Metformin is a drug approved by the U.S. Food and Drug Administration as a prescription medication used to decrease hepatic (liver) glucose production, to decrease GI glucose absorption and to increase target cell insulin sensitivity. It’s frequently used as an early treatment for type 2 diabetes, which affects more than 34 million Americans and is treated with a mix of diet and lifestyle modifications. However, scientists have discovered that metformin has anti-inflammatory capabilities, though the mechanism behind this is unknown.
A multi-institution team led by researchers at the University of California San Diego School of Medicine identified the molecular mechanism for metformin’s anti-inflammatory activity and found that metformin prevents pulmonary or lung inflammation in mice infected with SARS-CoV-2, the virus that causes COVID-19, in a study published online in the journal Cell Metabolism.
Several retrospective clinical studies published in the last year found that diabetic and obese individuals who took metformin before being admitted to the hospital for COVID-19 had a lower severity and mortality. Diabetes and obesity are both known COVID-19 risk factors that have been related to more severe results. Other blood sugar-controlling medicines, on the other hand, do not appear to have the same impact.
However, while these clinical investigations showed that metformin’s anti-inflammatory effect, rather than blood glucose reduction, may be responsible for reduced COVID-19 severity and mortality, none of the research provided a rationale or prompted large, randomized clinical trials.
“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, Ph.D., 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 worked on a mouse model of acute respiratory distress syndrome (ARDS), a potentially fatal illness in which fluid leaks into the lungs, making breathing difficult and limiting oxygen delivery to vital organs, with co-senior author Elsa Sanchez-Lopez, Ph.D., an associate professor in the Department of Orthopedic Surgery, postdoctoral scholar Hongxu Xian, Ph.D., and others.
Trauma, as well as bacterial or viral infections, can cause ARDS. It is a common cause of mortality among COVID-19 patients who are hospitalized. Metformin, given to mice before or after exposure to bacterial endotoxin, a surrogate for bacterial pneumonia, inhibited the onset of ARDS and reduced the severity of its symptoms, according to the researchers. Metformin significantly reduced mortality in endotoxin-challenged mice and suppressed the generation of IL-1 and the assembly of inflammasomes inside alveolar macrophages, which are immune cells present in the lungs.
IL-1β and IL-6 are cytokines, which are tiny proteins that produce inflammation as an early immunological response.
In those infected with SARS-CoV-2, their levels are frequently high, resulting in “cytokine storms” in which the body attacks its own cells and organs. They’re symptoms of a faulty acute immunological response.
The inflammasome, a major protein complex involved in IL-1 production, was discovered to be greatly increased in deceased COVID-19 patients’ lung tissue, according to co-authors Moshe Arditi, MD, and Timothy R. Crother, Ph.D., of Cedars-Sinai Medical Center in Los Angeles.
The UC San Diego researchers verified that metformin suppressed inflammasome activation and reduced SARS-CoV-2-induced lung inflammation in mice in collaboration with colleagues at The Scripps Research Institute.
Metformin’s anti-inflammatory action is mediated via a reduction in ATP generation by mitochondria, according to cell culture experiments utilizing macrophages. The molecule ATP is used by mitochondria to store chemical energy for cells. Although it is required for all cellular activities, metformin’s glucose-lowering action is due to a reduction in ATP synthesis in liver cells.
Lower ATP levels in macrophages inhibited mitochondrial DNA synthesis, which Karin’s group has previously discovered as a key step in NLRP3 inflammasome activation. Following that, researchers discovered that removing damaged mitochondria lowered NLRP3 inflammasome activity and inflammation.
UC San Diego researchers also found that removing the enzyme CMPK2 (cytidine monophosphate kinase 2) from macrophages suppressed IL-1 (but not IL-6) production and avoided the onset of ARDS.
“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 findings imply that metformin might be used to treat a number of neurological and cardiovascular disorders in which NLRP3 inflammasome activation is a role, according to the scientists. “Inhibition of inflammasome activation may also account for the poorly explained anti-aging effect of metformin,” said Karin.