In studies on mice infected with the SARS-CoV-2 coronavirus, the blood sugar-lowering drug metformin prevented pneumonia, which is an important factor in the severity and mortality of COVID-19

Metformin is a commonly prescribed blood sugar lowering drug. It is often used as early therapy (combined with diet and lifestyle changes) for type 2 diabetes, which affects more than 34 million Americans.

Metformin works by lowering glucose production in the liver and lowering blood sugar levels, which in turn improves the body’s response to insulin. However, scientists have also found that metformin has anti-inflammatory properties, although the basis for this activity was not known.

In a study published online on June 8, 2021 in the journal immunity, a multi-institutional team led by researchers from the University of California San Diego School of Medicine identified the molecular mechanism behind metformin’s anti-inflammatory effects and found in mouse studies that metformin prevents pneumonia in SARS-infected animals. CoV-2, the virus that causes COVID-19.

In the past year, several retrospective clinical studies had reported that the use of metformin in diabetic and obese patients prior to hospitalization for COVID-19 correlated with decreased severity and mortality. Both diabetes and obesity are recognized risk factors for COVID-19 and are associated with more serious consequences. Notably, other drugs used to control blood sugar levels do not appear to have a similar effect.

But while these clinical studies suggested that metformin’s anti-inflammatory activity, rather than lowering blood sugar, might be responsible for reducing the severity and mortality of COVID-19, none of the studies offered any explanation or prompted large, randomized clinical trials necessary for conclusive answers.

“The clinical trials were plagued by confounders that made it difficult to draw conclusions. Their results were skeptical, ”said the author of the corresponding study Michael Karin, PhD, Distinguished Professor of Pharmacology and Pathology and Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases at the UC San Diego School of Medicine. “And since metformin is an unpatented, inexpensive drug, there is little incentive to conduct large-scale studies that are quite expensive.”

Karin and co-senior author Elsa Sanchez-Lopez, PhD, assistant professor in the Department of Orthopedic Surgery, postdoctoral fellow Hongxu Xian, PhD, and others, focused on a mouse model of acute respiratory distress syndrome (ARDS), a life-threatening condition in which fluid enters leaks the lungs, making it difficult to breathe and reducing the supply of oxygen to important organs.

ARDS is triggered by trauma and by bacterial or viral infections. It is a common cause of death in patients hospitalized with COVID-19. The researchers found that metformin, given to mice before or after exposure to bacterial endotoxin, a substitute for bacterial pneumonia, inhibited the onset of ARDS and alleviated its symptoms. Metformin also significantly reduced mortality in endotoxin-exposed mice and inhibited IL-1β production and inflammasome composition in alveolar macrophages – immune cells found in the lungs.

IL-1β, together with IL-6, are small proteins called cytokines that cause inflammation as an early immune response. Their levels are often greatly increased in people infected with SARS-CoV-2, which creates “cytokine storms” in which the body begins to attack its own cells and tissues. They are signs of a failed acute immune response.

The production of IL-1β depends on a large protein complex called the inflammasome, the presence of which is greatly increased in lung tissue in deceased COVID-19 patients, a discovery by co-authors Moshe Arditi, MD, and Timothy R. Crother, PhD, am Cedars-Sinai Medical Center in Los Angeles.

Working with colleagues at the Scripps Research Institute, UC San Diego researchers confirmed that metformin inhibits inflammasome activation and prevents SARS-CoV-2-induced pneumonia in mice.

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

Lower levels of ATP in macrophages led to an inhibition of mitochondrial DNA synthesis, which Karin’s laboratory had previously identified as a critical step in the activation of NLRP3 inflammasomes. Later research found that eliminating damaged mitochondria reduced NLRP3 inflammasome activity and reduced inflammation.

Researchers at UC San Diego also confirmed that a specific disruption of mitochondrial DNA synthesis in macrophages caused by the removal of the enzyme CMPK2 (cytidine monophosphate kinase 2), IL-1β (but not IL-6) production and prevented the outbreak of ARDS.

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

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

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Co-authors are: 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.

Disclosure: Michael Karin is the 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.

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