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OBJECTIVE—To determine 1) foot ulcer rates for European, South-Asian, and African-Caribbean diabetic patients in the U.K and 2) the contribution of neuropathy and peripheral arterial disease (PAD) differences to altered ulcer risk between the groups.RESEARCH DESIGN AND METHODS—In this U.K. population–based study, we screened 15,692 type 1 and type 2 diabetic patients in the community health care setting for foot ulcers, foot deformities, neuropathy, and PAD plus other characteristics. In total, 13,409 were European (85.5%), 1,866 were South Asian (11.9%), and 371 were African Caribbean (2.4%).RESULTS—The age-adjusted prevalence of diabetic foot ulcers (past or present) for Europeans, South Asians, and African Caribbeans was 5.5, 1.8, and 2.7%, respectively (P < 0.0001). Asians and African Caribbeans had less neuropathy, PAD, and foot deformities than Europeans (P = 0.003). The unadjusted risk of ulcer (odds ratio [OR]) for Asians versus Europeans was 0.29 (95% CI 0.20–0.41) (P < 0.0001). PAD, neuropathy, foot deformities, and insulin use attenuated the age-adjusted OR from 0.32 to 0.52 (0.35–0.76) (P < 0.0001). African-Caribbean versus European ulcer risk in males was attenuated from 0.60 to 0.71 by vibration sensation.CONCLUSIONS—South Asians with diabetes in the U.K. have about one-third the risk of foot ulcers of Europeans. The lower levels of PAD, neuropathy, insulin usage, and foot deformities of the Asians account for approximately half of this reduced foot ulcer risk. Lower neuropathy is the main contributor to the reduced African-Caribbean ulcer rate, particularly in men. The reasons for these ethnic differences warrant further investigation.

Recent efforts to identify treatments for chronic diabetic complications have resulted in the discovery of a novel series of highly potent and selective (2-arylcarbamoyl-phenoxy)-acetic acid aldose reductase inhibitors. The compound class features a core template that utilizes an intramolecular hydrogen bond to position the key structural elements of the pharmacophore in a conformation, which promotes a high binding affinity. The lead candidate, example 40 , 5-fluoro-2-(4-bromo-2-fluoro-benzylthiocarbamoyl)-phenoxyacetic acid, inhibits aldose reductase with an IC 50 of 30 nM, while being 1100 times less active against aldehyde reductase, a related enzyme involved in the detoxification of reactive aldehydes. In addition, example 40 lowers nerve sorbitol levels with an ED 50 of 31 mg/kg/d po in the 4-day STZ-induced diabetic rat model.

OBJECTIVE—To examine the relationships among muscle weakness, foot deformities, and peroneal and tibial nerve conduction velocity in diabetic and nondiabetic men. RESEARCH DESIGN AND METHODS—A neuropathic and foot evaluation was undertaken in 10 nondiabetic control subjects (group C) and in 36 consecutive diabetic patients attending Diabetes Centre clinics, including 10 diabetic control subjects (group D), 15 diabetic neuropathic patients (group DN), and 11 diabetic patients with a history of ulceration (group DU). Neuropathy was defined as a peroneal motor nerve conduction RESULTS—Peroneal and tibial nerve conduction velocity were associated with weakness in muscles innervated by, respectively, the peroneal and tibial nerve (r = −0.70 and r = −0.51, P < 0.01) and foot deformities (r = −0.60 and r = −0.59, P < 0.001). The DN and DU groups had more weakness in intrinsic and extrinsic muscles compared with the C and D groups. Muscles innervated by the tibial nerve had a greater proportional muscle weakness than those innervated by the peroneal nerve in the DN and DU groups. The DN and DU patients had more foot deformities (median food deformity score [interquartile range]) (3 [2–3] and 2 [2–3]) compared with D and C patients (0 [0–0.75] and 0 [0–0]). CONCLUSIONS—Important relationships have been shown between motor nerve conduction deficit and muscle weakness; however, it is still not clear whether abnormal nerve function, leading to a decrease in muscle strength, could be responsible for the development of foot deformities.

