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Sep 6, 2007

Mechanism for Insulin’s Regulation of Gluconeogenesis Revealed

  • Insulin affects the ability of the TORC2 protein to bind to CREB, which in turn produces the blood sugar in liver, report researchers from the Salk Institute for Biological Studies.

    Insulin normally turns down gluconeogenesis, ensuring that blood sugar levels don’t rise too high. “However in people with insulin resistance, blood sugar levels are elevated because gluconeogenesis continues when it shouldn’t,” explains Marc Montminy, Ph.D., a professor in the Clayton Foundation Laboratories for Peptide Biology, who led the study.

    Previously, Dr. Montminy discovered that a protein called CREB responds to various physiological signals. During periods of fasting when blood sugar stocks run low, for example, CREB turns on gluconeogenesis in the liver. Dr. Montminy’s team also recently found that TORC2 binds to CREB and enables the switch to work.

    To learn how feeding and insulin affect TORC2, the Salk Institute team inserted mice with the luciferase gene, which produces the glow of firefly tails. They rigged the gene in such a way that it could only be turned on in the liver by the CREB/TORC2 switch. The researchers were thus able to measure the effect of various changes on the amount of light emitted from the liver.

    The experiments revealed that the rise in insulin during feeding turned off the CREB/TORC2 switch. Insulin first activated a liver enzyme called SIK2, which in turn inactivated TORC2 by chemically tagging it with a phosphate group. The extra phosphate group caused TORC2 to leave the cell nucleus where it would usually turn on genes. Once the protein left the nucleus, it was destroyed by the proteasome, report the researchers.

    The study was published in the September 5 advanced online edition of Nature.


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