Aims To determine the incidence of, and clinically relevant risk factors for, new foot ulceration in a large cohort of diabetic patients in the community healthcare setting.

Methods Diabetic patients (n = 9710) underwent foot screening in six districts of North-west England in various healthcare settings. All were assessed at baseline for demographic information, medical and social history, neuropathy symptom score, neuropathy disability score, cutaneous pressure perception (insensitivity to the 10 g monofilament), foot deformities, and peripheral pulses. Two years later, patients were followed up via postal questionnaire to determine the incidence of new foot ulcers. Cox’s proportional hazards regression analysis was used to determine the independent, relative risk of baseline variables for new foot ulceration.

Results New foot ulcers occurred in 291/6613 patients who completed and returned their 2-year follow-up questionnaire (2.2% average annual incidence). The following factors were independently related to new foot ulcer risk: ulcer present at baseline (relative risk (95% confidence interval)) 5.32 (3.71–7.64), past history of ulcer 3.05 (2.16–4.31), abnormal neuropathy disability score (≥ 6/10) 2.32 (1.61–3.35), any previous podiatry attendance 2.19 (1.50–3.20), insensitivity to the 10 g monofilament 1.80 (1.36–2.39), reduced pulses 1.80 (1.40–2.32), foot deformities 1.57 (1.22–2.02), abnormal ankle reflexes 1.55 (1.01–2.36) and age 0.99 (0.98–1.00).

Conclusions More than 2% of community-based diabetic patients develop new foot ulcers each year. The neuropathy disability score, 10 g monofilament and palpation of foot pulses are recommended as screening tools in general practice.

The North-West Diabetes Foot Care Study: incidence of, and risk factors for, new diabetic foot ulceration in a community-based patient cohort.

Endothelium-dependent vasodilation is impaired in humans with diabetes mellitus. Inactivation of endothelium-derived nitric oxide by oxygen-derived free radicals contributes to abnormal vascular reactivity in experimental models of diabetes. To determine whether this observation is relevant to humans, we tested the hypothesis that the antioxidant, vitamin C, could improve endothelium-dependent vasodilation in forearm resistance vessels of patients with non-insulin-dependent diabetes mellitus. We studied 10 diabetic subjects and 10 age-matched, nondiabetic control subjects. Forearm blood flow was determined by venous occlusion plethysmography. Endothelium-dependent vasodilation was assessed by intraarterial infusion of methacholine (0.3-10 micrograms/min). Endothelium-independent vasodilation was measured by intraarterial infusion of nitroprusside (0.3-10 micrograms/min) and verapamil (10-300 micrograms/min). Forearm blood flow dose-response curves were determined for each drug before and during concomitant intraarterial administration of vitamin C (24 mg/min). In diabetic subjects, endothelium-dependent vasodilation to methacholine was augmented by simultaneous infusion of vitamin C (P = 0.002); in contrast, endothelium-independent vasodilation to nitroprusside and to verapamil were not affected by concomitant infusion of vitamin C (P = 0.9 and P = 0.4, respectively). In nondiabetic subjects, vitamin C administration did not alter endothelium-dependent vasodilation (P = 0.8). We conclude that endothelial dysfunction in forearm resistance vessels of patients with non-insulin-dependent diabetes mellitus can be improved by administration of the antioxidant, vitamin C. These findings support the hypothesis that nitric oxide inactivation by oxygen-derived free radicals contributes to abnormal vascular reactivity in diabetes.

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Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus.

Diabetic retinopathy is a leading cause of adult vision loss and blindness. Much of the retinal damage that characterizes the disease results from retinal vascular leakage and nonperfusion. This study shows that diabetic retinal vascular leakage and nonperfusion are temporally and spatially associated with retinal leukocyte stasis (leukostasis) in the rat model of streptozotocin-induced diabetes. Retinal leukostasis increases within days of developing diabetes and correlates with the increased expression of retinal intercellular adhesion molecule-1 (ICAM-1). ICAM-1 blockade with a mAb prevents diabetic retinal leukostasis and vascular leakage by 48.5% and 85.6%, respectively. These data identify the causal role of leukocytes in the pathogenesis of diabetic retinopathy and establish the potential utility of ICAM-1 inhibition as a therapeutic strategy for the prevention of diabetic retinopathy.

https://www.pnas.org/content/pnas/96/19/10836.full.pdf

Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion molecule-1 inhibition

The glyoxalase system in health and disease.

