Dysregulated O-linked β-N-acetylglucosamine (O-GlcNAc) signaling can promote cytokine storm induced by a viral infection. Higher levels of blood glucose correlate with higher levels of proinflammatory cytokines. It can impair the host defense mechanism of the immune cells. (1) (2) Proinsulin c-peptide regulates and balances O-GlcNAc signaling that may be also increased by high glucose level. In this way, c-peptide may decrease pathogen-induced cytokine storm. (3) This goal can be achieved by the activation of AMP-activated protein kinase (AMPK). (4) Proinsulin c-peptide can increase vagus nerve activity that in turn can increase AMPK in myocardial ischemia. (5) (6) (7) AMPK activation can reduce O-GlcNAc counteracting cardiac hypertrophy. (8) AMPK is a master switch that promotes macrophage polarization to an anti-inflammatory functional phenotype. (9) According to post mortem findings, inflammatory macrophages have a prominent role in pulmonary injuries of COVID-19 patients. (10) The anti-inflammatory effect of AMPK is one of the promising therapeutic targets in acute and chronic inflammatory diseases. (11)
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