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OBJECTIVE— To examine the contribution of nerve-axon reflex-related vasodilation to total acetylcholine-induced vasodilation in the skin of normal and diabetic subjects. RESEARCH DESIGN AND METHODS— The skin microcirculation was evaluated at the forearm level in 69 healthy subjects and 42 nonneuropathic diabetic patients and at the foot level in 27 healthy subjects and 101 diabetic patients (33 with neuropathy, 23 with Charcot arthropathy, 32 with peripheral vascular disease and neuropathy, and 13 without complications). Two single-point laser probes were used to measure total and neurovascular vasodilation response to the iontophoresis of 1% acetylcholine, 1% sodium nitroprusside, and deionized water. RESULTS— The neurovascular response to acetylcholine was significantly higher than the response to sodium nitroprusside and deionized water (P < 0.01). At the forearm level, the contribution of neurovascular response to the total response to acetylcholine was 35% in diabetic patients and 31% in control subjects. At the foot level, the contribution was 29% in diabetic patients without neuropathy and 36% in control subjects, while it was significantly diminished in the three neuropathic groups. A significantly lower nonspecific nerve-axon-related vasodilation was observed during the iontophoresis of sodium nitroprusside,which does not specifically stimulate the C nociceptive fibers. CONCLUSIONS— Neurovascular vasodilation accounts for approximately one-third of the total acetylcholine-induced vasodilation at both the forearm and foot levels. The presence of diabetic neuropathy results in reduction of both the total vasodilatory response to acetylcholine and the percentage contribution of neurovascular vasodilation to the total response. Acetylcholine and sodium nitroprusside cause vasodilation in the skin microcirculation through different pathways.

Objective Foot problems are common in the remaining foot of diabetic amputees. Because high foot pressures are associated with foot ulceration, we studied foot pressures of the remaining foot of diabetic and nondiabetic unilateral amputees. Research Design and Methods Four age-matched groups of 11 subjects were studied. The groups were comprised of diabetic subjects with previous major amputation, nondiabetic nonneuropathic amputees, diabetic nonamputee patients with similar peripheral nerve involvement as the diabetic amputees, and nondiabetic control subjects. Vibration perception threshold (VPT) was assessed by biothesiometry and foot pressures with an optical pedobarograph. Results Mean ± SE VPT in the diabetic amputees was significantly higher than the nondiabetic amputees (40.2 ± 3.7 vs. 17.7 ± 2.8 V, P < 0.002) and similar to diabetic nonamputees (43.4 ± 3.3 V, NS). VPT was abnormal in 9 (82%) diabetic amputees, 2 (18%) nondiabetic amputees, and 10 (91%) nonamputee diabetic patients. The mean peak foot pressure in the diabetic amputees was higher compared with nondiabetic amputees (18.3 ± 2.2 vs. 11.3 ± 1.4 kg/cm2, P < 0.05) and control subjects (10.0 ± 1.5 kg/m2, P < 0.01), but no difference existed with diabetic nonamputees. Abnormally high foot pressures (> 12.3 kg/cm2) were present in 8 (73%) diabetic amputees, 3 (27%) nondiabetic amputees, 8 (73%) diabetic nonamputees, and 4 (36%) healthy subjects. Conclusions We conclude that high pressures are present under the remaining foot in diabetic amputees, and that these pressures are associated with diabetic neuropathy. Prosthetic usage does not increase the pressures under the remaining foot in nondiabetic amputees.

