New mechanism of action discovered in a first-line drug for diabetes

Researchers have discovered a mechanism of action for a widely used diabetes drug, which may expand its indications for use, and open new leads into pharmaceutical development.

A research group led by Professor Sanna Lehtonen at the University of Helsinki has demonstrated that a common type 2 diabetes drug metformin directly binds to the lipid phosphatase SHIP2, reducing its activity. The reduction in SHIP2 activity increased glucose uptake in muscle cells and decreased cell death in podocytes, or glomerular epithelial cells.

Metformin lowers blood glucose levels by inhibiting glucose production in the liver, but also improves glucose uptake and use by muscle tissue. The effect of metformin on hepatic glucose production is most likely transmitted through the mitochondrial respiratory chain. However, up to now the mechanism through which the drug increases glucose uptake in muscle tissue has been unknown.

New in­dic­a­tions – new drugs?

Identifying new mechanisms of action can expand metformin’s indications for use outside diabetes in treating, among other disorders, cancer and cardiovascular diseases – research is already underway in these fields – as well as in regulating aging.
“Our new study highlights SHIP2’s significance as a drug target. Prior studies support this notion, but knowing that the most common diabetes drug acts precisely through SHIP2 encourages us to find new SHIP2 inhibitors that are more effective than metformin,” Lehtonen says.

Read the original article on University of Helsinki website

Reference: Polianskyte-Prause et al. Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity.  The FASEB Journal. DOI: 10.1096/fj.201800529RR

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