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) 

(1) Wang, Qiming et al.: O-GlcNAc transferase promotes influenza A virus-induced cytokine storm by targeting interferon regulatory factor–5, In: Science Advances  15 Apr 2020: Vol. 6, no. 16, eaaz7086

(2) Hu, Ronghua, et al.: Effect of High Glucose on Cytokine Production by Human Peripheral Blood Immune Cells and Type I Interferon Signaling in Monocytes: Implications for the Role of Hyperglycemia in the Diabetes Inflammatory Process and Host Defense Against Infection, In: Clin Immunol. 2018 Oct;195:139-148.

(3) Sima, Anders A.F. et al.: Molecular Alterations Underlie Nodal and Paranodal Degeneration in Type 1 Diabetic Neuropathy and Are Prevented by C-Peptide, In: Diabetes 2004 Jun; 53(6): 1556-1563.

(4) Bhatt M.P. et al: C-Peptide Activates AMPKα and Prevents ROS-Mediated Mitochondrial Fission and Endothelial Apoptosis in Diabetes, In: Diabetes. 2013 Nov; 62(11): 3851–3862.

(5) Xue Run-Qing, et al.: Vagal nerve stimulation improves mitochondrial dynamics via an M3 receptor/CaMKKβ/AMPK pathway in isoproterenol‐induced myocardial ischaemia, In:  J Cell Mol Med. 2017 Jan; 21(1): 58–71.

(6) Kimura K. et al.: Proinsulin C-peptide Activates Vagus Efferent Output in Rats, Peptides. 2005 Dec;26(12):2547-53.

(7) Johansson B.L. et al.: C-peptide Improves Autonomic Nerve Function in IDDM Patients, In: Diabetologia. 1996 Jun;39(6):687-95.

(8) Gélinas R. et al.: AMPK activation counteracts cardiac hypertrophy by reducing O-GlcNAcylation, In: Nature Communications volume 9, Article number: 374 (2018) 

(9) Sag, Duygu, et al.: AMP-activated protein kinase promotes macrophage polarization to an anti-inflammatory functional phenotype, In: J Immunol. 2008 Dec 15; 181(12): 8633–8641.

(10) Carsana, L. Et al.: Pulmonary post-mortem findings in a large series of COVID-19 cases from Northern Italy, In: doi: https://doi.org/10.1101/2020.04.19.20054262

(11) Salt Ian P. et al.: Exploiting the Anti-Inflammatory Effects of AMP-activated Protein Kinase Activation, In: Expert Opin Investig Drugs. 2012 Aug;21(8):1155-67.