Diabetic retinopathy is a common cause of blindness in individuals younger than 60 years. Screening for retinopathy is undertaken using conventional color fundus photography and relies on the identification of hemorrhages, vascular abnormalities, exudates, and cotton-wool spots. These can sometimes be difficult to identify.

Multicolor scanning laser imaging, a new imaging modality, may have a role in improving screening outcomes, as well as facilitating treatment decisions.

Observational case series comprising two patients with known diabetes who were referred for further examination after color fundus photography revealed abnormal findings. Multicolor scanning laser imaging was undertaken. Features of retinal disease from each modality were compared.

Multicolor scanning laser imaging provides superior visualization of retinal anatomy and pathology, thereby facilitating risk stratification and treatment decisions.

Multicolor scanning laser imaging is a novel imaging technique offering the potential for improving the reliability of screening for diabetic retinopathy. Validation studies are warranted.

New data have emerged over the last few years about the role of fibrates in treatment of microvascular and macrovascular disease.

Endpoint studies have been conducted with fibrates in coronary heart disease (CHD) since 1971 and initial results were contradictory. Fibrates later showed benefits in patients with low HDL-C and low LDL-C. The prominence ascribed to the lipid triad of the metabolic syndrome and the increasing prevalence of diabetes has increased the topicality of fibrates given their main action of converting small dense to light buoyant LDL. The Fenofibrate Intervention in Endpoint Lowering in Diabetes (FIELD) study has carried on the tradition. Fenofibrate therapy in 9795 patients comprising a mixed low-risk primary and a medium-risk secondary prevention cohort resulted in an 11% reduction in coronary events (P = 0.16), a similar but significant reduction in cardiovascular events (P = 0.04; number-needed-to-treat = 70). The benefits were concentrated in primary prevention and on nonfatal myocardial events, and post-hoc greater effects were seen in patients with moderate hypertriglyceridaemia (>2.3 mmol/l) and low HDL-C, as had previously been noted in a trial with bezafibrate. Safety was generally good, including in combination with statins, but old concerns about sudden death, pancreatitis and venous thrombosis returned. Unexpected benefits were seen with fenofibrate for microvascular endpoints including microalbuminuria and retinopathy.

Fenofibrate and bezafibrate are reasonable second-line therapies for dyslipidaemia and in diabetes, and well tolerated in combination therapy. The benefits of fenofibrate for microvascular disease and its potential role in combination therapy require further confirmation.

The global pandemic of diabetes mellitus portends an alarming rise in the prevalence of microvascular complications, despite advanced therapies for hyperglycemia, hypertension and dyslipidemia. Peroxisome proliferator-activated receptor alpha (PPARalpha) is expressed in organs affected by diabetic microvascular disease (retina, kidney and nerves), and its expression is regulated specifically in these tissues. Experimental evidence suggests that PPARalpha activation attenuates or inhibits several mediators of vascular damage, including lipotoxicity, inflammation, reactive oxygen species generation, endothelial dysfunction, angiogenesis and thrombosis, and thus might influence intracellular signaling pathways that lead to microvascular complications. PPARalpha has emerged as a novel target to prevent microvascular disease, via both its lipid-related and lipid-unrelated actions. Despite strong experimental evidence of the potential benefits of PPARalpha agonists in the prevention of vascular damage, the evidence from clinical studies in patients with diabetes mellitus remains limited. Promising findings from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study on microvascular outcomes are countered by elevations in participants' homocysteine and creatinine levels that might potentially attenuate the benefits of PPARalpha activation. This Review focuses on the role of PPARalpha activation in diabetic microvascular disease and highlights the available experimental and clinical evidence from studies of PPARalpha agonists.

New data have emerged over the last few years about the role of fibrates in treatment of microvascular and macrovascular disease.