Capillary occlusions are characteristic features of the early diabetic retinopathy and are presumed to initiate neovascularization. Activated leukocytes can cause microvascular occlusions and cell damage by release of cytotoxic products. To explore the role of leukocytes in capillary occlusion, nonperfusion, and neovascularization of diabetic retinopathy, a rat model was used, in which a diabetic state was induced by alloxan. Retina flat preparations were differentially stained for monocytes and granulocytes. Capillary occlusion, nonperfusion, and neovascularization were assessed microscopically in the center, midperiphery, and periphery of the retina. In contrast to control retinas, 2- to 9-month diabetic rats showed many capillary occlusions by leukocytes, especially monocytes, endothelial cell damage, extravascular macrophage accumulation, and tissue damage. The percentage of activated monocytes and granulocytes in the circulating blood of diabetic rats was greatly increased, and areas of capillary 'loss' and neovascularization in the retina coincided with sites of extravascular leukocytes. The authors' results suggest a potential role of monocytes and macrophages in the pathogenesis of diabetic retinopathy.

Activated monocytes and granulocytes, capillary nonperfusion, and neovascularization in diabetic retinopathy.

Polymorphonuclear neutrophils' chemotaxis, surface charge, superoxide anions generation, NBT (nitro blue tetrazolium) reduction and intracellular lysozyme, and beta-glucuronidase content were estimated in patients with type I diabetes mellitus in a similar state of metabolic control. The chemotaxis of diabetic cells toward bacterial chemotactic factors was similar to controls, whereas migration toward complement-derived chemoattractants was significantly reduced. Polymorphonuclear neutrophils isolated from diabetic patients, when unstimulated, produced significantly greater amounts of superoxide anions and reduced NBT more efficiently. They also revealed reduced surface charge and lower intracellular content of lysozyme, whereas beta-glucuronidase content was similar to controls. The results obtained seem to indicate that neutrophils in patients with insulin-dependent diabetes manifest signs of being in the activated state. The possible mechanisms of such stimulation are discussed.

Evidence of polymorphonuclear neutrophils (PMN) activation in patients with insulin-dependent diabetes mellitus.

Metabolic control quality and free radical activity in diabetic patients.

Background Increased arterial stiffness or arteriosclerosis, represents a physiological part of ageing. Atherosclerosis is a process that does not affect the arterial bed uniformly but has a variable local distribution and is frequently superimposed on stiffened vessels. We therefore addressed the question of whether any correlation exists between the general characteristics of arterial stiffness or wave reflection and subclinical atherosclerosis as assessed by carotid intima-media thickness (IMT) in a sample of healthy subjects.

Methods  A total of 116 healthy subjects (mean age 55 years, 43 female) were evaluated. Arterial stiffness and wave reflection was assessed with the use of digital volume pulse analysis (DVP) and pulse wave analysis (PWA). Subclinical atherosclerosis was assessed by measurement of IMT.

Results  Stiffness Index (SIDVP), the measure of general arterial stiffness correlated significantly with IMT (r = 0·37, P < 0·01). IMT correlated significantly with age (r = 0·5, P < 0·0001), waist to hip ratio (WHR) (r = 0·39, P < 0·0001) and mean blood pressure (BPmean) (r = 0·4, P < 0·0001). IMT did not correlate with measures of wave reflection. SIDVP correlated significantly with age (r = 0·32, P < 0·005), WHR (r = 0·36, P < 0·0001), BPmean (r = 0·36, P < 0·0001) and measurements of wave reflection. However analysis of a model which included variables that significantly influenced SIDVP and IMT, such as age, WHR and mean BP showed that arterial stiffness is not independently associated with subclinical atherosclerosis.

Conclusions  The indices of subclinical atherosclerosis, arterial stiffness and wave reflection, indicate different aspects of vascular status in otherwise healthy subjects

H. Wysocki

Papers

Evidence of polymorphonuclear neutrophils (PMN) activation in patients with insulin-dependent diabetes mellitus.

Metabolic control quality and free radical activity in diabetic patients.

Arterial stiffness in relation to subclinical atherosclerosis.

Polymorphonuclear neutrophils adherence, superoxide anion (O2−) production and HBA1 level in diabetic patients

Augmentation index, pulse pressure amplification and superoxide anion production in patients with coronary artery disease.