OBJECTIVE: Diabetic foot ulceration is a preventable long-term complication of diabetes. A multicenter prospective follow-up study was conducted to determine which risk factors in foot screening have a high association with the development of foot ulceration. RESEARCH DESIGN AND METHODS: A total of 248 patients from 3 large diabetic foot centers were enrolled in a prospective study. Neuropathy symptom score, neuropathy disability score (NDS), vibration perception threshold (VPT), Semmes-Weinstein monofilaments (SWFs), joint mobility, peak plantar foot pressures, and vascular status were evaluated in all patients at the beginning of the study. Patients were followed-up every 6 months for a mean period of 30 months (range 6-40), and all new foot ulcers were recorded. The sensitivity, specificity, and positive predictive value of each risk factor were evaluated. RESULTS: Foot ulcers developed in 95 feet (19%) or 73 patients (29%) during the study. Patients who developed foot ulcers were more frequently men, had diabetes for a longer duration, had nonpalpable pedal pulses, had reduced joint mobility, had a high NDS, had a high VPT, and had an inability to feel a 5.07 SWE NDS alone had the best sensitivity, whereas the combination of the NDS and the inability to feel a 5.07 SWF reached a sensitivity of 99%. On the other hand, the best specificity for a single factor was offered by foot pressures, and the best combination was that of NDS and foot pressures. Univariate logistical regression analysis yielded a statistically significant odds ratio (OR) for sex, race, duration of diabetes, palpable pulses, history of foot ulceration, high NDSs, high VPTs, high SWFs, and high foot pressures. In addition, 94 (99%) of the 95 ulcerated feet had a high NDS and/or SWF which resulted in the highest OR of 26.2 (95% CI 3.6-190). Furthermore, in multivariate logistical regression analysis, the only significant factors were high NDSs, VPTs, SWFs, and foot pressures. CONCLUSIONS: Clinical examination and a 5.07 SWF test are the two most sensitive tests in identifying patients at risk for foot ulceration, especially when the tests are used in conjunction with each other. VPT measurements are also helpful and can be used as an alternative. Finally, foot pressure measurements offer a substantially higher specificity and can be used as a postscreening test in conjunction with providing appropriate footwear.

Abnormalities in vascular reactivity in the micro- and macrocirculation are well established in type 2 diabetes. However, little is known about changes in vascular reactivity in those at risk for developing type 2 diabetes. To address this situation, the vascular reactivity in both the micro- and macrocirculation was studied in four age and sex comparable groups: 30 healthy normoglycemic subjects with no history of type 2 diabetes in a first-degree relative (controls), 39 healthy normoglycemic subjects with a history of type 2 diabetes in one or both parents (relatives), 32 subjects with impaired glucose tolerance (IGT), and 42 patients with type 2 diabetes without vascular complications (diabetes). Laser Doppler perfusion imaging was used to measure vasodilation in the forearm skin in response to iontophoresis of 1% acetylcholine chloride (Ach) (endothelium-dependent) and 1% sodium nitroprusside (SNP) (endothelium-independent), whereas high-resolution ultrasound images were used to measure brachial artery diameter changes during reactive hyperemia. Plasma concentrations of endothelin-1 (ET-1), von Willebrand factor (vWF), soluble intercellular adhesion molecule (sICAM), and soluble vascular cell adhesion molecule (sVCAM) were also measured as indicators of endothelial cell activation. The vasodilatory responses to Ach, expressed as percent increase of blood flow over baseline, were reduced in relatives (98 +/- 48, mean +/- SD), IGT (94 +/- 52), and diabetes (74 +/- 45) compared with controls (126 +/- 67) (P < 0.001 controls versus relatives, IGT, and diabetes). The responses to SNP were similarly reduced: controls (123 +/- 46), relatives (85 +/- 46), IGT (83 +/- 48), and diabetes (65 +/- 31) (P < 0.001 controls versus relatives, IGT, and diabetes) as were the responses in the brachial artery diameter during reactive hyperemia: controls (13.7 +/- 6.1), relatives (10.5 +/- 6.7), IGT (9.8 +/- 4.5), and diabetes (8.4 +/- 5.0) (P < 0.01 controls versus relatives, IGT, and diabetes). Women had greater responses than men in both the micro- and macrovascular circulatory tests, but a similar progressive reduction was observed in both sexes with increasing degrees of glucose intolerance. A significant inverse correlation was found between microvascular reactivity and systolic blood pressure, fasting plasma glucose, HDL cholesterol, fasting plasma insulin, and homeostasis model assessment (HOMA) values, an index of insulin resistance. BMI and diastolic blood pressure had a significant inverse correlation only with endothelium-dependent vasodilation. In the macrocirculation, systolic blood pressure, HbA1c, HDL cholesterol, and HOMA had significant correlation with brachial artery diameter changes. Compared with control subjects, ET-1 was significantly higher in all groups, vWF was higher only in the diabetic group, sICAM levels were higher in the IGT and diabetic groups, while sVCAM concentrations were higher in the relatives and those with diabetes (P < 0.05). On stepwise multivariate analysis, age, sex, fasting plasma glucose, and BMI were the most important contributing factors to the variation of vascular reactivity. Addition of all clinical and biochemical measures explained only 32-37% of the variation in vascular reactivity. These results suggest that abnormalities in vascular reactivity and biochemical markers of endothelial cell activation are present early in individuals at risk of developing type 2 diabetes, even at a stage when normal glucose tolerance exists, and that factors in addition to insulin resistance may be operative.

