Since its introduction in the United States in the mid-1990s, metformin has become the standard first-line drug for type 2 diabetes. There are many reasons why clinical guidelines recommend metformin as the first-choice drug for type 2 diabetes. First and foremost, metformin is highly effective at reducing blood glucose levels. But unlike many oral diabetes drugs that were developed before metformin, metformin doesn’t carry a substantial risk for hypoglycemia (low blood glucose) — since it appears to work largely by stopping the liver from releasing glucose in to the blood, rather than by stimulating the pancreas to produce more insulin. Metformin is also linked to modest improvements in body weight, such as inducing weight loss or preventing weight regain in people who have lost weight. Taking metformin may help prevent dementia and progression of chronic kidney disease, and the drug may be a superior alternative to insulin for treating gestational diabetes.
Metformin also carries some notable disadvantages and risks, though. It’s well known that taking metformin increases the risk for vitamin B12 deficiency, so people who take the drug should be monitored for this outcome. Taking metformin has also been linked to more severe pain in people with diabetic peripheral neuropathy. And while metformin is generally very effective as a treatment for type 2 diabetes, it may not be effective enough at lowering blood glucose by itself as diabetes progresses over time. Many people with newly diagnosed type 2 diabetes also stop taking metformin soon after starting it, which may reflect the risk for digestive upset when people start taking the drug — a side effect that usually goes away over time, and that can also be addressed by switching to an extended-release version of metformin.
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How metformin works: research sheds new light
But for such a widely prescribed and studied drug, there’s still a lot that scientists don’t know about how metformin works. That may be changing, though, thanks to new research published in the Proceedings of the National Academy of Sciences. Researchers at Yale University were interested in looking at how, exactly, metformin inhibits the release of glucose by liver — something they confirmed is the main way that metformin lowers blood glucose, through physiological studies in humans. But at a deeper level, they wanted to know how metformin inhibits metabolic processes in the mitochondria of cells in the liver, as noted in a Yale News article on the study. Mitochondria are responsible for generating the energy in cells, and are sometimes nicknamed the “power plant” of cells.
Previous research has shown that there are four different protein complexes (groups of protein chains) involved in the release of energy through a series of chemical reactions in mitochondria. Before there latest study, it was widely believed that metformin inhibited what’s known as complex I — the largest of the energy-generating protein complexes in mitochondria. But when researchers looked at how metformin works on a molecular level in liver cells, they found that metformin inhibits a mitochondrial enzyme called GPD2. It does this by inhibiting not complex I, but complex IV — the fourth protein complex involved in the release of energy in mitochondria.
On a practical level, the most important finding of the latest research may be that metformin inhibits the conversion of a molecule called glycerol to glucose in the liver. This process appears to be dysregulated in people with type 2 diabetes, leading to increased glucose production by the liver — which explains why taking metformin tends to reduce blood glucose in people with type 2 diabetes, but not by as much in people without diabetes. Glycerol is released when fat in the body is broken down, and the researchers found that in some cases, 40% of a person’s blood glucose can come form the conversion of glycerol. So finding new ways to block the conversion of glycerol into glucose could form the basis of future research into new diabetes treatments.