Credit: Jeffrey Coolidge/The Image Bank

Metformin is commonly used in the treatment of patients with type 2 diabetes mellitus (T2DM). Metformin works by inhibiting hepatic gluconeogenesis; however, its precise mechanism of action is widely debated. New research by Gerald Shulman and colleagues provides insight into the mechanism that underlies the glucose-lowering effect of metformin.

Previous work from Shulman and his co-workers demonstrated that metformin reduces hepatic gluconeogenesis by inhibiting mitochondrial glycerol-3-phosphate dehydrogenase (GPD2), which increases the cellular redox state and results in the inhibition of the conversion of some substrates (such as lactate and glycerol) to glucose in vitro. “This current study builds on these previous studies and uses a novel 13C-labelling strategy to demonstrate that this redox-dependent substrate-specific effect is central to metformin’s mechanism of action to decrease rates of hepatic glucose production in awake rodent models of T2DM,” explains Shulman.

this redox-dependent substrate-specific effect is central to metformin’s mechanism of action

The researchers infused awake unrestrained rats that either did or did not have T2DM with 13C-labelled lactate or alanine and used 13C NMR spectroscopy to trace these molecules as they moved through the gluconeogenic pathway and were scrambled to the 1, 2, 5 or 6 carbon positions on glucose. The rats were also treated with metformin that achieved clinically relevant plasma concentrations. “We found that metformin impedes the hepatic conversion of redox-modulating substrates (lactate and glycerol), but not redox-neutral substrates (alanine and pyruvate) into glucose,” says Shulman. “These results would not be predicted to occur with any other proposed mechanism for the glucose-lowering effects of metformin.”

The investigators are now trying to determine how biguanides (the group of drugs that metformin belongs to) directly or indirectly regulate the activity of GPD2. They are also using similar tracer analyses to see if these findings translate to metformin-treated patients with T2DM. “Our findings also suggest that modulating the liver cytosolic redox state to influence flux through gluconeogenesis might be an effective strategy for developing potent novel therapies to treat T2DM,” concludes Shulman.