Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity

What is it about?

Metformin is the most commonly used drug to treat type 2 diabetes. It has been shown to inhibit mitochondrial glycerolphosphate dehydrogenase in liver to reduce generation of glucose. Metformin has also been shown to enhance glucose uptake in peripheral tissues, but its direct molecular target and the exact molecular mechanism have not been described. Here, we show that metformin directly binds to and inhibits the activity of lipid phosphatase SHIP2 in cultured cells and in skeletal muscle and kidney of diabetic mice. We also found that SHIP2 activity is elevated in kidney glomeruli of patients with type 2 diabetes receiving non-metformin medication, but not in patients receiving metformin, compared to people without diabetes. Also, loss of glomerular epithelial cells in kidneys of metformin-treated type 2 diabetes patients was reduced compared to patients receiving non-metformin medication. Collectively, our work shows that inhibition of SHIP2 by metformin enhances glucose uptake into cells, providing a novel molecular mechanism via which metformin facilitates glucose uptake in peripheral tissues. Our data also proposes that metformin protects kidneys from injury by inhibiting SHIP2 activity.

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