Current Pharmaceutical Design - Volume 11, Issue 18, 2005

Diabetic vascular complication is a leading cause of end-stage renal failure, acquired blindness, a variety of neuropathies and accelerated atherosclerosis, which could account for disabilities and high mortality rates in patients with diabetes. Recent large prospective clinical studies have shown that intensive glucose control reduces effectively microvascular complications among patients with diabetes, and insulin resistance and postprandial hyperglycemia seem to be involved in diabetic macrovascular complications. Chronic hyperglycemia is a major initiator of diabetic vascular complications. Indeed, high glucose, via various mechanisms such as increased production of advanced glycation end products, activation of protein kinase C, stimulation of the polyol pathway and enhanced reactive oxygen species generation, regulates vascular inflammation, altered gene expression of growth factors and cytokines, and platelet and macrophage activation, thus playing a central role in the development and progression of diabetic vascular complications. This article summarizes the molecular mechanisms of diabetic vascular complications and the potential therapeutic interventions that may prevent these disorders even in the presence of hyperglycemia, control of which is often difficult with current therapeutic options.

Studies over the last decade have revealed impairment of the microcirculation in the diabetic foot. Endothelial dysfunction along with derangements in numerous biochemical pathways has been implicated as causes of microcirculation impairment. Additionally, reduction or absence of the nerve-axon reflex renders the diabetic foot unable to mount a vasodilatory response under conditions of stress, such as injury or infection and makes it functionally ischemic even in the presence of satisfactory blood flow under normal conditions. Furthermore, these changes appear to be directly related to the presence of diabetic neuropathy. These alterations in the diabetic microcirculation may explain the poor wound healing commonly observed in diabetes.

Angiogenic eye disease is among the most common causes of blindness worldwide. Current treatment approaches are insufficiently effective and partially associated with significant adverse effects. From an investigational view, the eye provides an ideal setting to observe real-time and serial observations of angiogenesis in vivo in humans. The current understanding of molecular biology involved in angiogenesis has already led to the identification of a number of potential therapeutic targets, some of them being highly effective angiostatic molecules. Most experimental approaches currently favour or even require the systemic administ-ration of the investigated substances (somatostatin analogues, PKC-inhibitors). However, the systemic administration of bioactive substances always risks significant systemic adverse effects. Due to the morphological characteristics of the eye, local therapies including intraocular injection or even local gene transfer might be feasible. They might provide a valuable opportunity of targeted and sustained delivery of therapeutic proteins to the retina. This review aims to outline the current understanding of the pathogenesis of proliferative diabetic retinopathy and will focus on some as yet experimental, but potentially effective new therapeutic possibilities of this disease.

Blood platelets play a crucial role in physiological haemostasis and in pathology of prothrombotic states, including atherosclerosis. In this paper, we review major factors underlying altered platelet reactivity, with special attention paid to abnormalities in platelet function in people with diabetes mellitus (DM). The overall picture of platelet abnormalities in DM, including altered adhesion and aggregation, is hypersensitivity of diabetic platelets to agonists. “Primed” diabetic platelets respond more frequently even to subthreshold stimuli, sooner become exhausted, consumed and finally hyposensitive, thus contributing to accelerated thrombopoiesis and release of 'fresh' hyperreactive platelets. In diabetes disturbed carbohydrate and lipid metabolism may lead to physicochemical changes in cell membrane dynamics, and consequently result in altered exposure of surface membrane receptors. These phenomena, together with increased fibrinogen binding, prostanoid metabolism, phosphoinositide turnover and calcium mobilisation often present in diabetic patients, contribute to enhanced risk of small vessel occlusions and accelerated development of atherothrombotic disease of coronary, cerebral and other vessels in diabetes. As platelet hypersensitivity in DM makes a major contribution to enhanced risk of thromboembolic macroangiopathy, and consequently enhanced morbidity and mortality, it validates use of antiplatelet agents in diabetic individuals. Platelet hyperreactivity may be cured with various antiplatelet drugs to a considerably large extent notwithstanding, evidence gathered from clinical and experimental surveys shows that this approach may not always be equally efficient in people with diabetes. Observations from clinical studies rather support the use of multifactorial strategy under such circumstances, like a combined therapy of aspirin plus either purinoreceptor blocker or GPIIb-IIIa antagonist.

Endothelial dysfunction is an early sign of diabetic vascular disease. Due to their unique position at the border between blood and vascular tissue, endothelial cells (EC) are the first vascular cells to sensor humoral changes, and they are able to transmit the information about these changes to other vascular cell types by changing their gene expression profile and producing growth factors, cytokines, adhesion molecules, and other bioactive molecules. These signals alter vascular cell dynamics and interactions, vascular tone and result in inability of the vessel to maintain athrombogenic luminal surface and in alteration of vascular permeability. Although researchers have yet to uncover the precise mechanism(s) that leads to diabetic vascular disease, hyperglycemia has been identified as an independent risk factor for micro- and macrovascular complications. Elevated levels of glucose induce the expression of a variety of genes related to atherogenesis and angiogenesis regulation. However, most of our current knowledge about the molecular mechanisms used by glucose to regulate gene expression is based on studies that used cells with insulin-dependent glucose transport (hepatocytes, adipocytes). Such cells are significantly different than vascular cells, in which glucose uptake is mostly imparted by insulin-independent mechanisms. This review summarizes current information about the effects of hyperglycemia and elevated glucose in in vitro systems on vascular gene expression and molecular transcriptional and post-transcriptional mechanisms that may regulate the changes related to diabetic vascular complications.

The endothelium represents an important therapeutic target for containment of oxidative stress, thrombosis and inflammation involved in a plethora of acute and chronic conditions including cardiovascular and pulmonary diseases and diabetes. However, rapid blood clearance and lack of affinity to the endothelium compromise delivery to target and restrict medical utility of antioxidant enzymes (e.g., catalase) and fibrinolytics. The use of “stealth” PEG-liposomes prolongs circulation, whereas conjugation with antibodies to endothelial determinants permits targeting. Constitutive endothelial cell adhesion molecules (CAM, such as ICAM-1 and PECAM-1, which are stably expressed and functionally involved in oxidative stress and thrombosis) are candidate determinants for targeting of antioxidants and fibrinolytics. CAM antibodies and compounds conjugated with anti-CAM bind to endothelial cells and accumulate in vascularized organs (preferentially, lungs). Pathological stimuli enhance ICAM-1 expression in endothelial cells and facilitate targeting, whereas PECAM-1 expression and targeting are stable. Endothelial cells internalize 100-300 nm diameter conjugates possessing multiple copies of anti-CAM, but not monomolecular antibodies or micron conjugates. This permits size-controlled sub-cellular targeting of antioxidants into the endothelial interior and fibrinolytics to the endothelial surface. Targeting catalase to PECAM-1 or ICAM-1 protects endothelial cells against injury by oxidants in culture and alleviates vascular oxidative stress in lungs in animals. Anti-CAM/catalase conjugates are active for a few hours prior to lysosomal degradation, which can be delayed by auxiliary drugs. Conjugation of fibrinolytics to monovalent anti-ICAM permits targeting and prolonged retention on the endothelial surface. Therefore, CAM targeting of antioxidants and fibrinolytics might help to contain oxidative and thrombotic stresses, with benefits of blocking CAM. Avenues for improvement and translation of this concept into the clinical domain are discussed.