Glycation: A connecting link between diabetes and COVID-19

Sneha B Bansode; Rakesh S Joshi; Ashok P Giri; Mahesh J Kulkarni

doi:10.4103/cdrp.cdrp_8_21

REVIEW ARTICLE

Year : 2022 | Volume : 1 | Issue : 1 | Page : 27-30

Glycation: A connecting link between diabetes and COVID-19

Sneha B Bansode¹, Rakesh S Joshi², Ashok P Giri², Mahesh J Kulkarni²
¹ Biochemical Sciences Division, CSIR-National Chemical Laboratory, Pune, Maharashtra, India
² Biochemical Sciences Division, CSIR-National Chemical Laboratory, Pune, Maharashtra; Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh, India

Date of Submission	28-Oct-2021
Date of Decision	18-Nov-2021
Date of Acceptance	19-Nov-2021
Date of Web Publication	07-Jan-2022

Correspondence Address:
Mahesh J Kulkarni
Biochemical Sciences Division, CSIR-National Chemical Laboratory, Pune - 411 008, Maharashtra
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/cdrp.cdrp_8_21

Abstract

Diabetes is considered as a risk factor for the severity of coronavirus disease 2019 (COVID-19). The mortality rate of COVID-19 was found to be high among patients with diabetes. The exact molecular mechanism involved in diabetes-associated COVID-19 severity is not established. In this review, we discuss the exacerbated formation of advanced glycation end products (AGEs), AGE-receptor for AGE (RAGE) signaling induced spike in inflammatory cytokines, and the role of metformin, an antidiabetic drug with glycation inhibition property. The commonality between these two diseases is exacerbated immune response. AGEs interact with RAGE, leading to oxidative stress, activation of the pro-inflammatory pathway, and production of inflammatory cytokines, which may aberrantly activate the immune response. Based on these pieces of evidence, we propose a role for glycation in the pathogenesis of COVID-19 severity.

Keywords: Advanced glycation end product, coronavirus disease 2019, cytokine, diabetes, glycation, metformin, receptor for advanced glycation end product

How to cite this article:
Bansode SB, Joshi RS, Giri AP, Kulkarni MJ. Glycation: A connecting link between diabetes and COVID-19. Chron Diabetes Res Pract 2022;1:27-30

How to cite this URL:
Bansode SB, Joshi RS, Giri AP, Kulkarni MJ. Glycation: A connecting link between diabetes and COVID-19. Chron Diabetes Res Pract [serial online] 2022 [cited 2023 Mar 29];1:27-30. Available from: https://cdrpj.org//text.asp?2022/1/1/27/335260

Introduction

Coronavirus disease 2019 (COVID-19) has been announced as a pandemic disease in 2020. Globally, as of September 2021, around 22 million people are infected with COVID-19, including more than 4.5 million deaths. The symptoms of the disease generally begin with cough and fever, loss of taste and smell, eventually leading to pneumonia and severe respiratory tract infection.^[1] Among several other comorbidities, diabetes mellitus has been considered as a prominent risk factor for increased COVID-19 severity.^[2] Patients with diabetes having poorly controlled glycemia show increased hospitalizations, longer hospital stay duration, and increased mortality compared to COVID-19 patients without diabetes.^[3],[4] Although a large amount of data support more complications in COVID-19 patients with diabetes, the exact molecular reasons of this association are not understood in detail. In this review, we propose that glycation has a role in the COVID-19 severity by discussing the following evidences.

Increased Glycolysis During Severe Acute Respiratory Syndrome Coronavirus-2 Infection Promotes Advanced Glycation End Product Formation

The accumulation of advanced glycation end products (AGEs) increases with age but is significantly elevated due to hyperglycemia, oxidative stress, and inflammation. Hyperglycemia in diabetic conditions promotes the formation of AGEs due to increased glucose availability.^[5] AGE formation is a multi-step process that starts with the non-enzymatic reaction between reducing sugars such as glucose and free-amino group of proteins resulting in the formation of Schiff base, which further undergoes rearrangement to form a stable Amadori product. It further goes through a series of condensation reactions to form AGEs. AGEs contribute to diabetic complications such as cardiovascular diseases, nephropathy, and neuropathy, mainly through their interaction with the receptor of AGE (RAGE).^[6]

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection increases the production of reactive oxygen species (ROS), which elevate cellular injury and lead to intracellular stress. It thereby drives the infected cell to have increased glucose concentrations. Therefore, these cells reprogram their glucose metabolism and induce the expression of genes responsible for glycolysis to provide folate and one-carbon metabolism for its replication.^[7] It also causes increased expression of glucose transporter 1, glycolytic enzymes such as phosphofructokinase-2 which ultimately contributes to more glucose uptake in the cells. Therefore, the increased glucose consumption by cells and hyper-glycolytic events due to SARS-CoV-2 infection contributes to viral replication and inflammation.^[8] Moreover, increased glycolysis leads to overproduction of oxidative stress through activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. The increased glucose uptake accelerates glucose-6-phosphate production in the glycolytic pathway, and the same is also used in the pentose phosphate pathway for ribose-5-phosphate and NADPH production. NADPH oxidase uses this elevated NADPH as an electron donor for the production of ROS.^[9] The auto-oxidation products of reducing sugars such as glyoxal, methylglyoxal, and 3-deoxyglucosone are increased in the presence of high oxidative stress, which facilitate the formation of AGEs.^[10] Increased glycolysis may also result in the elevated formation of methylglyoxal, a highly reactive dicarbonyl compound, as it is an inevitable by-product of glycolysis.^[11] Therefore, it can be proposed that the increased glycolysis may enhance AGE production during the initial stage of SARS-CoV-2 infection, mainly in patients with diabetes [Figure 1]. As increased glycolysis plays an important role in the severity of SARS-CoV-2 infection, controlling hyper-glycolytic events will help to control the viral replication rate. Therefore, the administration of glycolytic inhibitor 2-deoxy-D-glucose (2-DG) is considered as a good strategy to mitigate COVID-19 severity by reducing the concentration of intermediaries of glycolysis that are required for SARS-CoV-2 viral infection. 2-DG, a glucose analog, inhibits the phosphoglucoisomerase enzyme in the glycolytic pathway which results in reduced production of glucose-6-phosphate, which is a crucial intermediate for the continuity of the glycolytic pathway.^[12] This mode of action of 2-DG inhibits metabolic reprogramming in the cell induced by SARS-CoV-2 infection. In addition to this, the dietary administration of chronic low-dose of 2-DG is also known to minimize ROS and AGEs in rats.^[13] Therefore, 2-DG may reduce the COVID-19 severity by decreasing viral replication through glycolysis inhibition and by diminishing AGEs.

