Pathogenetic mechanisms of diabetic microangiopathy

Abstract

Hyperglycaemia has been shown to play a central role in diabetic microangiopathy, together with the individual background. The pathogenetic sequence is initiated by a series of interrelated biochemical abnormalities associated with hyperglycaemia, including increased flux through the polyol and hexosamine pathways, oxidative stress, AGE formation and protein kinase C (PKC) activation. These abnormalities are capable of modifying the production pattern of several autocrine/paracrine factors by resident and nonresident cells of the tissues. These changes impair the vessel wall turnover, thus leading to an abnormal vascular remodelling, characterised by altered cell and matrix turnover and contacts, vascular tone and permeability and coagulation pattern, with distinct features depending on the target tissue. The hallmark of nephropathy is an abnormal extracellular matrix (ECM) accumulation within the mesangium, sustained by an upregulation of TGF-β, possibly triggered by a local activation of the renin–angiotensin system, whereas the characteristic alteration of retinopathy is retinal ischaemia due to the formation of acellular capillaries and triggering of a process of vascular endothelial growth factor (VEGF)-dependent neovascularization. This response is very active, but leads to the formation of noncompetent vessels, at variance with macrovascular disease, characterised by an impaired angiogenic response, with generation of competent vessels, potentially compensating for reduced flow.