Evidence-based medicine has become ubiquitous in modern-day medicine, including wound care. However, the application of evidence-based medicine into the arena of chronic wounds has not been uniformly performed and measured. Most wound care studies are plagued by inconsistencies in inclusion criteria, data measurements, and endpoint reporting. Furthermore, the small sample sizes prohibit drawing effective conclusions. However, that does not imply that the current guidelines of treatment are substandard. Instead, one must rely more heavily on current evidence and experts in the field until larger, more consistent studies can establish good practice patterns.

High plantar pressures and painless trauma are associated with the development of foot ulcers in diabetic patients. Padded hosiery has been reported to reduce plantar pressures in patients at risk of ulceration. Using the optical pedobarograph we have studied 10 patients who regularly wore experimental padded hosiery for 6 months. The hosiery continued to provide substantial and significant reduction in peak forefoot pressures at 3 months (mean reduction 15.5%, p less than 0.01) and 6 months (17.6%, p less than 0.01), although the level of reduction was less than that seen at baseline (31.3%, p less than 0.05). In addition, commercially available hosiery designed as sportswear has been tested, and compared with experimental hosiery. Although these socks (with high or medium density padding) provided significant pressure reduction versus barefoot (mean 17.4% and 10.4%, p less than 0.01), this was not as great as that seen with experimental hosiery (27%, p less than 0.05). Thus the use of socks designed to reduce pressure stress on diabetic neuropathic feet is effective, and continues to be so for a considerable period of time. Commercially available sports socks may also have a place in the management of the diabetic insensitive foot.

OBJECTIVE We have compared the hyperemic response to heat and the endothelium-dependent and endothelium-independent vasodilatation between the dorsum of the foot and the forearm in diabetic neuropathic and non-neuropathic patients and healthy control subjects. RESEARCH DESIGN AND METHODS We studied the cutaneous microcirculation in the forearm and foot in 15 diabetic patients with neuropathy, in 14 diabetic patients without neuropathy, and in 15 control subjects matched for age, sex, BMI, and in the case of diabetic patients, for the duration of diabetes. Patients with peripheral vascular disease and/or renal impairment were excluded. The cutaneous microcirculation of the dorsum of the foot and the flexor aspect of the forearm was tested in all subjects. Single-point laser Doppler was employed to measure the maximal hyperemic response to heating of the skin to 44°C and laser Doppler imaging scanner was used to evaluate the response to iontophoresis of 1% acetylcholine chloride (Ach) (endothelium-dependent response) and 1% sodium nitroprusside (NaNP) (endothelium-independent response). RESULTS The transcutaneous oxygen tension was lower in the neuropathic group at both foot and forearm level, while the maximal hyperemic response to heat was similar at the foot and forearm level in all three groups. The endothelium-dependent vasodilation (percent increase over baseline) was lower in the foot compared to the forearm in the neuropathic group (23 ± 4 vs. 55 ± 10 [mean ± SEM] P < 0.01)], the non-neuropathic group (33 ± 6 vs. 88 ± 14; P < 0.01), and the control subjects (43 ± 6 vs. 93 ± 13; P < 0.001). Similar results were observed during the iontophoresis of NaNP (P < 0.05). No differences were found among the three groups when the ratio of the forearm:foot response was calculated for both the endothelium-dependent (neuropathic group, 2.25 ± 0.24; non-neuropathic group, 2.55 ± 0.35; and control subjects, 2.11 ± 0.26; P = NS) and endothelium-independent vasodilation (neuropathic group, 1.54 ± 0.27; non-neuropathic group, 2.08 ± 0.33; and control subjects, 2.77 ± 1.03; P = NS). The vasodilatory response, which is related to the C nociceptive fiber action, was reduced at the foot level during iontophoresis of Ach in the neuropathic group. In contrast, no difference was found during the iontophoresis of NaNP at the foot and forearm level and of Ach at the forearm level among all three groups. CONCLUSIONS In healthy subjects, the endothelial-dependent and endothelial-independent vasodilatation is lower at the foot level when compared to the forearm, and a generalized impairment of the microcirculation in diabetic patients with neuropathy preserves this forearm-foot gradient. These changes may be a contributing factor for the early involvement of the foot with neuropathy when compared to the forearm.

