COVID-19 in Relation to Hyperglycemia and Diabetes Mellitus

Abstract

Coronavirus disease 2019 (COVID-19), triggered by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), may lead to extrapulmonary manifestations like diabetes mellitus (DM) and hyperglycemia, both predicting a poor prognosis and an increased risk of death. SARS-CoV-2 infects the pancreas through angiotensin-converting enzyme 2 (ACE2), where it is highly expressed compared to other organs, leading to pancreatic damage with subsequent impairment of insulin secretion and development of hyperglycemia even in non-DM patients. Thus, this review aims to provide an overview of the potential link between COVID-19 and hyperglycemia as a risk factor for DM development in relation to DM pharmacotherapy. For that, a systematic search was done in the database of MEDLINE through Scopus, Web of Science, PubMed, Embase, China National Knowledge Infrastructure (CNKI), China Biology Medicine (CBM), and Wanfang Data. Data obtained underline that SARS-CoV-2 infection in DM patients is more severe and associated with poor clinical outcomes due to preexistence of comorbidities and inflammation disorders. SARS-CoV-2 infection impairs glucose homeostasis and metabolism in DM and non-DM patients due to cytokine storm (CS) development, downregulation of ACE2, and direct injury of pancreatic β-cells. Therefore, the potent anti-inflammatory effect of diabetic pharmacotherapies such as metformin, pioglitazone, sodium-glucose co-transporter-2 inhibitors (SGLT2Is), and dipeptidyl peptidase-4 (DPP4) inhibitors may mitigate COVID-19 severity. In addition, some antidiabetic agents and also insulin may reduce SARS-CoV-2 infectivity and severity through the modulation of the ACE2 receptor expression. The findings presented here illustrate that insulin therapy might seem as more appropriate than other anti-DM pharmacotherapies in the management of COVID-19 patients with DM due to low risk of uncontrolled hyperglycemia and diabetic ketoacidosis (DKA). From these findings, we could not give the final conclusion about the efficacy of diabetic pharmacotherapy in COVID-19; thus, clinical trial and prospective studies are warranted to confirm this finding and concern.

Keywords: COVID-19; SARS-CoV-2; cardiometabolic disturbances; diabetes mellitus; hyperglycemia.

Figure 1

SARS-CoV-2 and renin-angiotensin system (RAS) interaction: SARS-CoV-2 down-regulates ACE2 leading to over-activation of AngII and reduction of Ang 1-7. Ang II through angiotensin receptor type 1 (AT1R) leads to lung injury, inflammation, and vasoconstriction. Ang 1-7 through Mas receptor leads to vasodilation and lung protection.

Figure 2

SARS-CoV-2-induced hyperglycemia in COVID-19 patients. SARS-CoV-2 leads to hyperglycemia either directly through pancreatic β-cells injury or indirectly through cytokine storm-induced insulin resistance (IR). Hyperglycemia increased SARS-CoV-2 entry through glycation of ACE2. Hyperglycemia may cause acute respiratory distress syndrome (ARDS) and multiorgan damage (MOD) through the induction of endothelial dysfunction and coagulopathy.

Figure 3

The interaction between SARS-CoV-2 and pancreatic ACE2. Binding of SARS-CoV-2 to the pancreatic ACE2 leads to pancreatic injury (PI)-induced hyperglycemia and activation of A disintegrin and metalloprotease-17 (ADAM-17), which activate shedding of ACE2 receptors and production of TNF-α and IL-6. Hyperglycemia activates ADAM-17 and vice versa. These changes together participate in the development of ALI and ARDS.

Figure 4

The interaction between diabetes mellitus and COVID-19. In diabetes mellitus (DM), poor immunity, high pro-inflammatory cytokine, low ACE2, and oxidative stress increase susceptibility for COVID-19. Below, COVID-19-induced pancreatic injury, insulin resistance (IR), cytokine storm, and uses of corticosteroids in the management of COVID-19 collectively participate in the induction of DM.

Figure 5

Metformin inhibits pathogenesis of COVID-19 through inhibition of pro-inflammatory cytokines, inflammatory signaling pathway, and binding to ACE2.

Figure 6

Thiazolidinedione attenuates the pathogenesis of COVID-19 through inhibition of IL-6 and ADAM-17 with the modulation of ACE2, as thiazolidinediones can regulate the AngII-mediated effects.

Figure 7

Potential effects of DPP4 inhibitors on the pathogenesis of COVID-19. Dipeptidyl peptidase-4 inhibitors (DPP4Is) have anti-inflammatory effects through the activation of anti-inflammatory cytokines, the activation of macrophage polarizations, and the inhibition of pro-inflammatory cytokines. DPP4Is inhibit the entry of SARS-CoV-2 through blocking of DPP4 receptors. The net effects of DPP4Is are lung protection with improvement in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS).