Cecilia Lee

Yale researchers investigating the mechanism of the diabetes drug metformin have now elucidated a model for the drug and how it functions to treat Type 2 diabetes. 

The research study was published in the Proceedings of the National Academy of Sciences through the lab of Gerald Shulman, professor of endocrinology and cellular and molecular physiology at the Yale School of Medicine. The study was headed by lead author Traci LaMoia GRD ’24, a current doctoral student in Shulman’s lab. Metformin has been used for almost over half a century to treat Type 2 diabetes, but only recently have studies been able to decipher its true pathway of action and disprove previously held theories. 

“My lab has been exploring the mechanism by which metformin lowers blood glucose in patients with type 2 diabetes for over two decades,” Shulman said. “We started with physiological studies in humans and demonstrated that the major effect of metformin is to decrease hepatic gluconeogenesis.” 

Type 2 diabetes impairs the way that the body regulates and uses glucose or simple sugars as fuel. The two primary causes are insufficient production of insulin by the pancreas and poor response to insulin by cells. Insulin is a hormone that promotes the intake of simple sugars from the bloodstream to the cells of the body. Due to these deficiencies, blood sugar levels chronically continue to rise until damage to organs of the circulatory, nervous and immune systems can occur. 

Furthermore, there are many other processes that can increase blood sugar levels, such as gluconeogenesis, where the liver produces glucose from nonglucose starting materials such as amino acids or lactate. Previous studies have shown that metformin inhibits this process of gluconeogenesis to decrease blood sugar levels through inhibition of metabolic complexes in the cells’ mitochondria. 

Mitochondria all have electron transport chains that are responsible for generating energy, and there are four involved protein complexes that release energy through a series of reactions. Before this study, it was commonly believed that metformin inhibited complex I, the first and largest of these energy-producing complexes, to inhibit the process of gluconeogenesis in the liver. 

After making the move to examine the molecular basis by which metformin inhibits gluconeogenesis, the researchers found that metformin inhibits the mitochondrial enzyme glycerol 3-phosphate dehydrogenase, or GPD2. Their most recent study demonstrates that metformin and other chemically related compounds inhibit glycerol conversion to glucose and indirectly inhibit GPD2 by inhibiting the fourth complex of mitochondrial electron transfer chains, complex IV. This showed that complex I inhibition is not likely to be a clinically significant mechanism for metformin. 

“Glycerol-3-phosphate dehydrogenase, or GPD2, catalyzes one step in the process of converting glycerol to glucose by the liver (glycerol gluconeogenesis), and here we show that in fact, metformin and the other guanides/biguanides significantly reduce gluconeogenesis from glycerol in vivo,” LaMoia wrote to the News. “This is clinically very important because gluconeogenesis from glycerol is dysregulated in patients with type 2 diabetes, which leads to increased hepatic glucose production. So, we think this explains why metformin has a more pronounced glucose-lowering effect in patients with type 2 diabetes than those without.” 

In other words, the researchers found that metformin inhibits GPD2 by inhibiting complex IV which in turn prevents the catalysis of glycerol to glucose conversion and prevents high levels of gluconeogenesis in the liver. To experimentally test this, the researchers developed a liver slice system, opposed to the standard model of using hepatocytes, or liver cells, for assessing rates of hepatic glucose production. The liver slice system had the advantage of keeping the liver tissue intact, which allowed other structures and cells such as blood vessels to remain present. 

The researchers were then able to measure how much glucose is produced by each liver slice and released into the experimental environment after inserting the appropriate inhibitors for complex IV and other different conditions. LaMoia added that another benefit of the system is that drugs that would be toxic to living rodents, such as cyanide, are able to be used on the liver slices. 

“Another finding of the paper is that metformin averts glycerol from becoming blood sugar,” Brandon Hubbard GRD ’25, a current doctoral student in Shulman’s lab, wrote. “Glycerol is released during the breakdown of fat, and we show that under some conditions 40% of blood sugar comes from glycerol. Since such a large fraction of blood sugar can come from glycerol, this makes glycerol a particularly important substrate to target in diabetes, where blood sugar is too high.”

LaMoia added that there are some key reasons why it is necessary to discern the true mechanism of metformin, such as alleviating side effects in prescribed patients and application of the medication on other indicated illnesses. Some patients experience gastrointestinal side effects that can contraindicate the use of metformin, but understanding its mechanism could help alleviate the side effects since it is one of the most effective treatments for Type 2 diabetes. 

Furthermore, studies have shown that metformin could be beneficial for other illnesses in addition to Type 2 diabetes, such as cardiovascular disease, aging and certain cancers. Therefore, a deeper understanding of the mechanism of metformin can open venues for metformin to be used as a treatment in these indications as well. 

“Metformin is currently one of the most widely prescribed drugs in the world, and it is now not only being used to treat type 2 diabetes but also for the treatment of certain cancers and aging,” Shulman added. “My hope is that a better understanding of the mechanism of action of metformin will lead to new treatments for type 2 diabetes, cancer and promote healthy aging.” 

According to the Centers for Disease Control, 37 million Americans have diabetes, with approximately 90- 95 percent of them having Type 2 diabetes.