A new Northwestern Medicine study has provided direct evidence in mice that the drug reversibly cuts the cell’s energy supply by interfering with mitochondria to lower glucose levels.
More specifically, metformin blocks a specific part of the cell’s energy-making machinery called mitochondrial complex I.
They compared blood glucose levels in mice with and without metformin, and with or without the expressed yeast NDI1 protein.
Glucose levels in the control mice lowered upon metformin administration.
By contrast, NDI1-expressing mice ameliorated metformin reduction in glucose levels, indicating that metformin targets mitochondrial complex I to reduce glucose levels.
Metformin, a blood sugar-lowering drug for type 2 diabetes, is taken by millions of people. Additionally, the “wonder drug” has been demonstrated to lower inflammation, enhance COVID outcomes, and slow the growth of cancer. However, scientists still don’t know exactly how the drug works.
The drug reversibly cuts the cell’s energy supply by interfering with mitochondria to lower glucose levels, according to direct evidence from a recent Northwestern Medicine study in mice.
More precisely, metformin inhibits mitochondrial complex I, a particular component of the cell’s energy-generating apparatus. Without seriously harming healthy, normal cells, the medication can then target cells that might be accelerating the course of the disease.
The journal Science Advances published the study.
“We now have a better understanding of how metformin functions thanks to this research,” corresponding author Navdeep Chandel, the David W. Cugell, MD, is a professor of medicine at Northwestern University Feinberg School of Medicine who specializes in pulmonary and critical care. He is also an investigator with the Chan Zuckerberg Initiative and teaches biochemistry and molecular genetics. The first author of the study is Colleen Reczek, a research assistant professor of medicine at Feinberg who specializes in pulmonary and critical care medicine.
“This research significantly advances our understanding of the mechanism of action of metformin,” Chandel stated. Even though millions of people take metformin, its precise mechanism has not been fully understood. The way that metformin lowers blood sugar by interfering with cell mitochondria is explained by this study. “..”.
For over 60 years, metformin has been used to treat diabetes. According to Chandel, the first line of treatment for many type 2 diabetic patients worldwide is the reasonably priced drug, which is derived from compounds in the French lilac plant. In the United States. A. Some patients take it in combination with other medications, such as weight-loss drugs like Ozempic or Mounjaro, and new diabetes medications.
There are numerous theories among scientists regarding the impact of metformin on cells, but they are frequently based on research from different disciplines and have only offered circumstantial evidence to support their claims, according to Chandel.
According to Chandel, “every year there’s a new mechanism, a new target of metformin, and the next few years people debate those and don’t come to a consensus,”.
Metformin only affects a small number of cell types, primarily those in the gut, liver, and kidney, because it needs a transporter to enter the interior of cells, where mitochondria reside. Reczek developed mice genetically modified to express a yeast enzyme (NDI1) that resembles mitochondrial complex I but is resistant to metformin inhibition in order to test the function of mitochondrial complex I in glucose reduction.
Blood glucose levels in mice with and without metformin and the yeast NDI1 protein were compared. When metformin was given to the control mice, their blood sugar levels dropped. However, metformin’s ability to lower glucose levels was improved in mice that expressed NDI1, suggesting that metformin works by targeting mitochondrial complex I.
According to Chandel, “the NDI1-expressing mice were not completely resistant to its glucose-lowering effects, suggesting metformin may also target other pathways to some extent, but more research is needed,”.
The Chandel group had previously shown using NDI1 that the anti-cancer effects of metformin in cells expressing the metformin transporter were also caused by the blocking of mitochondrial complex I in cancer cells.
Furthermore, Chandel and Dr. Scott Budinger, the chief of pulmonary and critical care in the Feinberg department of medicine and one of the co-authors of the current study, have previously demonstrated that metformin can reduce pollution-induced inflammation in mice by interfering with mitochondrial complex I.