Endpoint studies have been conducted with fibrates in coronary heart disease since 1971 and results have been contradictory. Fibrates have shown benefits in patients with low HDL-cholesterol and low LDL-cholesterol. Fibrates remain topical, given their actions on the lipid triad present in the metabolic syndrome and in diabetes. In the Fenofibrate Intervention in Endpoint Lowering in Diabetes study of mixed primary and secondary prevention cohorts, fenofibrate therapy resulted in an 11% reduction in coronary or cardiovascular events in monotherapy. Despite frequent use, there was little endpoint data on fibrate-statin combination therapy until recently. The Action to Control Cardiovascular Risk in Diabetes trial of fenofibrate added to baseline simvastatin therapy in diabetes showed a nonsignificant 8% reduction in cardiovascular events. The benefits were concentrated in men, and women did slightly worse with fibrate therapy. In post-hoc analysis, slight beneficial effects of fenofibrate were seen in patients with moderate hypertriglyceridaemia (>2.3 mmol/l) and low HDL-cholesterol (<0.88 mmol/l). The safety profile of fibrate-simvastatin combination was good.

Fenofibrate and bezafibrate are reasonable second-line therapies for dyslipidaemia and in diabetes. They are safe in combination therapy with statins but add little endpoint benefit except possibly in patients with a significant degree of atherogenic dyslipidaemia (high triglycerides and low HDL-cholesterol). The benefits of fibrates on microvascular disease remain to be fully explored.

Proliferative diabetic retinopathy is the main cause of vision loss in young and middle-aged adults. There is no accepted pharmaceutical therapy for this disease, although analogs of the naturally occurring growth hormone inhibitor, somatostatin, have been considered leading candidates for developing such therapies. This review examines the history of somatostatin analogs, especially octreotide, in the treatment of ocular complications of diabetes mellitus. The historical observations that indicated a role for somatostatin in retinopathy are discussed from an endocrinology perspective. The molecular mechanisms by which somatostatin may exert its anti-angiogenic effects, both indirect (through antagonism of the growth hormone axis) and direct (through direct antiproliferative and apoptotic effects on endothelial cells mediated by specific receptor subtypes) are described. Animal models that were used to demonstrate an anti-angiogenic effect of octreotide are detailed, as are the results of numerous clinical trials that used octreotide and other somatostatin analogs to treat diabetic retinopathy. The mixed results of these clinical results are examined along with possible explanations as to why these analogs both have and have not shown efficacy in limited clinical settings. Even with these mixed results, somatostatin analogs remain the only therapeutic alternative to patients with proliferative diabetic retinopathy who have failed to respond to panretinal photocoagulation.

Diabetic retinopathy (DR) is the most severe of several ocular complications of diabetes. The earliest clinical signs of DR are microaneurysms and haemorrhages. Later signs include dilated, tortuous irregular veins and retinal non-profusion, leading to retinal ischaemia that ultimately results in neovascularisation. Diabetic macular oedema, which involves the breakdown of the blood-retinal barrier, also occurs and is responsible for a major part of vision loss, particularly in Type 2 diabetes. The pathogenesis of DR is very complex. Many biochemical mechanisms have been proposed as explanations for the development and progression of DR. Chronic hyperglycaemia leads to oxidative injury, microthrombi formation, cell adhesion molecule activation, leukostasis and cytokine activation. Next, ischaemia-mediated overexpression of growth factors and cytokines occurs. These factors include vascular endothelial growth factor, insulin-like growth factor-1, angiopoetin-1 and -2, stromal-derived factor-1, fibroblast growth factor-2 and tumour necrosis factor. Because of the complex interplay between these factors, targeting a single growth factor will be unlikely to result in therapeutic inhibition of angiogenesis. These growth factors no doubt act in synergy to mediate the steps of angiogenesis, including protease production, endothelial cell proliferation, migration and tube formation. This review attempts to provide an overview of perspectives regarding the pathogenesis of this disease. The focus, however, is on describing the unique features of selected relevant factors and how each growth factor may act in a synergistic manner with other factors.

To verify the clinical correlation between retinopathy progression and the change of venous filling time (VFT), measured before and after panretinal photocoagulation (PRP), in proliferative diabetic retinopathy (PDR) patients.

