Metformin is a extensively prescribed blood sugar-lowering drug. It is commonly used as an early remedy (together with weight loss plan and way of life adjustments) for sort 2 diabetes, which afflicts greater than 34 million Americans.
Metformin works by decreasing glucose manufacturing within the liver, lowering blood sugar ranges that, in flip, enhance the physique’s response to insulin. But scientists have additionally famous that metformin possesses anti-inflammatory properties, although the idea for this exercise was not identified.
In a examine revealed on-line June 8, 2021 within the journal Immunity, a multi-institution group led by researchers at University of California San Diego School of Medicine recognized the molecular mechanism for the anti-inflammatory exercise of metformin and, in mouse research, discovered that metformin prevents pulmonary or lung inflammation in animals contaminated with SARS-CoV-2, the virus that causes COVID-19.
Over the previous 12 months, a number of retrospective scientific research had reported that metformin use by diabetic and overweight sufferers previous to hospital admission for COVID-19 correlated to lowered severity and mortality. Both diabetes and weight problems are acknowledged threat components for COVID-19, and are linked to extra extreme outcomes. Notably, different medication used to manage blood sugar ranges don’t seem to provide an analogous impact.
But whereas these scientific research instructed metformin’s anti-inflammatory exercise, slightly than decreasing of blood glucose, may very well be accountable for lowered COVID-19 severity and mortality, not one of the research provided a proof or prompted massive, randomized scientific trials wanted for acquiring conclusive solutions.
“The clinical studies were plagued by confounders that made conclusions hard to reach. There was some skepticism in their findings,” mentioned corresponding examine creator 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 creator Elsa Sanchez-Lopez, PhD, an assistant professor on the Department of Orthopedic Surgery, postdoctoral fellow Hongxu Xian, PhD, and others, turned their focus to a mouse mannequin of acute respiratory misery syndrome (ARDS), a life-threatening situation by which fluids leak into the lungs, making respiratory troublesome and proscribing oxygen provide to important organs.
ARDS is triggered by trauma and by bacterial or viral infections. It is a frequent explanation for loss of life in sufferers hospitalized with COVID-19. The researchers discovered that metformin administered to mice previous to or after publicity to bacterial endotoxin, a surrogate for bacterial pneumonia, resulted within the inhibition of ARDS onset and lessening of its signs. Metformin additionally produced a marked discount in mortality in endotoxin-challenged mice and inhibited IL-1? manufacturing and inflammasome meeting inside alveolar macrophages — immune cells discovered within the lungs.
IL-1?, together with IL-6, are small proteins known as cytokines that trigger inflammation as an early immune response. Their quantities are sometimes extremely elevated in individuals contaminated by SARS-CoV-2, creating “cytokine storms” by which the physique begins attacking its personal cells and tissues. They are indicators of an acute immune response gone awry.
Production of IL-1? is dependent upon a big protein advanced known as the inflammasome, whose presence in lung tissue is discovered to be extremely elevated in deceased COVID-19 sufferers, 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 tradition research utilizing macrophages revealed the underlying mechanism by which metformin exerts its anti-inflammatory exercise: lowered manufacturing of ATP by mitochondria. ATP is the molecule that mitochondria use to retailer chemical power for cells. It is crucial to all mobile processes, however blunted ATP manufacturing in liver cells is accountable for the glucose decreasing impact of metformin.
Lower quantities of ATP in macrophages led to inhibition of mitochondrial DNA synthesis, which had been beforehand recognized by Karin’s lab as a essential step in NLRP3 inflammasome activation. Subsequent analysis discovered that clearing away broken mitochondria lowered NLRP3 inflammasome exercise and lowered inflammation.
UC San Diego researchers additionally confirmed that particular interference with mitochondrial DNA synthesis in macrophages attributable to elimination of the enzyme CMPK2 (cytidine monophosphate kinase 2) inhibited IL-1? (however not IL-6) manufacturing 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,” mentioned Sanchez Lopez.
The authors mentioned the findings recommend metformin could have therapeutic potential for treating quite a lot of neurodegenerative and cardiovascular ailments by which NLRP3 inflammasome activation is an element. “Inhibition of inflammasome activation may also account for the poorly explained anti-aging effect of metformin,” mentioned Karin.
Co-authors embrace: 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 founding father of Elgia Pharmaceuticals, the place he’s additionally an inventor and serves on the advisory board. Karin additionally receives analysis assist from Gossamer Bio, Janssen Pharmaceuticals and Merck.