OBJECTIVE—To determine the relative roles of different modalities of sensory nerve function (large and small fiber) and the role of microvascular dysfunction in foot ulceration in type 2 diabetic subjects. RESEARCH DESIGN AND METHODS—A total of 20 control subjects and 18 type 2 diabetic subjects with foot ulceration and 20 without were studied. None of the subjects had clinical features of peripheral vascular disease. The Computer-Aided Sensory Evaluator IV (CASE IV) was used to determine vibration detection threshold (VDT), cold detection threshold (CDT), warm detection threshold (WDT), and heat pain onset threshold (HPO). Vibration perception threshold (VPT) was also assessed by a neurothesiometer. Microvascular function (maximum hyperemia to skin heating to 44°C) was assessed using laser Doppler flowmetry (mean maximum hyperemia using laser Doppler flowmeter [LDFmax]), laser Doppler imaging (mean maximum hyperemia using laser Doppler imager [LDImax]), and skin oxygenation with transcutaneous oxygen tension (TcpO2). RESULTS—VPT, VDT, CDT, and HPO were all significantly higher in individuals with ulceration than in those without (VPT and VDT: P < 0.0001) (CDT and HPO: P = 0.01). LDFmax, LDImax, and TcpO2 were significantly lower in the two diabetic groups than in the control subjects, but there was no difference between individuals with and without ulceration. Univariate logistic regression analysis revealed similar odds ratios for foot ulceration for VDT, CDT, HPO, and VPT (OR 1.97 [95% CI 1.30–2.98], 1.58 [1.20–2.08], 2.30 [1.21–4.37], and 1.24 [1.08–1.42], respectively). None of the microvascular parameters yielded significant odds ratios for ulceration. CONCLUSIONS—This study found that there was no additional value in measuring small-fiber function with the CASE IV over measuring vibration by either CASE IV or the inexpensive neurothesiometer in discriminating between individuals with and without ulceration. Furthermore, none of the tests of microvascular function including the TcpO2 were able to discriminate between individuals with and without ulceration, suggesting that such tests may not be of benefit in identifying subjects at greater risk of foot ulceration.

OBJECTIVE—This study examined motor nerve conduction velocity (MNCV) and other peripheral nerve and vascular tests as predictors for foot ulceration, amputation, and mortality in diabetes over a 6-year follow-up period. RESEARCH DESIGN AND METHODS—We recruited 169 diabetic subjects (without significant peripheral vascular disease with an ankle brachial pressure index [ABPI] ≥0.75) for the study and separated them into groups (to ensure diversity of nerve function). The control group consisted of 22 nondiabetic people. At baseline, all subjects underwent assessment of MNCV; vibration, pressure, and temperature perception thresholds; peripheral vascular function; and other diabetes assessments. RESULTS—Over the 6-year outcome period, 37.3% of the diabetic subjects developed at least one new ulcer, 11.2% had a lower-limb amputation (LLA) (minor or major), and 18.3% died. Using multivariate Cox’s regression analysis (RR [95% CI] and removing previous ulcers as a confounding variable, MNCV was found to be the best predictor of new ulceration (0.90 [0.84–0.96], P = 0.001) and the best predictors of amputation were pressure perception threshold (PPT) (5.18 [1.96–13.68], P = 0.001) and medial arterial calcification (2.88 [1.13–7.35], P = 0.027). Creatinine (1.01 [1.00–1.01], P < 0.001), MNCV (0.84 [0.73–0.97], P = 0.016), and skin oxygen levels (14.32 [3.04–67.52], P = 0.001) were the best predictors of mortality. CONCLUSIONS—This study shows that MNCV, which is often assessed in clinical trials of neuropathy, can predict foot ulceration and death in diabetes. In addition, tests of PPT and medial arterial calcification can be used in the clinic to predict LLA in diabetic subjects.

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.

