PKC alpha Isoform Inhibits Insulin Signaling and Aggravates Neuronal Insulin Resistance

Overexpression of PKC alpha has been linked to inhibit insulin signaling disrupting IRS-1 and Akt phosphorylations in skeletal muscle. PKC alpha inhibits IRS-1 and Akt phosphorylations, but not required for insulin-stimulated glucose transport in skeletal muscles. Inhibition of PKC alpha increased whereas in some studies decreased GLUT-4 levels at the plasma membrane in skeletal muscles and adipocytes. Controversial studies have reported opposite expression pattern of PKC alpha expression in insulin-resistant skeletal muscles. These findings indicate that the role of PKC alpha on insulin signaling is controversial and could be tissue specific. Evidently, studies are required to decipher the role of PKC alpha in regulating insulin signaling and preferably in other cellular systems. Utilizing neuronal cells, like Neuro-2a, SHSY-5Y and insulin-resistant diabetic mice brain tissues; we have demonstrated that PKC alpha inhibits insulin signaling, through IRS-Akt pathway in PP2A-dependent mechanism by an AS160-independent route involving 14-3-3 zeta. Inhibition and silencing of PKC alpha improves insulin sensitivity by increasing GLUT-4 translocation to the plasma membrane and glucose uptake. PKC alpha regulates GSK3 isoforms in an opposite manner in insulin-sensitive and in insulin-resistant condition. Higher activity of PKC alpha aggravates insulin-resistant neuronal diabetic condition through GSK3 beta but not GSK3 alpha. Our results mechanistically explored the contribution of PKC alpha in regulating neuronal insulin resistance and diabetes, which opens up new avenues in dealing with metabolic disorders and neurodegenerative disorders.

Automated summary

Overexpression of PKC alpha inhibits insulin signaling by disrupting IRS-1 and Akt phosphorylations in skeletal muscle. PKC alpha is not necessary for insulin-stimulated glucose transport in skeletal muscles. Controversial studies have reported opposite expression pattern of PKC alpha in insulin-resistant skeletal muscles. Our study demonstrates that PKC alpha inhibits insulin signaling in neuronal cells through IRS-Akt pathway and PP2A-dependent mechanism, and silencing of PKC alpha improves insulin sensitivity. PKC alpha regulates GSK3 isoforms differently in insulin-sensitive and insulin-resistant conditions. These findings provide insights into the role of PKC alpha in regulating insulin resistance and diabetes in neuronal cells.