We conducted this study on 32 patients (32 eyes) who received PRP for PDR. These patients were subdivided into two groups in accordance with the clinical course of PRP: the stabilized group in which retinal neovascularization was regressed and the progressed group in which retinal neovascularization was continued and a complication, such as vitreous hemorrhage or tractional retinal detachment, was developed within 12 months of laser treatment. Arteriovenous passage time (AVP) and VFT were measured by video fluorescein angiogram (FAG) using scanning laser ophthalmoscope (SLO) before and after PRP. VFT values were assigned by measuring by the time duration from start of venous lamina flow to the fullness of fluorescence on the vascular arch.

In the stabilized group, AVP was decreased by 0.20 +/- 0.89 sec and VFT was decreased by 0.30 +/- 1.69 sec through PRP. In the progressed group, AVP was increased in 0.12 +/- 1.22 sec and VFT was increased by 0.99 +/- 1.60 sec through PRP. In both groups, the VFT changes were significant (P=0.04) but the AVP changes were not (P=0.34).

VFT was significantly decreased in the stabilized group and significantly increased in the progressed group after PRP. Accordingly, we suggest that VFT changes after PRP can be utilized as a prognostic indicator for evaluating clinical course of diabetic retinopathy after performing PRP and for monitoring the clinical effect of PRP.

In diabetic eye disease the factors leading to compromised circulation and the resulting loss of visual function are poorly understood. Although retinal circulation has been widely investigated, it accounts for only a fraction of total eye blood flow. Blood flow was investigated in the larger vessels feeding the eye in patients with early diabetic retinopathy.

Eleven patients with early diabetes with minimal or no retinopathy and 11 healthy controls were evaluated for retrobulbar blood flow velocity using colour Doppler imaging for the ophthalmic and central retinal arteries. Patients and subjects were tested while breathing room air and again under conditions of isocapnic hyperoxia.

Hyperoxia induced a significant change in the central retinal artery end diastolic velocity (EDV) (p = 0.008) and resistance index (RI) (p = 0.032) in normal subjects, but not in diabetic patients. Consequently, during hyperoxia, the diabetic patients were significantly higher for EDV (p = 0.006) and significantly lower for RI (p = 0.002) compared with normal controls. Hyperoxia caused no significant change in either group in the ophthalmic artery; nevertheless, under isocapnic hyperoxia conditions the diabetic patients had lower peak systolic velocity (p = 0.05) and lower RI (p = 0.05) than normal subjects.

Imposition of isocapnic hyperoxia produces significant differences in the ophthalmic and central retinal artery blood flow velocities in diabetic patients with early disease when compared with normal subjects. These results demonstrate that diabetic patients with minimal or no retinopathy suffer from irregular ocular vascular function in the major vessels feeding the eye.

A cohort of 6792 NIDDM patients attending a diabetes centre at Madras in South India was screened using a combination of retinal photography and clinical examination by retinal specialists. A total of 2319 patients (34.1%) had evidence of retinopathy. This included 2090 patients (30.8%) with non-proliferative diabetic retinopathy including 435 patients (6.4%) with maculopathy and 229 patients (3.4%) with proliferative diabetic retinopathy. Multiple logistic regression analyses showed that duration of diabetes, glycosylated haemoglobin, type of treatment (insulin treatment versus non-insulin treatment), systolic and diastolic blood pressures and serum creatinine, showed a positive association with retinopathy while body mass index (BMI) showed an inverse association. The prevalence rates of retinopathy in Southern Indians are comparable to those seen in Europeans. However in view of the high prevalence of diabetes in the Indian sub-continent, diabetic retinopathy could become a formidable challenge in the future.

Long-term visual results in the first 124 consecutively vitrectomized eyes of 105 diabetic patients in our department were evaluated. The indications for vitrectomy were unresorbable vitreous haemorrhage (77 eyes, 62%) (group A), central traction retinal detachment (21 eyes, 17%) (group B), and a combination of both (26 eyes, 21%) (group C). Initially visual acuity (VA) improved at least by one category in 83 eyes (67%). The latest postoperative VA after the mean follow-up of 3.7 +/- 0.2 years was greater than = 0.3 in 36 eyes (29%), 0.1-0.25 in 15 eyes (12%), 0.05-0.08 in 9 eyes (7%), counting fingers (CF) 1-less than 3 m in 13 eyes (11%), and less than CF 1 m in 51 eyes (41%). The latest VA of 0.3 or better was significantly more common in group A (40%) than in group B (10%) or group C (12%) (P = 0.0087 and 0.0076, respectively). The most common causes of visual failure (VA less than C F 1m) were neovascular glaucoma and/or retinal detachment. At the latest follow-up visit 50% of the patients had VA of 0.3 or better, 16% were in the low-vision category, and 34% were blind (VA less than 0.05).

