Endothelial dysfunction in diabetes: potential application of circulating markers as advanced diagnostic and prognostic tools

Abstract

Endothelial dysfunction is a predisposing factor for vascular disease in diabetes, which contributes significantly to the mortality of diabetic patients. The currently utilized assessment methods of endothelial function/dysfunction in humans are associated with various limitations. Circulating endothelial-derived/associated markers have been proposed as potential alternatives for evaluation of the endothelium in condition of vascular disorders. These indicators include von Willebrand factor, soluble thrombomodulin, soluble E-selectin, asymmetric dimethylarginine, tissue plasminogen activator, endothelial microparticles, circulating endothelial cells and circulating endothelial progenitor cells. While tentative evidence is available for most of these biomarkers to serve as reliable sources of information, their usefulness for routine clinical applications has not yet been established. Thus, circulating endothelial markers are currently the subject of intense research interest and it is anticipated that as more information becomes available their improved quantification will provide a suitable diagnostic and prognostic tool for vascular events in diabetes and related diseases.

Fig. 1

Endothelial cell as a regulator of vascular smooth muscle tone. Endothelial cells synthesize NO which diffuses into adjacent smooth muscle cells to activate sGS, generating cGMP. cGMP, through a reduction in intracellular calcium (Ca_i²⁺), causes relaxation of smooth muscle cells. Abbreviations: NO: nitric oxide; sGS: soluble guanylate cyclase; GTP: guanosine triphosphate; cGPM: cyclic GMP; eNOS: NO synthase-type III; EC: endothelial cell; VSMC: vascular smooth muscle cell

Fig. 2

Effect of type 1-like diabetes of 14 weeks duration on acetylcholine-mediated, endothelium-dependent relaxant responses of aortas from male streptozotocin-treated rats (n = 6 rats/group). *Significantly different from corresponding control responses (P < 0.05)

Fig. 3

Effect of high-glucose (45 mM for 3 h) on acetylcholine-mediated, endothelium-dependent relaxant responses of aortas from male rats (n = 6 rats/group). *Significantly different from corresponding control responses (P < 0.05)

Fig. 4

Proposed mechanisms by which hyperglycemia and subsequent overproduction of reactive oxygen species such as superoxide (from mitochondria and other sources) cause oxidative DNA damage and activation of PARP. In turn, increased PARP activity causes addition of ADP-ribose polymer onto the GAPDH resulting in its inhibition. Inhibition of GAPDH will result in build up of glycolytic intermediates and their subsequent diversion into and augmentation of the following four pathways: the sorbitol/polyol, hexosamine, PKC and glycosylation pathways. Abbreviations: NADPH: reduced nicotinamide adenine dinucleotide phosphate; eNOS: nitric oxide synthase-type III; PKC: protein kinase C; ROS: reactive oxygen species; PARP: poly(ADP-ribose) polymerase; GAPDH: glyceraldehydes-3-phosphate dehydrogenase; AGEs: advanced glycation end (products)

Fig. 5

Insulin signaling pathways in endothelial cells. The PI3K/Akt branch regulates NO production in endothelial cells and vasodilation in vascular smooth muscle cells. The MAPK branch controls secretion of endothelin-1 in the endothelium, and also regulates growth and mitogenesis. Under normal conditions, there is an optimum balance between these pathways. Abbreviations: IRS-1: insulin receptor substrate protein-1; PI3K: phosphatidylinositol-3-kinase; PDK-1: phospho-3’-phosphoinositide-dependent kinase-1; NO: nitric oxide; eNOS: NO synthase-type III; MAPK: mitogen-activated protein kinase; Et-1: endothelin-1; VSMC: vascular smooth muscle cell

Fig. 6

Major endothelial-derived circulating biomarkers. While vWF, sTM, ADMA, EMP, sE-selectin, tPA and endotheline-1 are released into the circulation specifically by endothelial cells, the other biomarkers shown are also released by other types of cells, making assay of the latter less specific to precisely reflect the status of the endothelium. In addition, the assay method available for endothelin-1 is not sensitive enough to reveal relatively subtle changes in the endothelium. Abbreviations: NO: nitric oxide; eNOS: NO synthase-type III; NF-kB: nuclear factor kB; EMP: endothelial microparticle; TM: thrombomodulin; sTM: soluble TM; vWF: von Willebrand factor; WPB: Weibel-Palade body; tPA: tissue plasminogen activator; ADMA: asymmetric dimethylarginine; sVCAM: soluble vascular cell adhesion molecule-1; sICAM: soluble intracellular adhesion molecule

Fig. 7

Proposed role of circulating EPCs in endothelial function/dysfunction and disorder of the vasculature in diabetes. EPCs released from bone marrow are involved in the repair of endothelial cells under normal conditions and their levels in the circulation have been shown to decrease significantly when there is impairment or damage to the endothelium. Abbreviations: EPCs: endothelial progenitor cells; ECs: endothelial cells