OBJECTIVE— To assess the efficacy of a specialist foot care program designed to prevent a second amputation and to assess peripheral vascular disease (PVD) and peripheral neuropathy in diabetic unilateral lower-limb amputees. RESEARCH DESIGN AND METHODS— Investigations were carried out in 143 diabetic lower-limb unilateral amputees referred to a subregional rehabilitation center for prosthetic care from a catchment area of ∼3 million people. Peripheral vascular and nerve assessment, education, and podiatry were provided for each patient. RESULTS— For the patients referred to the foot care program,there were no baseline differences between the patients who proceeded to a bilateral amputation (n = 22) and those who remained as unilateral amputees (n = 121) in their level of foot care knowledge and mean neuropathy scores. Mean ankle-brachial pressure index was significantly lower for the bilateral amputees (0.75 ± 0.04) compared with the unilateral amputees (0.90 ± 0.03, mean ± SEM, P < 0.05), but there was no difference in the level of oxygen in the skin. However, the level of carbon dioxide was significantly lower in patients with bilateral amputation (24.21 ± 2.16 vs. 31.20 ± 0.85 mmHg, P CONCLUSIONS— PVD is more closely associated with diabetic bilateral amputation than neuropathy or level of foot care knowledge. Preventative foot care programs for diabetic unilateral amputees should therefore place greater emphasis on peripheral vascular assessment to identify patients at risk and on the development of timely intervention strategies.

Summary Background Diabetes is a common cause of polyneuropathy. The development and progression of nephropathy, retinopathy, and neuropathy are closely related. Angiotensin-converting enzyme (ACE) inhibitors delay progression of both nephropathy and retinopathy. We investigated the effect of ACE inhibition on diabetic neuropathy. Methods We recruited 41 normotensive patients with type I or type II diabetes and mild neuropathy into a randomised double-blind placebo-controlled trial. Changes in the neuropathy symptom and deficit scores, vibration-perception threshold, peripheral-nerve electrophysiology, and cardiovascular autonomic function, were assessed at 6 and 12 months. The primary endpoint was the change in peroneal nerve motor conduction velocity. Findings We found no significant difference at baseline for age, HbA 10 , blood pressure, or severity of neuropathy between two groups. There was no change in HbA 10 over the treatment period. Peroneal motor nerve conduction velocity (p=0·03) and M-wave amplitude (p=0·03) increased, and the F-wave latency (p=0·03) decreased and sural nerve action potential amplitude increased (p=0·04) significantly after 12 months of treatment with trandolapril compared with placebo. Vibration-perception threshold, autonomic function, and the neuropathy symptom and deficit score showed no improvement in either group. Interpretation The ACE inhibitor trandolapril may improve peripheral neuropathy in normotensive patients with diabetes. Larger clinical trials are needed to confirm these data before changes to clinical practice can be advocated.

To determine 1) foot ulcer rates for European, South-Asian, and African-Caribbean diabetic patients in the U.K and 2) the contribution of neuropathy and peripheral arterial disease (PAD) differences to altered ulcer risk between the groups.In this U.K. population-based study, we screened 15,692 type 1 and type 2 diabetic patients in the community health care setting for foot ulcers, foot deformities, neuropathy, and PAD plus other characteristics. In total, 13,409 were European (85.5%), 1,866 were South Asian (11.9%), and 371 were African Caribbean (2.4%).The age-adjusted prevalence of diabetic foot ulcers (past or present) for Europeans, South Asians, and African Caribbeans was 5.5, 1.8, and 2.7%, respectively (P0.0001). Asians and African Caribbeans had less neuropathy, PAD, and foot deformities than Europeans (P = 0.003). The unadjusted risk of ulcer (odds ratio [OR]) for Asians versus Europeans was 0.29 (95% CI 0.20-0.41) (P0.0001). PAD, neuropathy, foot deformities, and insulin use attenuated the age-adjusted OR from 0.32 to 0.52 (0.35-0.76) (P0.0001). African-Caribbean versus European ulcer risk in males was attenuated from 0.60 to 0.71 by vibration sensation.South Asians with diabetes in the U.K. have about one-third the risk of foot ulcers of Europeans. The lower levels of PAD, neuropathy, insulin usage, and foot deformities of the Asians account for approximately half of this reduced foot ulcer risk. Lower neuropathy is the main contributor to the reduced African-Caribbean ulcer rate, particularly in men. The reasons for these ethnic differences warrant further investigation.

