Novel mechanism identified for widely used diabetes drug

By Amanda Chase, PhD, Stanford Cardiovascular Institute

January 30, 2019

Metformin is the fourth most prescribed drug worldwide, yet its mechanism of action is not fully understood. Based on their research, Stanford investigators have published a novel unifying framework for how metformin works.

Metformin was introduced over 60 years ago and remains standard of care in the initial treatment of type 2 diabetes. The American Diabetes Association and the American College of Physicians recommend prescribing metformin for all newly diagnosed patients with type 2 diabetes before trying any other drug based on its effectiveness, low cost, minimal side effects, and long-term safety profile. Beyond its well-established beneficial effects on glucose metabolism in diabetes, there is evidence that metformin may have a protective effect against particular cancers, cardiovascular disease, and certain degenerative processes associated with aging. Despite its long history of use and extensive research, there has been no unified understanding of its mechanism of action until now.

Recent work published in G3: Genes, Genomes, Genetics by Dr. Xiyan Li, Dr. Xin Wang, and senior author Dr. Michael Snyder, Professor and Chair of the Department of Genetics at Stanford University, supports a unifying framework for metformin effects based on direct interaction with heme-containing and other porphyrin-containing groups. The researchers first used yeast to begin to elucidate the mechanism of metformin. Then in an elegant series of experiments, they extended their findings by studying the effects of metformin in primary human red blood cells, liver cells, a proliferative myelogenous cell line, and a simple cell-free system.

"The awesome power of yeast genetics helped illuminate the mechanism of action of a commonly used drug, whose mechanism of action was unknown," said Dr. Brenda Andrews, Editor-in-Chief of G3 and Professor at University of Toronto.

The researchers found that metformin reduced heme levels in proliferating cells that were capable of heme synthesis and helped preserve heme in cells that were unable to produce heme. Furthermore, they found that metformin reduced loss of ferrous heme in red blood cells due to spontaneous oxidation. The authors speculated that given the high metformin dose required for clinical effect and high abundance of hemoproteins, metformin effects might be mediated through direction interaction with heme. In a cell-free system, they demonstrated that metformin suppresses heme oxidation and enzyme activity in three protein scaffolds: cytochrome c, myoglobin and hemoglobin at concentrations suggestive of a direct effect. Finally they showed that metformin also inhibited NADPH cytochrome c reductase and decreased cytochrome c reduction at levels suggesting a direct effect on heme reduction.

This study is the first to describe a unified mechanistic framework for metformin based on direct effects on the redox equilibrium of heme and heme-like molecules. This framework suggests new avenues for investigation and may help guide clinical applications in the treatment of diabetes and other diseases.

This work was funded by NIH and CIRM grants.

Michael Snyder, PhD