Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I

Abstract

Hyperglycemia and insulin resistance are key players in the development of atherosclerosis and its complications. A large body of evidence suggest that metabolic abnormalities cause overproduction of reactive oxygen species (ROS). In turn, ROS, via endothelial dysfunction and inflammation, play a major role in precipitating diabetic vascular disease. A better understanding of ROS-generating pathways may provide the basis to develop novel therapeutic strategies against vascular complications in this setting. Part I of this review will focus on the most current advances in the pathophysiological mechanisms of vascular disease: (i) emerging role of endothelium in obesity-induced insulin resistance; (ii) hyperglycemia-dependent microRNAs deregulation and impairment of vascular repair capacities; (iii) alterations of coagulation, platelet reactivity, and microparticle release; (iv) epigenetic-driven transcription of ROS-generating and proinflammatory genes. Taken together these novel insights point to the development of mechanism-based therapeutic strategies as a promising option to prevent cardiovascular complications in diabetes.

Keywords: Diabetes; Pathophysiology; Vascular disease.

Figure 1

Mechanisms of hyperglycemia-induced vascular damage. High intracellular glucose concentrations lead to PKC activation and subsequent ROS production by NADPH oxidase and p66^Shc adaptor protein. Increased oxidative stress rapidly inactivates NO leading to formation of the pro-oxidant ONOO⁻ responsible for protein nitrosylation. Reduced NO availability is also due to PKC-dependent eNOS deregulation. Indeed, PKC triggers enzyme up-regulation thus enhancing eNOS uncoupling and leading to a further accumulation of free radicals. On the other hand, hyperglycemia reduces eNOS activity blunting activatory phosphorylation at Ser1177. Together with the lack of NO, glucose-induced PKC activation causes increased synthesis of ET-1 favouring vasoconstriction and platelet aggregation. Accumulation of superoxide anion also triggers up-regulation of pro-inflammatory genes MCP-1, VCAM-1, and ICAM-1 via activation of NF-kB signalling. These events lead to monocyte adhesion, rolling, and diapedesis with formation of foam cells in the sub-endothelial layer. Foam cell-derived inflammatory cytockines maintain vascular inflammation as well as proliferation of smooth muscle cells, accelerating the atherosclerotic process. Endothelial dysfunction in diabetes also derives from increased synthesis of TXA₂ via up-regulation of COX-2 and inactivation of PGIS by increased nitrosylation. Furthermore, ROS increase the synthesis of glucose metabolite methylglyoxal leading to activation of AGE/RAGE signalling and the pro-oxidant hexosamine and polyol pathway flux. PKC, protein kinase C; eNOS, endothelial nitric oxide synthase; ET1, endothelin 1; ROS, reactive oxygen species; NO, nitric oxide; MCP-1, monocyte chemoattractant protein-1; VCAM-1, vascular cell adhesion molecule-1; ICAM-1, intracellular cell adhesion molecule-1; AGE, advanced glycation end product.

Figure 2

Insulin resistance as trigger of atherothrombosis. In subjects with obesity or type 2 diabetes the increase in FFA activates TLR leading NF-kB nuclear translocation and subsequent up-regulation of inflammatory genes IL-6 and TNF-α. On the other hand, JNK and protein kinase C phosphorylate insulin receptor substrate-1 (IRS-1), thus blunting its downstream targets PI3-kinase and Akt. This results in down-regulation of glucose transporter GLUT-4 and, hence, insulin resistance. Impaired insulin sensitivity in the vascular endothelium leads to increased FFA oxidation, ROS formation, and subsequent activation of detrimental biochemical pathways such as AGE synthesis, PKC activation, protein glicosylation as well as down-regulation of PGI2. These events blunt eNOS activity thereby leading to endothelial dysfunction. Lack of insulin signalling in platelets impairs the IRS1/PI3K pathway resulting in Ca²⁺ accumulation and increased platelet aggregation. FFA, free fatty acids; TLR, toll-like receptor; JNK, c-Jun amino-terminal kinase; IRS-1, Insulin receptor substrate-1; NO, nitric oxide; eNOS, endothelial nitric oxide shyntase; IL-6, interleukin-6; TNF-α, tumor necrosis factor.

Figure 3

MicroRNAs involved in diabetic vascular disease. Schematic representation of microRNAs and their relative targets contributing to reduced vascular repair and, hence, diabetes-related vascular dysfunction. VEGF, vascular endothelial growth factor; IGF-1, insulin-like growth factor-1; ECs, endothelial cells; AGEs, advanced glycation end-products.

Figure 4

Coagulation and platelet reactivity in diabetes. In patients with diabetes chronic hyperglycemia and insulin resistance determine a significant alteration in the coagulation factors as well as increased platelet aggregation, leading to a prothrombotic state. Diabetes-induced increase of TF levels activates thrombin converting fibrinogen into fibrin. Fibrin organization is further enhanced due to high PAI-1 and reduced t-PA levels. Increased Ca²⁺ content, thrombin stimulation as well as interaction with vWF via gpIIb/IIIa receptor lead to platelet shape change, granule release, and aggregation. Release of MPs from injured endothelium and circulating platelets contribute to accelerate thrombus development. Endothelial dysfunction precipitates rupture of the endothelial layer leading to exposure of collagen and vWF thereby activating platelets and favouring vascular thrombosis. TF, tissue factor; t-PA, tissue plasminogen activator; PAI-1, plasminogen activator inhibitor -1; MPs, microparticles; vWF, von Willebrand factor; ECs, endothelial cells.

Figure 5

Intracellular signalling of vascular hyperglycemic memory. Hyperglycemia causes a deregulation of SIRT1 resulting in increased acetylation of histone 3-binding p66^Shc promoter. Together with these changes, hypomethylation of p66^Shc promoter leads to persistent overexpression of the adaptor protein despite glucose normalization. SIRT1 down-regulation also causes increased p53 activation further promoting p66^Shc gene transcription. Overexpression of p66^Shc causes mitochondrial ROS accumulation leading to vascular apoptosis, vascular inflammation (Set7/9-dependent methylation of p65 promoter and expression of inflammatory genes) and endothelial dysfunction via a detrimental vicious cycle involving ROS, PKCβ₂ and eNOS inhibiting phosphorylation at Thr-495. H3, histone 3; ROS, reactive oxygen species; PKCβII, protein kinase C βII; NO, nitric oxide; MCP-1, monocyte chemoattractant protein 1; VCAM-1, vascular cell adhesion molecule 1.