To examine the relationships among muscle weakness, foot deformities, and peroneal and tibial nerve conduction velocity in diabetic and nondiabetic men.A neuropathic and foot evaluation was undertaken in 10 nondiabetic control subjects (group C) and in 36 consecutive diabetic patients attending Diabetes Centre clinics, including 10 diabetic control subjects (group D), 15 diabetic neuropathic patients (group DN), and 11 diabetic patients with a history of ulceration (group DU). Neuropathy was defined as a peroneal motor nerve conduction40 m/s. Muscle weakness was assessed in seven intrinsic and seven extrinsic muscles of the foot using a semiquantitative score (max score per muscle = 3). Foot deformities were assessed using a foot deformity score (max score = 3). A higher score indicated increased muscle weakness or more severe foot deformities. Muscle weakness and foot deformities were assessed without prior knowledge of patient and neuropathy status.Peroneal and tibial nerve conduction velocity were associated with weakness in muscles innervated by, respectively, the peroneal and tibial nerve (r = -0.70 and r = -0.51, P0.01) and foot deformities (r = -0.60 and r = -0.59, P0.001). The DN and DU groups had more weakness in intrinsic and extrinsic muscles compared with the C and D groups. Muscles innervated by the tibial nerve had a greater proportional muscle weakness than those innervated by the peroneal nerve in the DN and DU groups. The DN and DU patients had more foot deformities (median food deformity score [interquartile range]) (3 [2-3] and 2 [2-3]) compared with D and C patients (0 [0-0.75] and 0 [0-0]).Important relationships have been shown between motor nerve conduction deficit and muscle weakness; however, it is still not clear whether abnormal nerve function, leading to a decrease in muscle strength, could be responsible for the development of foot deformities.

The streptozotocin (STZ)-diabetic rat, the most commonly employed model of experimental diabetic neuropathy, is characterised by a reduction in nerve conduction velocity, pain threshold and blood flow. Whether or not structural abnormalities underlie these functional abnormalities is unclear. 10 adult male Sprague–Dawley STZ-diabetic rats (diabetes duration 27 d) and 10 age-matched (23 wk) control animals were studied. Motor nerve conduction velocity (m s−1) was significantly reduced in diabetic (41.31±0.8) compared with control (46.15±1.5) animals (PPPPPPP

OBJECTIVE: Biomechanical studies in diabetic neuropathy have clearly demonstrated abnormal foot pressures, but information on other aspects of gait is limited. This study aimed to investigate and describe the forces transmitted through the foot during walking in diabetic subjects with varying degrees of peripheral neuropathy and to determine if abnormalities in these forces might contribute to the risk of plantar ulceration. RESEARCH DESIGN AND METHODS: Subjects from the following groups were included: healthy control subjects (C); diabetic control subjects (D); subjects with diabetic neuropathy (DN); subjects with previous neuropathic ulceration (DNU); and subjects with Charcot neuro-arthropathy (CH). Gait analysis was performed as subjects walked over a Kistler force plate. Peak forces were measured (as percent body weight) in the vertical and horizontal planes. Comparisons were made between all of the groups and between each diabetic group and a healthy control group matched for walking speed. RESULTS: There were 181 subjects studied. In comparison with that of the speed-matched controls, the mean peak vertical force was higher in each of the diabetic groups, especially in the most neuropathic subjects (DNU, 113 vs. 110%, P < 0.01). This increase was entirely due to higher forces during heel contact (DNU, 111 vs. 106%, P < 0.001). The single peak force occurred during heel strike (rather than during foot push-off) in 23-38% of footsteps of healthy and diabetic control subjects but in 53-73% of footsteps of neuropathic subjects. There was also a trend for higher peak medial forces (CH, 6.2 vs. 5.5%, P < 0.05). CONCLUSIONS: Diabetic neuropathy is associated with a change in the time pattern of the forces transmitted through the foot and an increase in the vertical forces through the heel. The magnitude of the changes is small in absolute terms, but these changes may contribute to the risk of plantar foot ulceration.

