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Review
. 2021 Dec:144:112230.
doi: 10.1016/j.biopha.2021.112230. Epub 2021 Oct 6.

Metformin to decrease COVID-19 severity and mortality: Molecular mechanisms and therapeutic potential

Olexandr Kamyshnyi  1 , Victoriya Matskevych  2 , Tetyana Lenchuk  2 , Olha Strilbytska  3 , Kenneth Storey  4 , Oleh Lushchak  5
Affiliations
Review

Metformin to decrease COVID-19 severity and mortality: Molecular mechanisms and therapeutic potential

Olexandr Kamyshnyi et al. Biomed Pharmacother. 2021 Dec.

Abstract

The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 has become a serious challenge for medicine and science. Analysis of the molecular mechanisms associated with the clinical manifestations and severity of COVID-19 has identified several key points of immune dysregulation observed in SARS-CoV-2 infection. For diabetic patients, factors including higher binding affinity and virus penetration, decreased virus clearance and decreased T cell function, increased susceptibility to hyperinflammation, and cytokine storm may make these patients susceptible to a more severe course of COVID-19 disease. Metabolic changes induced by diabetes, especially hyperglycemia, can directly affect the immunometabolism of lymphocytes in part by affecting the activity of the mTOR protein kinase signaling pathway. High mTOR activity can enhance the progression of diabetes due to the activation of effector proinflammatory subpopulations of lymphocytes and, conversely, low activity promotes the differentiation of T-regulatory cells. Interestingly, metformin, an extensively used antidiabetic drug, inhibits mTOR by affecting the activity of AMPK. Therefore, activation of AMPK and/or inhibition of the mTOR-mediated signaling pathway may be an important new target for drug therapy in COVID-19 cases mostly by reducing the level of pro-inflammatory signaling and cytokine storm. These suggestions have been partially confirmed by several retrospective analyzes of patients with diabetes mellitus hospitalized for severe COVID-19.

Keywords: COVID-19; Immunometabolism; Lymphocytes; Metformin.

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Conflict of interest statement

The authors have no conflict of interest to declare.

Figures

Fig. 1
Fig. 1
Lymphocytes as sensors of metabolic changes. Notation keys: mTOR – target of rapamycin, AMPK – AMP-activated protein kinase, PPARγ – receptors activated by peroxisome proliferators, Glut 1 – glucose transporters type 1, P2XR – purinergic receptors, FFAR2 – short-chain fatty acid receptors, AHR – aryl-hydrocarbon receptors, PRR – pattern-recognizing receptors of innate immunity, PAMP – pathogen-associated molecular patterns, DAMP – damage- associated molecular patterns.
Fig. 2
Fig. 2
Mechanisms of the positive effects of metformin to decrease COVID-19 severity.
See this image and copyright information in PMC

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