A new research solves the mystery of how the drug metformin lowers blood sugar for people with type 2 diabetes despite the fact it does not work directly on glucose. Published in the journal Nature Medicine, the study shows that metformin, which is the best medicine world over for type 2 diabetes with no risk of the blood sugar falling too low, reduces fat in the liver, which allows insulin to work better.
The finding may help scientists develop more effective therapies for diabetes. “This work, the result of a great international collaboration, has the potential to help develop more effective treatments for type 2 diabetes,” says Prof. Bruce Kemp from the University of Melbourne who has worked closely on the project. Senior author on the study Greg Steinberg, an associate professor at McMaster University in Canada, says the key is that metformin doesn’t work to lower blood glucose by directly working on the glucose.
“It works on reducing harmful fat molecules in the liver, which then allows insulin to work better and lower blood sugar levels.” Sandra Galic from St Vincent’s Institute and co-lead author on the study, was keen to work out the mechanism of action of metformin.
“We knew that metformin activates the metabolic sensor AMP-activated protein kinase (AMPK), but didn’t know how that action resulted in the improvements seen in patients taking the drug. “When we introduced mutations into two proteins in the AMPK pathway in mice so that they could no longer be switched off by AMPK, we found that that the mice developed fatty liver and pre-diabetes, but did not become obese as expected.”
She says when they put the mice on a high-fat diet, the mice did become obese, “but we were surprised to find that metformin failed to lower their blood sugar levels,” she notes. Kemp says that many people taking metformin have a fatty liver, which is frequently caused by obesity.
“Fat is likely a key trigger for pre-diabetes in humans. Our study indicates that metformin doesn’t directly reduce sugar metabolism, as previously suspected, but instead reduces fat in the liver, which in turn allows insulin to work effectively,” adds Kemp.