OBJECTIVE To investigate longitudinally prognostic factors for foot ulceration in a large population of diabetic patients with established neuropathy. RESEARCH DESIGN AND METHODS A double-blind multicenter study of a potential new agent for diabetic neuropathy provided the opportunity for this 1-year investigation since intervention demonstrated no efficacy in the condition. A total of 1,035 patients with N1DDM and IDDM were included. Inclusion criteria were vibration perception threshold (VPT) at the great toe ≥25 V in at least one foot and ≤50 V in both feet, normal peripheral circulation, and no previous foot ulceration. VPT and clinical components of the Michigan diabetic polyneuropathy (DPN) score were assessed at baseline and subsequent visits. RESULTS After 1 year, the incidence of first foot ulcers for the total population was 7.2%. Neuropathy parameters were the same between the treatment and placebo groups at baseline and were unchanged at 1 year; therefore, baseline data were combined for multiple regression analysis. VPT, age, and Michigan DPN scores for muscle strength and reflexes were significant independent predictors for first foot ulceration (P < 0.01). For each 1-U increase in VPT values at baseline, the hazard of the first foot ulcer increased by 5.6%. Similarly, for each 1-U increase in muscle strength and reflex components of the Michigan DPN scores, the hazard of the first foot ulcer increased by 5.0%. CONCLUSIONS Tests of VPT and Michigan DPN scores for muscle strength and reflexes are useful clinical predictors for foot ulceration in diabetic patients with established neuropathy. The rate of subsequent ulceration in the following year was alarmingly high, however, despite standardized foot care education at baseline and regular follow-up visits.

Multiple factors, including peripheral vascular disease and neuropathy, contribute to the development and perpetuation of complications of the lower extremities in diabetes. The main aim of the present study was to assess the peripheral vascular and nerve status of diabetic and non-diabetic subjects that had undergone lower limb amputation. Various non-invasive tests of peripheral vascular and nerve function were carried out on subjects who had undergone unilateral lower limb amputation and were now attending a Rehabilitation Centre. The control group (n = 23), the diabetic amputee group (n = 64) and the non-diabetic amputee group (n = 32) were age-matched. Only the diabetic amputee group had evidence of medial arterial calcification. Transcutaneous oxygen levels were significantly lower in the diabetic amputee group (median 43 mmHg; interquartile range 33–49 mmHg) than in the control (59; 56–74 mmHg) and non-diabetic amputee (57; 43–65 mmHg) groups (control compared with diabetic amputee group, P < 0.001; diabetic amputee compared with non-diabetic amputee group, P < 0.01). The same trend was found for carbon dioxide levels in the skin [mmHg: diabetic amputees, 25 (21–37); controls, 38 (32–42); non-diabetic amputee, 34 (31–39)] (control compared with diabetic amputee, P < 0.01; diabetic amputee compared with non-diabetic amputee, P < 0.05). Vibration and pressure perception measurements (which assess Aβ nerve fibre function) showed that both the diabetic amputee and non-diabetic amputee subjects had significantly greater impairment than the controls. However, measures of Aα and C nerve fibre function were abnormal only in the diabetic amputee group. Thus the peripheral vascular and nerve functions of age-matched diabetic and non-diabetic subjects having undergone lower limb amputation show specific differences, with non-diabetic amputees exhibiting signs of neuropathy. This indicates that factors characteristic of diabetes (such as hyperglycaemia and non-enzymic glycation) are associated with calcification, lower oxygen and carbon dioxide levels in the skin, and abnormal Aα and C nerve fibre function.