Role of lipopolysaccharide in genesis of microvascular complications in type 1 diabetes mellitus

Abstract

Despite significant advances in pathogenetic treatments for patients with diabetes mellitus type 1 (DM1) and reduction of mortality in this cohort of patients, as compared with general population, the difference in life expectancy in DM1 patients at the age of 20 years is about 10-12 years. Microvascular complications that increase the risk of cardiovascular disease (CVD) and overall mortality represent one of the most important problems in management of patients with DM1. The excessive risks persist even with proper control of all CVD risk factors, thus determining the need for in-depth research, in order to clarify and identify all factors of development and progression of microvascular complications in patients with DM1, as well as to develop methods for their modification and correction. According to current literature, the main pathogenetic links in the development of microvascular complications in DM1 concern, e.g., direct glucosemediated endothelial damage, oxidative stress, as well as microvascular fibrotic processes. In this review article, we consider additional possible route of these changes, i.e., chronic exposure to increased burden of bacterial lipopolysaccharide (LPS) derived from Gram-negative flora retained in systemic blood flow. LPS, by promoting generation of reactive oxygen species via NADPH-oxidase, thus leading to a significantly decreased bioavailability of endothelial NO and development of endothelial dysfunction (ED). Activation of toll-like receptor type 4 (TLR4) is accompanied by activation of p38MAPK, and subsequent translocation of NF-κB to the nucleus, increasing transcription of the interleukin-6 (IL-6) gene and adhesion molecules (ICAM-1, VCAM-1 and E-selectin). LPS is able to inhibit the anti-inflammatory effect of TGF-β, increasing the number of polarized M1 macrophages and leading to persistence of inflammation, activate TGFBR1 receptors, promotes PAI-1 gene expression, thus increasing the risk of atherogenesis and thrombosis in the vascular bed. The data presented in this literature review suggest a possible “LPS-gut-microvascular network” axis, which is an important pathogenic component of microvascular complications in patients with DM1. Chronic excessive intake of LPS into the systemic bloodstream can lead to the development of persistent low-grade inflammation accompanied by changes in architectonics of extracellular matrix, potentiate the development of endothelial dysfunction and vascular inflammation. The studies of LPS effects upon clinical course of DM1 are promising and require further in-depth research.

Keywords

• type 1 diabetes mellitus
• lipopolysaccharide
• endothelial dysfunction
• vascular inflammation
• fibrosis
• intestinal permeability