Metformin is a widely prescribed blood sugar-lowering drug. It is often used as an early therapy (in combination with diet and lifestyle changes) for type 2 diabetes, which afflicts more than 34 million Americans.

Metformin works by lowering glucose production in the liver, reducing blood sugar levels that, in turn, improve the body’s response to insulin. But scientists have also noted that metformin possesses anti-inflammatory properties, though the basis for this activity was not known.

In a study published online June 8, 2021 in the journal Immunity, a multi-institution team led by researchers at University of California San Diego School of Medicine identified the molecular mechanism for the anti-inflammatory activity of metformin and, in mouse studies, found that metformin prevents pulmonary or lung inflammation in animals infected with SARS-CoV-2, the virus that causes COVID-19.

Over the past year, several retrospective clinical studies had reported that metformin use by diabetic and obese patients prior to hospital admission for COVID-19 correlated to reduced severity and mortality. Both diabetes and obesity are recognized risk factors for COVID-19, and are linked to more severe outcomes. Notably, other drugs used to control blood sugar levels do not appear to produce a similar effect.

But while these clinical studies suggested metformin’s anti-inflammatory activity, rather than lowering of blood glucose, could be responsible for reduced COVID-19 severity and mortality, none of the studies offered an explanation or prompted large, randomized clinical trials needed for obtaining conclusive answers.

“The clinical studies were plagued by confounders that made conclusions hard to reach. There was some skepticism in their findings,” said corresponding study author Michael Karin, PhD, Distinguished Professor of Pharmacology and Pathology and Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases at UC San Diego School of Medicine. “And because metformin is an out-of-patent, low-cost drug, there is little impetus to conduct large-scale trials, which are quite expensive.”

Karin, with co-senior author Elsa Sanchez-Lopez, PhD, an assistant professor at the Department of Orthopedic Surgery, postdoctoral fellow Hongxu Xian, PhD, and others, turned their focus to a mouse model of acute respiratory distress syndrome (ARDS), a life-threatening condition in which fluids leak into the lungs, making breathing difficult and restricting oxygen supply to essential organs.

ARDS is triggered by trauma and by bacterial or viral infections. It is a frequent cause of death in patients hospitalized with COVID-19. The researchers found that metformin administered to mice prior to or after exposure to bacterial endotoxin, a surrogate for bacterial pneumonia, resulted in the inhibition of ARDS onset and lessening of its symptoms. Metformin also produced a marked reduction in mortality in endotoxin-challenged mice and inhibited IL-1β production and inflammasome assembly within alveolar macrophages — immune cells found in the lungs.

IL-1β, along with IL-6, are small proteins called cytokines that cause inflammation as an early immune response. Their amounts are often highly elevated in persons infected by SARS-CoV-2, creating “cytokine storms” in which the body starts attacking its own cells and tissues. They are signs of an acute immune response gone awry.

Production of IL-1β depends on a large protein complex called the inflammasome, whose presence in lung tissue is found to be highly increased in deceased COVID-19 patients, a discovery made by co-authors Moshe Arditi, MD, and Timothy R. Crother, PhD, at Cedars-Sinai Medical Center in Los Angeles.

Working with colleagues at The Scripps Research Institute, the UC San Diego researchers confirmed that metformin inhibited inflammasome activation and prevented SARS-CoV-2-induced pulmonary inflammation in mice.

Cell culture studies using macrophages revealed the underlying mechanism by which metformin exerts its anti-inflammatory activity: reduced production of ATP by mitochondria. ATP is the molecule that mitochondria use to store chemical energy for cells. It is essential to all cellular processes, but blunted ATP production in liver cells is responsible for the glucose lowering effect of metformin.

Lower amounts of ATP in macrophages led to inhibition of mitochondrial DNA synthesis, which had been previously identified by Karin’s lab as a critical step in NLRP3 inflammasome activation. Subsequent research found that clearing away damaged mitochondria reduced NLRP3 inflammasome activity and reduced inflammation.

UC San Diego researchers also confirmed that specific interference with mitochondrial DNA synthesis in macrophages caused by removal of the enzyme CMPK2 (cytidine monophosphate kinase 2) inhibited IL-1β (but not IL-6) production and prevented ARDS onset.

“These experiments strongly suggest that improved delivery of metformin or CMPK2 inhibitors into lung macrophages can provide new treatments for severe COVID-19 and other forms of ARDS,” said Sanchez Lopez.

The authors said the findings suggest metformin may have therapeutic potential for treating a variety of neurodegenerative and cardiovascular diseases in which NLRP3 inflammasome activation is a factor. “Inhibition of inflammasome activation may also account for the poorly explained anti-aging effect of metformin,” said Karin.

Co-authors include: Alexandra Rundberg Nilsson, Raphaella Gatchalian and Sarah Kang, UC San Diego; Warren G. Tourtellote and Yi Zhang, Cedars-Sinai; German R. Aleman-Muench, Gavin Lewis, Weixuan Chen and Pejman Soroosh, Janssen Research & Development; and Melissa Luevanos, Dorit Trudler, Stuart A. Lipton, John Teijaro, and Juan Carlos de la Torre, The Scripps Research Institute.

Funding for this research came, in part, from the National Cancer Institute (CCSG P30CA23100) and the National Institutes of Health (grants R01NS095894, R01AI072726, K01AR077111, P30AR073761 U54CA260591, R01A1043477 and P4ES010337).

Disclosure: Michael Karin is founder of Elgia Pharmaceuticals, where he is also an inventor and serves on the advisory board. Karin also receives research support from Gossamer Bio, Janssen Pharmaceuticals and Merck.