15 th Golgi lecture: from hyperglycaemia to the dysregulation of vascular remodelling in diabetes

Abstract

Hyperglycaemia has been shown to play a central part in diabetic vascular disease, which is also influenced by individual background. Hyperglycaemia initiates the pathogenetic sequence through a series of interrelated biochemical abnormalities, including increased flux through the polyol and hexosamine pathways, oxidative stress, AGE formation and protein kinase C activation. These abnormalities are capable of modifying the function of resident and non-resident vascular cells by changing their production pattern of several autocrine and paracrine factors, including growth, vasoactive and coagulation factors and adhesion molecules. These mediators profoundly impair the physiologic turnover of the vessel wall, thus leading to an abnormal process of vascular remodelling, with alterations in cell and matrix turnover and contacts, vascular tone and permeability and coagulation pattern. This process has distinct features depending on the target tissue. The hallmark of nephropathy is an abnormal accumulation of extracellular matrix within the mesangium, sustained by an upregulation of TGF-b, possibly triggered by a local activation of the renin-angiotensin system. The central pathological lesion in retinopathy is retinal ischaemia due to the formation of acellular capillaries. The resulting vascular endothelial growth factor-dependent neovascularization is a detrimental phenomenon leading to the formation of noncompetent vessels. Conversely, in macrovascular disease, arterial occlusion resulting from plaque formation with superimposed thrombosis elicits an angiogenic response which is impaired, but generates competent vessels, potentially compensating for reduced flow. Thus, upstream interventions interrupting the pathogenetic sequence at the level of hyperglycaemia (and related biochemical events) are the most effective, whereas downstream interventions should be targeted to the tissue affected. [Diabetologia (2001) 44: 674±692]

Evaluation of Polyneuropathy Markers in Type 1 Diabetic Kidney Transplant Patients and Effects of Islet Transplantation

“…Previous works have already reported beneficial effects of islet transplantation on DPN (24,25), though there are relevant differences from our study. First, both of the above-mentioned studies included type 1 diabetic patients and not type 1 diabetic patients with ESRD.…”

“…In the secondary intervention cohort patients, i.e., those who had neuropathy at baseline (as in our population), although less severe, intensive therapy reduced the appearance of clinical neuropathy at 5 years by 57% (5). The injurious effect of chronic hyperglycemia on vessels and nerves has been attributed to various biochemical consequences of intracellular metabolism of excess glucose, including nonenzymatic glycation with formation of AGEs (24). AGEs are heterogeneous compounds originating from precursors formed both nonoxidatively and oxidatively; the latter group includes the monolysyl adduct CML, which has been detected in peripheral nerves from diabetic patients (25).…”

Vascular growth factor binding kinetics to the endothelial cell basement membrane, with a kinetics-based correction for substrate binding

“…Of particular interest is diabetes, which is marked by dysregulated angiogenesis throughout varied vascular beds. Advanced glycation end products increase both extracellular matrix and growth factor expression, perhaps contributing to the enhanced tissue VEGF observed in diabetic nephropathy and retinopathy (Di Mario and Pugliese 2001;Tsilibary 2003). In diabetic wounds, the precise cellular growth factor response required for efficient healing is disrupted either by altered growth factor concentrations or by unresponsive cells (Falanga 2005).…”

Metallothionein rescues hypoxia-inducible factor-1 transcriptional activity in cardiomyocytes under diabetic conditions

“…Sustained damage to endothelial cells by hyperglycemia ultimately leads to cell loss, reduced blood flow, hypoxia, and tissue ischemia [2,3]. Hypoxia-inducible factor-1 (HIF-1) is a transcriptional factor that functions as a major regulator of oxygen homeostasis.…”