Akt inhibitors reduce glucose uptake independently of their effects on Akt

Area of Science:

• Biochemistry
• Cell Biology
• Pharmacology

Background:

• The protein kinase Akt is crucial for cell proliferation, growth, and metabolism, with its hyperactivation linked to human tumors.
• Akt also regulates glucose transport into muscle and fat cells, essential for whole-body glucose homeostasis, primarily via GLUT4 transporter translocation.
• Targeted drug discovery has focused on the Akt pathway, but potential metabolic side effects require investigation.

Purpose of the Study:

• To investigate the metabolic side effects of non-ATP-competitive allosteric Akt inhibitors.
• To determine the mechanism by which these inhibitors affect glucose uptake.
• To explore the potential of these inhibitors in cancer therapy.

Main Methods:

• Utilized 3T3-L1 adipocytes to study Akt signaling and glucose uptake.
• Assessed GLUT4 translocation to the plasma membrane.
• Tested inhibitor effects on glucose transport in human erythrocytes and T-47D breast cancer cells.

Main Results:

• Non-ATP-competitive allosteric Akt inhibitors decreased Akt signaling and glucose uptake in 3T3-L1 adipocytes.
• Inhibitors reduced glucose uptake independently of the Akt pathway and GLUT4 translocation.
• Inhibitors demonstrated efficacy in reducing glucose transport across various cell types, not limited to GLUT4-mediated transport.

Conclusions:

• The inhibitory effects of these Akt inhibitors on glucose uptake are independent of the Akt signaling pathway.
• These compounds can inhibit glucose transport in multiple cell types, suggesting broader applicability.
• Akt inhibitors may possess anti-tumorigenic potential by inhibiting tumor cell glucose transport.