Hyperglycemia and Loss of Redox Homeostasis in COVID-19 Patients

Abstract

The infection with SARS-CoV-2 impairs the glucose−insulin axis and this contributes to oxidative (OS) and nitrosative (NSS) stress. Here, we evaluated changes in glucose metabolism that could promote the loss of redox homeostasis in COVID-19 patients. This was comparative cohort and analytical study that compared COVID-19 patients and healthy subjects. The study population consisted of 61 COVID-19 patients with and without comorbidities and 25 healthy subjects (HS). In all subjects the plasma glucose, insulin, 8-isoprostane, Vitamin D, H2S and 3-nitrotyrosine were determined by ELISA. The nitrites (NO2−), lipid-peroxidation (LPO), total-antioxidant-capacity (TAC), thiols, glutathione (GSH) and selenium (Se) were determined by spectrophotometry. The glucose, insulin and HOMA-IR (p < 0.001), 8-isoprostanes, 3-nitrotyrosine (p < 0.001) and LPO were increased (p = 0.02) while Vitamin D (p = 0.01), H2S, thiols, TAC, GSH and Se (p < 0.001) decreased in COVID-19 patients in comparison to HS. The SARS-CoV-2 infection resulted in alterations in the glucose−insulin axis that led to hyperglycemia, hyperinsulinemia and IR in patients with and without comorbidities. These alterations increase OS and NSS reflected in increases or decreases in some oxidative markers in plasma with major impact or fatal consequences in patients that course with metabolic syndrome. Moreover, subjects without comorbidities could have long-term alterations in the redox homeostasis after infection.

Keywords: H2S; SARS-CoV-2; homeostasis redox; hyperglycemia; lipid peroxidation; nitrotyrosine; selenium; thiols.

Figure 1

(a) The values of glucose significantly increased in the moderate and severe COVID-19 patients in comparison with HS. (b) Insulin had a significant increase in the moderate and severe COVID-19 patients in comparison to HS. (c) The HOMA index significantly increased in the moderate and severe COVID-19 patients in comparison with HS. Abbreviations: HS = healthy subjects, HOMA index = marker of insulin resistance which if the values are greater than 2.5 is an indication of insulin resistance.

Figure 2

(a) The 8-isoprostane concentrations statistically increased in both the moderate and severe COVID-19 patients in comparison with HS. (b) 3-NT statistically increased in the moderate and severe COVID-19 patients in comparison to HS. Abbreviations: HS = healthy subjects, 3-NT = 3-nitrotyrosine.

Figure 3

(a) Changes in the values of Vit D and (b) changes in the concentration of the H₂S, there was a significant decrease in the moderate and severe COVID-19 patients in comparison with HS. Abbreviations: Vit D = Vitamin D, H₂S = hydrogen sulfide, HS = healthy subjects.

Figure 4

(a) The LPO index significantly increased in the moderate and severe COVID-19 patients in comparison with HS. (b) The TAC significantly decreased in the moderate and severe COVID-19 patients in comparison to HS. (c) The NO₂^– concentration significantly decreased in the moderate and severe COVID-19 patients in comparison with HS. Abbreviations: LPO = Lipid peroxidation, TAC = Total antioxidant capacity, NO₂^– = Nitrites.

Figure 5

(a) The thiol concentrations significantly decreased in the moderate and severe COVID-19 patients in comparison to HS. (b) GSH concentration statistically decreased in the moderate and severe COVID-19 patients in comparison with HS. (c) The Se concentration significantly decreased in both the moderate and severe COVID-19 patients in comparison with HS. Abbreviations: HS = healthy subjects, GSH = glutathione, Se = selenium.

Figure 6

Alteration of the glucose–insulin axis by SARS-CoV-2, and the impact on some antioxidant markers in patients. (1) Entry of COVID-19 through various receptors in the pancreas. (2) COVID-19 increases lactate levels, favoring viral replication. (3) Increased free fatty acids are used for viral membrane formation. (4) Increased glucose overstimulates pancreatic β-cells and subsequently impairs their function. (5) Chronically increased insulin concentrations will lead to depletion of insulin reserves. (6) Hyperinsulinemia may favor the development of thrombosis. (7) Hyperglycemia inactivates GLUT 1 but SARS-CoV-2 could increase -3, -4 and -8, transporters. (8) Increased lipolysis blocks the response to insulin by the liver, adipose tissue and muscles. (9) Metformin prevents the interaction of the ACE2 receptor and COVID-19. (10) Increased free fatty acid synthesis favors the generation of 8-isoprostanes, which favor ACE2 receptor overexpression. (11) ONOO^– favors interleukin storm. (12) ONOO^– decreases H₂S concentration. (13) Nitrosative stress and depletion of GSH concentrations is associated with ferroptosis and mitochondrial sequestration by the virus. (14) Under conditions of hyperinsulinemia, Vitamin D is sequestered in adipose tissue and inactivated in the kidney, which favors the interaction of virus S protein with the ACE2 receptor. (15) Vitamin D deficiency generates ruptures in the gap junctions of lung endothelial cells. (16) Vitamin D deficiency is associated with Se deficiency which affects selenoenzymes. Abbreviations: ARDS = acute respiratory distress syndrome, H₂O₂ = hydrogen peroxide, H₂S = sulfhydryl acid, G-6-P = glucose 6 phosphate, GR = glutathione reductase, GSH = glutathione, GSSG = oxidized glutathione, NO = nitric oxide, NSS = nitrosative stress, O₂^– = superoxide, ONOO^– = peroxynitrite, ROS = reactive oxygen species, SOD = Superoxide dismutase.