We studied endothelial-mediated microvascular blood flow in neuropathic diabetic patients to determine the association between endothelial regulation of the microcirculation and the expression of endothelial constitutive nitric oxide synthetase (ecNOS) in the skin. Vasodilation on the dorsal foot in response to heating and iontophoresis of acetylcholine (endothelium-dependent) and sodium nitroprusside (endothelium-independent) were measured using single-point laser Doppler and laser Doppler imaging in diabetic patients with neuropathy (DN), with neuropathy and vascular disease (DI), with Charcot arthropathy (DA), and without complications (D), and in healthy control subjects (C). The response to heat was reduced in the DN (321 [21-629] percentage of increase over the baseline, median [interquartile range]) and DI (225 [122-470]) groups but was preserved in the DA (895 [359-1,229]), D (699 [466-1,029]), and C (810 [440-1,064], P < 0.0001) groups. The endothelial-mediated response to acetylcholine was reduced in the DN (17 [11-25]), DA (22 [2-34]), and DI (13 [2-30]) groups compared with the D (47 [24-58]) and C (44 [31-70], P < 0.001) groups. The non-endothelial-mediated response to sodium nitroprusside was also reduced in the DI (4 [0-18]), DN (17 [9-26]), and DA (21 [11-31]) groups compared with the D (37 [19-41]) and C (44 [26-67], P < 0.0001) groups. There was a significant reduction in vasodilation in the DI group compared with all other groups (P < 0.0001). Full thickness skin biopsies from the dorsum of the foot of 15 DN, 10 DI, and 11 C study subjects were immunostained with antiserum to human ecNOS, the functional endothelial marker GLUT1, and the anatomical endothelial marker von Willebrand factor. The staining intensity of ecNOS was reduced in both diabetic groups. No differences were found among the three groups in the staining intensity of von Willebrand factor and GLUT1. We conclude that the endothelium-dependent and endothelium-independent vasodilations are impaired in diabetic patients predisposed to foot ulceration and that neuropathy is the main factor associated with this abnormality. Reduced expression of ecNOS may be a major contributing factor for endothelial dysfunction. These data provide support for a close association of neuropathy and microcirculation in the pathogenesis of foot ulceration.

1. Epidemiology of Diabetic Neuropathy 2. Pathogenesis of Diabetic Neuropathy 3. Clinical Features of Diabetic Neuropathy 4. Diagnosis of Diabetic Neuropathy 5. Histologic Changes: Implications for Treatment Strategies 6. Clinical Management of Diabetic Neuropathy: An Overview 7. Implications of the DCCT in the Management of Diabetic Neuropathy 8. Aldose Reductase Inhibitors and Other Potential Therapeutic Agents for the Treatment of Diabetic Neuropathy 9. Painful Diabetic Neuropathy: Etiology and Nonpharmacological Treatment 10. Pharmacological Treatment of Painful Diabetic Neuropathy 11. Focal Diabetic Neuropathology 12. Diabetic Autonomic Neuropathy: An Overview 13. Autonomic Neuropathy and Heart Disease Efthymios 14. Diabetic Impotence: Pathogenesis and Treatment 15. Gastrointestinal Disorders 16. Exercise and Diabetic Neuropathy 17. Epidemiology of Diabetic Foot: Ulcerations and Amputations 18. The Pathogenesis of Foot Problems 19. Management of the Diabetic Foot 20. The Impact of Micro- and Macrovascular Disease on Diabetic Neuropathy and Foot Problems Index.

