Diabetic endothelial microangiopathy and pulmonary dysfunction

Abstract

Type 2 diabetes mellitus (T2DM) is a widespread metabolic condition with a high global morbidity and mortality rate that affects the whole body. Their primary consequences are mostly caused by the macrovascular and microvascular bed degradation brought on by metabolic, hemodynamic, and inflammatory variables. However, research in recent years has expanded the target organ in T2DM to include the lung. Inflammatory lung diseases also impose a severe financial burden on global healthcare. T2DM has long been recognized as a significant comorbidity that influences the course of various respiratory disorders and their disease progress. The pathogenesis of the glycemic metabolic problem and endothelial microangiopathy of the respiratory disorders have garnered more attention lately, indicating that the two ailments have a shared history. This review aims to outline the connection between T2DM related endothelial cell dysfunction and concomitant respiratory diseases, including Coronavirus disease 2019 (COVID-19), asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF).

Keywords: COPD; COVID-19; asthma; endothelial cells; type-2 diabetes.

Figure 1

PKA,AGE,AMPK, NF-κB,eNOS are presented as an example for a list of prospective therapeutic targets that diabetes and pulmonary diseases potentially explore through vascular endothelial cells. NF-κB, Nuclear factor kappa B; AT2, Alveolar Type II Cells; COPD, Chronic obstructive pulmonary disease; PKC, Protein kinase C; COVID-19, Coronavirus disease 2019; eNOS, Endothelial NO synthase; AMPK, AMP-activated protein kinase.

Figure 2

illustrates how endothelial cell damage from T2DM and COVID-19 infection are related. As a result, T2DM paired with COVID-19 infection may trigger the same signaling pathways and processes via endothelial cells, including endothelial glycocalyx (A), RAGE, and AGEs (B). Additionally, maintaining good management of diabetes and using glucose-lowering medicines (C) by acting on endothelial cells may lessen the likelihood that COVID-19 infection may result in decreased pulmonary function. GLP-1 RAs, GLP-1 receptor agonists; DPP-4i, Dipeptidyl peptidase 4 inhibitors.

Figure 3

In endothelial cells, COPD and T2DM create a similar pathogenic pathway. Endothelial cells in T2DM may impact how a lung disease develops in the end. Endothelial cells become dysfunctional in patients who have T2DM and COPD because of the accumulation of glycosylated proteins (A), a rise in endothelial microparticles (EMPs) (B), and an increase in VEGF (C). GLP-1 RAs, GLP-1 RAs and DPP-4i can treat COPD and diabetes simultaneously (D). GLP-1 RAs, GLP-1 receptor agonists; DPP-4i, Dipeptidyl peptidase 4 inhibitors; VEGF, Vascular endothelial growth factor.

Figure 4

Mechanisms shared by asthma and T2DM in endothelial cells. Metabolite (A), L-selectin, ICAM-1 (B), tissue transglutaminase 2 (TG2) (C), and VEGF (D) are all intimately connected to and have an impact on each other in endothelial cells, which may represent a common mechanism of lung function decline. GLP-1 RAs targeting endothelial cells, DPP-4i and other drugs can treat asthma and diabetes (E). GLP-1 RAs, GLP-1 receptor agonists; DPP-4i, Dipeptidyl peptidase 4 inhibitors; VEGF, Vascular endothelial growth factor; ICAM-1, Adhesion molecule 1.

Figure 5

There are shared mechanisms in endothelial cell dysfunction in T2DM with IPF, with existing research focused on AGEs (A), RAGE (B), and Ang II (C). In the meanwhile, diabetic therapies such as metformin, GLP-1 receptor agonists, DPP-4 inhibitors, and PPAR-agonists may alleviate pulmonary function decline by enhancing endothelial function (D). GLP-1 RAs, GLP-1 receptor agonists; DPP-4i, Dipeptidyl peptidase 4 inhibitors.