An international research team, including scientists from Vanderbilt University, has discovered how the diabetes drug metformin blocks glucose production by the liver. The discovery, reported August 27 in the journal Nature Medicine, could lead to development of new ways to treat type 2 diabetes.

“The most common drug to manage type 2 diabetes is metformin,” said David Wasserman, PhD, Annie Mary Lyle Professor of Molecular Physiology and Biophysics at Vanderbilt University School of Medicine, who contributed to the study.

“Even though it is under wide usage and the most effective therapy in most patients, the mechanism of metformin action had been unclear,” Wasserman said. “These studies define the site-specific mechanism of action of metformin on blood glucose control.”

Type 2 diabetes occurs when the body loses its ability to respond to insulin, the pancreatic hormone that normally moves glucose from the bloodstream into the tissues, where it is used as fuel.

In response, insulin production increases but ultimately it cannot keep up and blood glucose levels rise.

Metformin, originally derived from the plant Galega officinalis (also known as goat’s rue or French lilac), has been used for more than 50 years to lower blood glucose levels in patients with type 2 diabetes. But the precise mechanism of action for the drug remains unclear.

Fructose 1,6-bisphosphatase (FBP1) is a rate-controlling enzyme in the production of glucose by the liver.

In a series of elegant experiments, the researchers demonstrated that the enzyme also functions as a major contributor to the therapeutic action of metformin.

In particular, they found that metformin induces mild energy stress in the liver, leading to an increase of adenosine monophosphate (AMP).

This chemical compound, in turn, inhibits FBP1 and turns down glucose production by the liver.

Wasserman, director of the National Institutes of Health-funded Mouse Metabolic Phenotyping Center (MMPC) at Vanderbilt University Medical Center, is a pioneer in the development and optimization of miniaturized experimental techniques for conducting metabolic studies in a mouse model.

Using a variation of techniques developed here, the Vanderbilt researchers showed that in mice with a mutated and abnormally functioning FBP1 enzyme, the glucose-lowering effect of metformin was significantly reduced.

These findings validate FBP1’s role in lowering blood glucose, and suggest that it may be possible to mimic the energy-stressing effect of metformin on the liver through the use of natural substances that avoid the drug’s side effects, notably diarrhea and abdominal discomfort.

“This might indeed be the reason for the apparent glucose-lowering effect of many biologically active metabolites identified in traditional Chinese medicine and edible natural products,” Kei Sakamoto, PhD, the paper’s corresponding author, said in a news release.