We used peripheral retinal cryopexy to treat 20 eyes in 15 patients with subtotal vitreous hemorrhage secondary to proliferative diabetic retinopathy. In 18 eyes, complete panretinal photocoagulation had been performed before the subtotal vitreous hemorrhage and the subsequent cryopexy. The length of follow-up averaged 16 months. The vitreous hemorrhage completely cleared in 11 eyes (55%) and partially cleared in six eyes (30%). Visual acuity after treatment improved in 13 eyes (65%), remained unchanged in six eyes (30%), and decreased in one eye (5%).

Using panretinal fluorescein angiography, three patterns (A, B, C) of capillary nonperfusion were identified in 308 eyes with proliferative diabetic retinopathy. Statistical analysis showed that there was a significant association with different retinal complications and clinical parameters. Pattern A (83.7%: midperipheral location of capillary nonperfusion) occurs in type I and II diabetes and is associated with early retinal neovascularization and focal macular edema. Pattern B (8.1%: capillary exclusions disseminated on the whole retina) is typical of young type-I diabetics and is complicated by early disc new vessels and ischemic maculopathy. Pattern C (8.1%: capillary nonperfusion confined to the peripheral retina) is observed in type-I diabetic females and associated with multiple, retinal new vessels, without maculopathy. This study also demonstrated that eyes with pattern B retinal ischemia respond less well to laser treatment than eyes with other pattern types. Various pathogenetic factors could lead to these three distinct types of proliferative diabetic retinopathy.

Problems related to general anaesthesia of 109 consecutive vitrectomies performed on diabetic patients were retrospectively reviewed. On the morning of surgery a normal or a slightly reduced dose of the patient's regular insulin was administered subcutaneously. The amount of intravenous infusion, mostly 5% glucose, was calculated according to the pre-operative urine volume. After surgery, hypoglycaemic (less than 3 mmol/l) values were seen in less than 11% of the patients, and high glucose in less than 30%; 20% had a mild ketoacidosis post-operatively. Difficulties in tracheal incubation was encountered in 10%. Three patients complained of chest pain after surgery, and in one of them a myocardial infarction was diagnosed. Forty-one per cent of the patients complained of nausea or vomited in the afternoon after surgery, and 21% had difficulties in urination the night after surgery. Two of four patients with peritoneal dialysis complained of stomach pain post-operatively. There was no significant association between recurrent vitreous haemorrhage and blood glucose concentration or arterial blood pressure in the early post-operative period.

Characteristics, and the occurrence of other diseases, and complications related to diabetes mellitus of 91 consecutive diabetic patients who underwent vitreous surgery in 1979-1985 were examined. The mean age of the patients was 40 years (median 37, range 19-74), and the mean duration of diabetes 23 years (range 5-44). All, but one, had insulin therapy. Abnormalities in the cardiovascular and/or renal function were found in 89 of the 91 patients (98%). Signs of cardiovascular disease were observed in 58 patients (64%): 42% had elevated blood pressure (greater than or equal to 150/100 mmHg), 46% were on antihypertensive therapy, 14% had a history or signs of ischaemic heart disease, 12% had been digitalized, 7% had a history of cerebral ischaemia, and 8% had had surgery for gangrene of the lower limb. Signs of nephropathy were recorded in 64 patients (70%); 6 of them were on dialysis therapy, and two had received a kidney transplant. Symptoms possibly related to autonomic neuropathy e.g. postural hypotension, urinary tract symptoms, and gastric discomfort were found in 27%. Nine patients (10%) had some kind of thyroid disease, and two of them signs of multiple autoimmune endocrinopathy. The percentage surviving decreased from 96% at one year to 80% after 5 years of follow-up.

