Better molecular ‘brake’ could yield new diabetes drugs

Light Switches
A newly discovered "brake" for the mTor pathway could not only lead to new diabetes treatments, but may also have applications in cancer and a congenital muscle disease.

Inhibiting the mTor pathway to treat diabetes is not new—the drug metformin does just this to reduce blood sugar levels. But scientists at the Leibniz-Forschungsinstitut für Molekulare Pharmakologie have discovered a new, potentially better “off-switch.”

The mTor kinase is an enzyme that joins with other proteins to make two protein complexes. One complex plays a role in cell growth, while the other helps to activate insulin receptors and insulin-like growth factor receptors.

Previous research has shown the mTor kinase to be less active in the cells’ lysosome when starved for extended periods. So, the Berlin-based researchers looked for a natural mTor “brake” in this part of the cell.

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“We found a local lipid kinase on the lysosome,” said Volker Haucke, director of the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), in a statement. “This kinase deactivates mTor.” When the cell doesn’t receive insulin signals from, the kinase, PI3KC2ß, adds a phosphate group to a lipid, which “switches off” mTor. The findings are published in Science.

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“If we succeed in activating the discovered lipid kinase, we will have another, possibly better shut-off switch for mTor. This will enable us to devise therapies, which influence sugar and fat metabolism,” said Alexander Wallroth, a postdoctoral researcher in FMP’s Department of Molecular Pharmacology and Cell Biology.

What makes PI3KC2ß an attractive target is the body doesn’t need it for survival, the team said in the statement. While a PI3KC2ß activator has obvious uses in “switching off” mTor and treating diabetes, a compound that inhibits the kinase could be useful in treating a rare muscle disease, the team says. Canadian researchers have found that blocking PI3KC2ß can “partially cure” myotubular myopathy—a congenital disease that causes muscle weakness and poor muscle tone—in animal models.

While the team is focusing on treating diabetes, Wallroth said their discovery might have implications for cancer, too.

“It is generally known that patients treated with Metformin are less prone to developing cancer even though obesity actually increases the cancer risk,” he said. Last fall, UC San Diego researchers pinpointed a cellular mechanism involving the cells that line body cavities and organs that could explain why the drug may lower cancer risk.