Core Messages

¥Diabetic retinopathy is a leading cause of vision loss in the working population of developed countries.

¥Changes in retinal haemodynamics have been proposed to play a key role in the initiation and progression of diabetic retinopathy.

¥Substantial evidence suggests that there is an early reduction in retinal perfusion prior to the onset of diabetic retinopathy followed by a gradual increase in blood ßow as the disease progresses.

¥Twomajormechanismshavebeenproposed to explain how hyperglycaemia decreases retinal blood ßow in early diabetes, namely, protein kinase C (PKC) activation and ion channel dysfunction in the contractile mural cells of retinal microvessels.

¥The functional reduction in retinal blood ßow observed during early diabetic retin-

T.M. Curtis, Ph.D. ( )

Centre for Vision and Vascular Sciences School of Medicine, Dentistry and Biomedical Sciences,

The QueenÕs University of Belfast, Institute of Clinical Science - Block A, Royal Victoria Hospital,

Grosvenor Road, Belfast, Northern Ireland BT12 6BA, UK e-mail: t.curtis@qub.ac.uk

T.A. Gardiner, Ph.D.

Centre for Biomedical Sciences Education, School of Medicine, Dentistry and Biomedical Sciences, The QueenÕs University of Belfast, Whitla Medical Building, 97 Lisburn Road, Belfast, Northern Ireland BT9 7B, UK e-mail: t.gardiner@qub.ac.uk

opathy may be additive or synergistic to pro-inßammatory changes, leukostasis and vaso-occlusion and thus may be intimately linked to the progressive ischaemic hypoxia and increased blood ßow associated with later stages of the disease.

¥A unifying haemodynamic framework is presented that explains how changes in retinal perfusion may contribute to the microvascular lesions and vision loss in diabetic retinopathy.

¥Large-scale prospective studies are currently needed to determine whether retinal blood ßow measurements may be useful as a surrogate end point for clinical drug trials in diabetic retinopathy.

15.1Introduction

Diabetes mellitus is a condition of chronic hyperglycaemia and is currently classiÞed into two main forms. Type 1 diabetes is due primarily to autoimmune-mediated destruction of pancreatic- b-cell islets, resulting in absolute insulin deÞciency. People with type 1 diabetes are usually younger than 30 years old at diagnosis and are dependent on continuing supplemental insulin. Type 2 diabetes is a metabolic disorder normally of middle-life characterised by insulin resistance and/or abnormal insulin secretion, either of which may predominate. People with type 2 diabetes

are not usually dependent on exogenous insulin but may require it for control of blood glucose levels if this is not achieved with diet alone or with oral hypoglycaemic agents.

Diabetes is associated with a number of complications which share an aetiology that is, at least in part, vascular. As a consequence of microvascular pathology, diabetes is a leading cause of blindness, end-stage renal disease and a variety of debilitating neuropathies. Macrovascular complications manifest themselves as accelerated atherosclerosis resulting in an increased risk of myocardial infarction, stroke and limb amputation. Diabetes is increasing at a startling rate and consequently imposes an everincreasing burden on health-care authorities in both developed and developing countries. The global Þgure of people with diabetes is set to rise from the present estimate of 150Ð220 million in 2010 and 300 million in 2025 [13, 110]. Most cases will be of type 2 diabetes, which is strongly associated with sedentary lifestyle and obesity [199].

Retinopathy is one of the most common microvascular complications of diabetes [10]. After 20 years of diabetes, nearly all patients with type 1 diabetes will have at least some retinopathy. Approximately 80% of type 2 diabetic patients who require insulin and 50% type 2 diabetic patients who do not require insulin will have retinopathy after 20 years [111]. Although the pathogenic basis of diabetic retinopathy is not wholly understood at the cellular and molecular level, large-prospective clinical studies have demonstrated a strong relationship between time-averaged mean levels of glycaemia and the rate of development of retinopathy in both type 1 and type 2 diabetes [1, 3].

Diabetic retinopathy is traditionally regarded as disease of the intra-retinal microvessels and is generally classiÞed into two main clinical forms: non-proliferative diabetic retinopathy and proliferative diabetic retinopathy. Mild non-proliferative diabetic retinopathy (background retinopathy) and severe proliferative retinopathy represent different ends of a spectrum of the same disease process. Non-proliferative diabetic retinopathy is characterised by a complex array of vasodegenerative lesions within the retinal microvascular bed, including thickening of capillary basement membranes [77], pericyte and vascular smooth muscle cell dropout [81, 123], microaneurysms [34] and

capillary occlusion and acellularity [67]. Visual impairment normally occurs in the later stages of diabetic retinopathy with the development of macula oedema as a direct consequence of bloodretinal barrier breakdown. In the proliferative phase of the disease, there is an abnormal growth of new blood vessels (retinal neovascularisation) that give rise to sight-threatening complications such as vitreous haemorrhage and tractional retinal detachment [76]. Arguably, both macular oedema and retinal neovascularisation occur as a result of increasing inner retinal ischaemia and hypoxia-driven secretion of vascular endothelial growth factor (VEGF). Sight-threatening diabetic retinopathy can be treated or contained to some extent by laser photocoagulation or vitreoretinal surgery, but this is often at the expense of functional retina and visual performance [79]. The use of VEGF-blocking agents has shown efÞcacy in both of these sight-threatening sequelae, but the underlying vascular insufÞciency may compromise retinal cell survival [148].

While there is no doubt that hyperglycaemia is the primary insult in the pathogenesis of diabetic retinopathy [1, 3], haemodynamic factors have also been implicated in the development of this condition. This chapter begins by providing an overview of the haemodyamic changes that occur in the retina during the development of diabetic retinopathy. Attention is also given to the pathophysiological mechanisms that have been proposed to underlie these alterations. The remainder of the chapter is then devoted to describing how retinal blood ßow changes in diabetes may contribute the sight-threatening lesions of diabetic retinopathy. From these discussions, it is clear that treatments designed to normalise retinal blood ßow during early and long-term diabetes may provide a novel means of delaying the onset and progression of this devastating condition.

15.2Retinal Blood Flow in Diabetes

The earliest suggestion that retinal blood ßow may be disrupted in diabetes came from studies performed over 60 years ago showing that dilation of retinal veins is common in persons