Figure 1: The link of glycation in diabetes with COVID-19: advanced glycation end product- receptor for advanced glycation end product signalling increases the reactive oxygen species and pro-inflammatory cytokines in diabetic condition. It may contribute to the cytokine storm induced by severe acute respiratory syndrome coronavirus-2 and hence, lead to increased COVID-19 severity

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Advanced Glycation End Product-Receptor for Advanced Glycation End Product Interaction Exacerbates Oxidative and Inflammatory Reactions

AGEs activate RAGE signaling and increase oxidative stress. The oxidative stress is increased through an increase in the expression of NADPH oxidase.^[14] AGE-RAGE signaling also induces activation and translocation of the P65 component of NF-κB to the nucleus. It leads to targeted gene expression of inflammatory cytokines and induction of oxidative stress.^[15] NF-κB is linked with several cellular pathways such as immune response, inflammation, proliferation, and apoptosis. In addition to this, the nuclear translocation of the P65 subunit leads to its binding to RAGE promoter and hence, increased RAGE expression.^[16] Thus, it continues the vicious cycle of AGE-RAGE signaling and amplifying production of ROS, pro-inflammatory cytokines such as Interleukin-6, Interleukin-1, and tumor necrosis factor-α^[5] [Figure 1]. Several studies suggested that the SARS-CoV-2 infection elicits an immune response in COVID-19 patients by releasing pro-inflammatory cytokines in a process called “cytokine storm.” The hyperactive immune response in the host due to SARS-CoV-2 infection directly correlates with lung damage, multiorgan failure, and COVID-19 severity.^[17] The RAGE was found to be mainly expressed in the epithelial cells of the lungs sac, which could possibly increase the inflammation and lung injury in COVID-19.^[18] It may act as a drug target for attenuating cytokine storm in COVID-19 disease management.^[19] A recent study has observed that the serum sRAGE levels were found to be correlated with the severity of COVID-19. Thus, it is proposed that sRAGE should be considered as a biomarker for predicting the ventilators requirement during SARS-CoV-2 infection.^[20]

On the contrary, another study reported that asymptomatic and younger COVID-19 patients had higher levels of sRAGE, and older patients with severe symptoms had low sRAGE levels suggesting that the RAGE pathway plays a vital role in the aggravation of COVID-19 complications.^[21] Hence, it can be speculated that the increased expression of pro-inflammatory cytokines in diabetic conditions through the AGE-RAGE axis may contribute to the cytokine storm in COVID-19 and add to the tissue damage caused by SARS-CoV-2. Therefore, the AGE-RAGE axis can be one of the pivotal factors for enhanced inflammatory response and high mortality rate in patients with diabetes who develop COVID-19. Considering the above findings, the inhibition of glycation and AGE-RAGE signalling can act as a potential therapeutic target in COVID-19 pathogenesis.

Glycation Inhibitors for Reducing Coronavirus Disease 2019 Severity

Recent studies have suggested the positive effects of metformin, a routinely used anti-diabetic drug, in COVID-19 patients irrespective of its glucose-lowering capabilities.^[22] One of the possible explanations for metformin's effect on the reduced diabetes-associated COVID-19 severity could be its ability to reduce AGEs and reactive dicarbonyl compounds.^[23] Metformin inhibits AGEs by binding and inactivating dicarbonyl compounds like methylglyoxal by condensation reaction. Furthermore, it also reduces oxidative stress by blocking AGE-RAGE axis and decreasing further complications. Metformin is known to act as an adjuvant in the treatment of tuberculosis. Apart from inhibition of glycation, metformin regulates host immune responses through activation of AMP-activated protein kinase.^[24] Similarly, another drug Aspirin, an anti-inflammatory and a blood-thinner molecule, is also associated with reduced severity in COVID-19 patients.^[25] In addition to anti-thrombotic, anti-inflammatory, and immune-modulatory effects of aspirin, it has also been shown to be the potent inhibitor of protein glycation and cross-linking. Aspirin protect proteins from AGE modification by acetylating lysine residues and thereby, preventing the binding of AGEs to the proteins^[26],[27] [Figure 1].

Conclusion

Considering the link between AGEs with COVID-19-associated risk factors such as, diabetes, ageing, hypertension, and cardiovascular diseases, in-depth study of AGEs and its effect on COVID-19 severity is needed to understand about the tissue injuries in COVID-19. The overlap between the pathways induced by SARS-CoV-2 and AGEs suggests that the drugs used to reduce AGEs or inhibition of AGE-RAGE signalling can be potential molecules for the management of COVID-19 and its associated diseases.

Acknowledgment

This work is supported by BIRAC grant (BT/COVID0079/02/20).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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