A comparison was made of insulin secretion in response to i.v. glucose between noninsulin dependent diabetics with and without severe microangiopathy. During i.v. glucose tolerance testing those with complications had significantly lower serum insulin concentration (at 40 and 60 min 15.2 +/- 2.9 and 11.7 +/- 2.5 mU-1 respectively) than those without (26.1 +/- 4.7 and 24.3 +/- 3.6 mU-1, p less than 0.01). The differences were also significant when insulin increment above basal was determined. All subjects had raised plasma beta-thromboglobulin concentration (indicating increased tendency to platelet aggregation), but with no significant difference between the two groups. There was also no difference in fasting glucose, kg values, HbAl or blood viscosity. We conclude that non-insulin dependent diabetics with severe microangiopathy have significantly reduced insulin secretory capacity in response to i.v. glucose when compared with those without.

At present there is no simple, reliable and non-invasive method for monitoring progression and improvement in diabetic microangiopathy. However, some diabetic patients with severe microvascular complications show a fairly specific pattern of impaired left ventricular function (abnormal relaxation, cavity filling and wall thinning) and abnormalities of haemorheology (increased viscosity, erythrocyte rigidity and beta-thromboglobulin and decreased threshold for platelet ADP aggregation). A single-blind, 6-months' crossover study of an antiplatelet agent, ticlopidine, was conducted in 20 diabetics with clinical evidence of microvascular disease. Response to therapy was monitored by digitised M-mode echocardiographic analysis of left ventricular diastolic function and haemorheology. All patients had abnormal basal values with no significant change during the 3-month placebo run-in period but, although significant alterations in viscosity, erythrocyte deformability, beta-thromboglobulins and ADP threshold were observed, no change in left ventricular function was detected. It is concluded that, while it may be possible to alter abnormal haemorheology in diabetes, there was no change in one parameter of microvascular end-organ damage.

Retinal neovascularization is a serious complication of the retinopathy associated with diabetes, branch vein occlusion, sickle cell anemia, and retrolental fibroplasia. Retinal capillary nonperfusion, demonstrated on fluorescein angiography, precedes the development of neovascularization in each of these conditions. Our working hypothesis is that the nonperfused (ischemic or hypoxic) retina liberates a vasoproliferative or angiogenic substance. Although I have delineated the clinical and experimental observations relating to the hypothesis of an ischemic-mediated angiogenesis substance, other postulated mechanisms for the development of retinal neovascularization may be involved. Recent observations on the experimental model of retrolental fibroplasia have demonstrated the markedly abnormal persistence and apparent proliferation of the hyaloid vessels in mice following oxygen-induced retinal vascular closure.

The incidence of HLA antigens B8, BW15, DW3 and DW4 was found to be significantly increased in 99 patients with growth onset, insulin-dependent diabetes of more than 15 years duration. Different degrees of retinopathy were seen in 75% of the patients. No significant correlation between the presence of specific HLA alleles and the stage of retinopathy was found. We have discussed the possibility that all patients who develop diabetes have identical disease-predisposing genes, irrespective of their HLA alleles. If this was the case, the HLA phenotype would not determine the risk of developing diabetic retinopathy.

1. Levels of serum UDP-galactose:glycoprotein galactosyltransferase in 117 unselected diabetics were compared with those in 60 non-diabetic healthy controls. 2. Enzyme activity (mean +/- 2 S.D.) of control sera was found to be 90.2 +/- 21.5 etamoles/ml/hr at 37 degrees. In 30 of the 117 diabetic sera (26%) enzyme activity was elevated (greater than mean + 2 S.D. of the controls). Sixteen of 19 (84%) patients with retinopathy, 16 of 26 (62%) patients with peripheral vasculopathy and 13 of 26 (50%) patients with neuropathy had higher levels of serum enzyme. When serum enzyme levels of groups of diabetics with retinopathy, peripheral vasculopathy and neuropathy were compared with the enzyme level in all diabetics, there was a significant difference with p values of 0.001, 0.05 and 0.05 respectively.