Biology
• Endocrinology

Background:

• Insulin signaling inhibits hepatic glucose production via AKT and FOXO1 phosphorylation.
• FOXO1 and TORC2 (CRTC2) cooperate to promote gluconeogenic gene expression under fasting conditions.
• Glucagon signaling leads to TORC2 nuclear translocation and CREB-mediated stimulation of gluconeogenesis.

Purpose of the Study:

• To elucidate the mechanism by which insulin inhibits gluconeogenic gene expression during re-feeding.
• To investigate the role of SIK2 and COP1 in insulin's regulation of TORC2.

Main Methods:

• Studies were conducted in mice.
• Investigated protein phosphorylation, degradation, and localization using molecular biology techniques.
• Utilized ubiquitination assays and proteasome degradation studies.

Main Results:

• Insulin promotes the phosphorylation and ubiquitin-dependent degradation of TORC2 during re-feeding.
• Insulin induces SIK2, which phosphorylates and promotes cytoplasmic translocation of TORC2.
• COP1 mediates TORC2 ubiquitination and degradation by the 26S proteasome.

Conclusions:

• Insulin suppresses gluconeogenesis by targeting TORC2 for degradation via the SIK2-COP1 pathway.
• Dysregulation of this pathway, characterized by increased TORC2 levels in diabetes, contributes to impaired glucose homeostasis.
• This mechanism highlights a critical role for TORC2 regulation in maintaining blood glucose balance.