Diabetes drug shows promise for COVID-19 lung inflammation

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Researchers have identified the molecular mechanism for the anti-inflammatory activity of diabetes drug metformin, reports the University of California – San Diego. They say it prevents lung inflammation in animals infected with SARS-CoV-2.

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.

It 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.

The study by a multi-institution team led by researchers at the University of California – San Diego’s School of Medicinewas published online in the journal Immunity on 9 June 2021, according to ScienceDaily.

They 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 before hospital admission for COVID-19 correlated to reduced severity and mortality. Both diabetes and obesity are recognised 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 offered an explanation or prompted large, randomised clinical trials needed for obtaining conclusive answers.

"The clinical studies were plagued by confounders that made conclusions hard to reach. There was some scepticism in their findings," said corresponding study author Dr Michael Karin, 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 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 Dr Elsa Sanchez-Lopez, an assistant professor in the Department of Orthopedic Surgery, postdoctoral fellow Dr Hongxu Xian 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 hospitalised 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 Dr Moshe Arditi, MD, and Dr Timothy R Crother 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.

 

Study details

Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation

Authors Hongxu Xian, Yuan Liu, Alexandra Rundberg Nilsson, Raphaella Gatchalian, Timothy R. Crother, Warren G. Tourtellotte, Yi Zhang, German R. Aleman-Muench, Gavin Lewis, Weixuan Chen, Sarah Kang, Melissa Luevanos, Dorit Trudler, Stuart A. Lipton, Pejman Soroosh, John Teijaro, Juan Carlos de la Torre, Moshe Arditi, Michael Karin, Elsa Sanchez-Lopez.

Published in Immunity on 9 June 2021

 

Highlights

  • Metformin inhibits macrophage IL-1β and IL-6 production and blunts ARDS severity.
  • Metformin inhibits cytosolic Ox-mtDNA production and NLRP3 inflammasome activation.
  • By targeting ETCCI, metformin blocks macrophage ATP-dependent mtDNA synthesis.
  • Myeloid targeted inhibition of mtDNA synthesis blunts IL-1β production and ARDS.

Summary

Acute respiratory distress syndrome (ARDS), an inflammatory condition with high mortality rates, is common in severe COVID-19, whose risk is reduced by metformin rather than other anti-diabetic medications. Detecting of inflammasome assembly in post-mortem COVID-19 lungs, we asked whether and how metformin inhibits inflammasome activation while exerting its anti-inflammatory effect.

We show that metformin inhibited NLRP3 inflammasome activation and interleukin (IL)-1β production in cultured and alveolar macrophages along with inflammasome-independent IL-6 secretion, thus attenuating lipopolysaccharide (LPS)- and SARS-CoV-2-induced ARDS.

By targeting electron transport chain complex 1 and independently of AMP-activated protein kinase (AMPK) or NF-κB, metformin blocked LPS-induced and ATP-dependent mitochondrial (mt) DNA synthesis and generation of oxidized mtDNA, an NLRP3 ligand.

Myeloid-specific ablation of LPS-induced cytidine monophosphate kinase 2 (CMPK2), which is rate limiting for mtDNA synthesis, reduced ARDS severity without a direct effect on IL-6. Thus, inhibition of ATP and mtDNA synthesis is sufficient for ARDS amelioration.

 

Science Daily report from University of California, San Diego – Common diabetes drug shows promise as treatment for COVID-19 lung inflammation (Open access)

Immunity journal article – Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation (Open access)

 

SEE ALSO FROM THE MEDICALBRIEF ARCHIVES

 

Metformin may reduce mortality risk 3x in patients with COVID-19 and diabetes

Coronavirus: 'Promising new treatments must be explored immediately’

20% of hospitalised COVID-19 patients with diabetes died within 28 days — CORONADO

 

 


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