Metformin is a widely prescribed hypoglycemic drug. It is often used as an early treatment (combined with diet and lifestyle changes) for type 2 diabetes that afflicts more than 34 million Americans.
Metformin reduces glucose production in the liver, lowers blood sugar levels, and improves the body’s response to insulin. However, scientists have also noted that metformin has anti-inflammatory properties, but the basis for this activity is unknown.
In a study published online in the journal on June 8, 2021 ImmunityA multicenter team led by researchers at the University of California, San Diego Medical School has identified the molecular mechanism of anti-inflammatory activity of metformin and, in a mouse study, prevented metformin-infected lung or lung inflammation in SARS-infected animals. Found-a virus that causes CoV-2, COVID-19.
Over the past year, several retrospective clinical studies have reported that the use of metformin by pre-hospital diabetic and obese patients with COVID-19 correlates with reduced severity and mortality. Both diabetes and obesity are recognized as risk factors for COVID-19, with more serious consequences. In particular, other drugs used to control blood sugar levels do not appear to produce similar effects.
However, these clinical studies suggested that the anti-inflammatory activity of metformin, rather than lowering blood glucose levels, may be responsible for the lowering of COVID-19 severity and mortality, but the definitive answer. None of the studies provided the explanations needed to obtain or facilitated large-scale randomized clinical trials.
“Clinical studies have been plagued by confounding factors that make it difficult to draw conclusions. There was some skepticism about their findings,” said the corresponding research author, Pharmacology and Pathology. Said Dr. Michael Karin, a professor and Ben and Wonder Hildyard Chair for confounding and metabolic disorders. Faculty of Medicine, University of California, San Diego. “And because metformin is an unpatented, low-cost drug, it has little impetus for conducting large-scale, very expensive trials.”
Karin, along with co-authors Elsa Sanchez-Lopez, PhD, orthopedic assistant professor, and postdoctoral researchers Hongxu Xian, PhD, and others, focused on a mouse model of acute respiratory distress syndrome (ARDS). A life-threatening condition in which fluid leaks into the lungs, making breathing difficult and limiting oxygen supply to critical organs.
ARDS is caused by trauma and bacterial or viral infections. This is a common cause of death in patients hospitalized with COVID-19. Researchers have found that administration of metformin to mice before or after exposure to bacterial endotoxin, a substitute for bacterial pneumonia, suppresses the development of ARDS and alleviates its symptoms. Did metformin also significantly reduce endotoxin challenge mouse mortality and inhibit IL-1? Production in alveolar macrophages and assembly of inflammasomes-immune cells found in the lung.
IL-1? Along with IL-6, is a small protein called a cytokine that causes inflammation as an early immune response. Their amount is often very high in people infected with SARS-CoV-2, causing a “cytokine storm” in which the body begins to attack its cells and tissues. They are signs that the acute immune response has failed.
IL-1 production? It relies on a large protein complex called the inflammasome, and its presence in lung tissue has been shown to be significantly increased in deceased COVID-19 patients. This is a discovery made by co-authors Moshe Arditi, MD and Timothy R. Crother, PhD in Cedars. -Sinai Medical Center in Los Angeles.
Researchers at the University of California, San Diego have collaborated with colleagues at the Scripps Research Institute to confirm that metformin inhibits inflammasome activation and prevents SARS-CoV-2 -induced pneumonia in mice. did.
Cell culture studies using macrophages have revealed the underlying mechanism by which metformin exerts its anti-inflammatory activity: mitochondrial reduction in ATP production. ATP is a molecule used by mitochondria to store the chemical energy of cells. Although it is essential for all cellular processes, slowed ATP production in hepatic cells is responsible for the glucose-lowering effect of metformin.
Low levels of ATP in macrophages inhibit mitochondrial DNA synthesis. This was previously identified by Karin’s lab as an important step in NLRP3 inflammasome activation. Subsequent studies have shown that clearing damaged mitochondria reduces NLRP3 inframasome activity and reduces inflammation.
Did researchers at the University of California, San Diego also confirm that specific interference of macrophages with mitochondrial DNA synthesis caused by the removal of the enzyme CMPK2 (citidine monophosphate kinase 2) inhibits IL-1? Production (not IL-6) and prevention of the development of ARDS.
“These experiments strongly suggest that improved delivery of metformin or CMPK2 inhibitors to pulmonary macrophages can provide new treatments for severe COVID-19 and other forms of ARDS,” Sanchez Lopez said. Stated.
The authors suggest that metformin may have therapeutic potential for the treatment of various neurodegenerative and cardiovascular diseases caused by NLRP3 inframasome activation. Said that. “Inhibition of inflammasome activation may also be responsible for the poorly explained anti-aging effects of metformin,” Karin said.
The co-authors are: AlexandraRundbergNilsson, Raphaella Gatchalian, Sarah Kang, University of California, San Diego. Warren G. Tourtellote and Yi Zhang, Cedars-Sinai; German R. Aleman-Muench, Gavin Lewis, Weixuan Chen, Pejman Soroosh, Janssen Research & Development; Melissa Ruevanos, Dorit Tradler, Stuart A. Lipton, John Teijaro, Juan -Carlos de la Torre, Scripps Research Institute.
Disclosure: Michael Karin is the founder, inventor and advisory board member of Elgia Pharmaceuticals. Karin also receives research support from Gossamer Bio, Janssen Pharma and Merck.