Molecular mechanisms of diabetic vascular complications

Abstract

Diabetic complications are the major causes of morbidity and mortality in patients with diabetes. Microvascular complications include retinopathy, nephropathy and neuropathy, which are leading causes of blindness, end-stage renal disease and various painful neuropathies; whereas macrovascular complications involve atherosclerosis related diseases, such as coronary artery disease, peripheral vascular disease and stroke. Diabetic complications are the result of interactions among systemic metabolic changes, such as hyperglycemia, local tissue responses to toxic metabolites from glucose metabolism, and genetic and epigenetic modulators. Chronic hyperglycemia is recognized as a major initiator of diabetic complications. Multiple molecular mechanisms have been proposed to mediate hyperglycemia's adverse effects on vascular tissues. These include increased polyol pathway, activation of the diacylglycerol/protein kinase C pathway, increased oxidative stress, overproduction and action of advanced glycation end products, and increased hexosamine pathway. In addition, the alterations of signal transduction pathways induced by hyperglycemia or toxic metabolites can also lead to cellular dysfunctions and damage vascular tissues by altering gene expression and protein function. Less studied than the toxic mechanisms, hyperglycemia might also inhibit the endogenous vascular protective factors such as insulin, vascular endothelial growth factor, platelet-derived growth factor and activated protein C, which play important roles in maintaining vascular homeostasis. Thus, effective therapies for diabetic complications need to inhibit mechanisms induced by hyperglycemia's toxic effects and also enhance the endogenous protective factors. The present review summarizes these multiple biochemical pathways activated by hyperglycemia and the potential therapeutic interventions that might prevent diabetic complications. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00018.x, 2010).

Keywords: Diabetes mellitus; Diabetic complications; Endogenous protective factors.

Figure 1

Mechanisms by which hyperglycemia induced diabetic vascular complications. ET‐1, endothelin‐1; NADPH, nicotinamide adenine dinucleotide phosphate; PDGF, platelet‐derived growth factor; TGF‐β, transforming growth factor‐β; VEGF, vascular endothelial growth factor.

Figure 2

Outline for mechanisms of diabetic retinopathy. (A) Activation of protein kinase C (PKC)‐β in retinal endothelial cells contributes to increased vascular permeability and formation of microaneurisms. (B) Activation of PKC‐δ induce retinal pericytes apoptosis through activation of nuclear factor‐κB (NF‐κB) by oxidative stress and activating Src homology‐2 domain containing phosphatase‐1 (SHP‐1) to inhibit platelet‐derived growth factor’s (PDGF) survival actions. Akt, protein kinase B; ERK, extracellular signal regulated kinase; ET‐1, endothelin‐1; MAPK, mitogen activated protein kinase; NADPH, nicotinamide adenine dinucleotide phosphate; PDGF, platelet‐derived growth factor; ROS, reactive oxygen species; TGF‐β, transforming growth factor‐β; VEGF, vascular endothelial growth factor.

Figure 3

Dual action of hyperglycemia to induce diabetic vascular complications. Induction of toxic pathways and inhibition of endogenous protective factors. AGE, advanced glycation end‐products; APC, activated protein C; NF‐κB, nuclear factor‐κB; PDFG, platelet‐derived growth factor; PKC, protein kinase C; ROS, reactive oxygen species; VEGF, vascular endothelial growth factor.