It has been more than 20 yr since the first aldose reductase inhibitor was tested in diabetic and galactosemic rats and found to control polyol accumulation (1). Since then, a considerable number of aldose reductase inhibitors have been tested in experimental and human diabetes and have considerably increased our knowledge in this field (Table 1). A thorough review of work on experimental diabetes would be outside the scope of this volume; however, the interested reader can find more information in recently published extensive reviews. The following chapter will focus on the results from clinical trials in diabetic neuropathy (2,3).

The diagnosis and staging of severity of the diabetic neuropathy plays an important role not only for following up patients in a daily clinical practice, but also for the conduction of research that studies the etiopathogenesis of the disease and the development of new therapeutic modalities.

The aim of the present study was to examine if diabetes in the absence of neuropathy affects the exercising capacity of IDDM patients, and whether regular, intense training has a beneficial effect on endothelial function. Five groups of subjects were studied: 23 healthy control subjects who exercised regularly (age 33 ± 6 years), 23 nonneuropathic type 1 diabetic patients who exercised regularly (age 33 ± 6 years, IDDM duration 11 ± 8 years), 7 neuropathic type 1 diabetic patients who exercised regularly (age 36 ± 7 years, IDDM duration 22 ± 8 years), 18 healthy subjects who did not exercise regularly (age 34 ± 7 years), and 5 nonneuropathic type 1 diabetic patients who did not exercise regularly (age 31 ± 4 years, IDDM duration 20 ± 3 years). All groups were matched for age, sex, and body weight. No differences existed in the energy expenditure per week in physical activity among the three exercising groups or between the two nonexercising groups. The maximal oxygen uptake was similar between control and diabetic nonneuropathic exercisers, and among diabetic neuropathic exercisers, control nonexercisers, and diabetic nonexercisers; however, a significant difference existed between the first two and the last three groups (P < 0.0001). A stepwise increase was found in the resting heart rate among the groups, ranging from the lowest in control exercisers to the highest in diabetic nonexercisers, but the maximal heart rate was lower only in diabetic neuropathic exercisers compared with all other groups (P < 0.05). Assessments of endothelial function in both macro- and microcirculation were performed in 12 control exercisers, 10 diabetic nonneuropathic exercisers, 5 diabetic neuropathic exercisers, 17 control nonexercisers, and 4 diabetic nonexercisers. When all diabetic patients were considered as one group and all control subjects as another, the microcirculation endothelial function in the diabetic group was reduced compared with the control subjects (91 ± 49 vs. 122 ± 41% flux increase over baseline; P < 0.05). In contrast, no differences existed among the three diabetic groups or between the two control groups. Similarly, in macro-circulation, a reduced response during reactive hyperemia was observed in the diabetic patients compared with control subjects (7.0 ± 4.5 vs. 11.2 ± 6.6% diameter increase; P < 0.05), whereas again no difference existed among the three diabetic groups or between the two control groups. These data suggest that diabetes per se does not affect aerobic exercise capacity (Vo2max) in physically active individuals, but is reduced in the presence of neuropathy. In addition, regular exercise training involving the lower extremities does not improve the endothelial function in the micro- and macrocirculation of the nonexercised upper extremity in type 1 diabetic patients.

Foot problems are common in diabetic patients, with neuropathy and peripheral vascular disease being the main causative factors. Identification of high-risk feet can be accomplished by using basic clinical skills and simple equipment. Limb amputation is the most preventable of the long-term diabetes complications and a multidisciplinary approach can achieve a dramatic reduction of major limb amputations.

To determine whether reversal of hypoxia slows the progression of neuropathy.Cohort study with a mean follow-up of 19.2 months.Institutional and private hospital.A volunteer sample of 55 patients with diabetes (mean age, 62 years; range, 30-74 years; mean duration of diabetes, 21 years; range, 1-57 years) requiring lower-extremity arterial bypass. Twenty-one successfully treated patients were reexamined at the conclusion of the study. Neuropathy and hypoxia were assessed the day before the operation and during the follow-up visit.Lower-extremity arterial reconstruction.Peroneal nerve conduction velocity and transcutaneous oxygen tension.In the leg operated on, the peroneal nerve conduction velocity remained unchanged during the follow-up period (preoperative, mean [+/- SD] 35.79 +/- 6.02 vs postoperative 35.33 +/- 7.51 m/s; P.05), but deteriorated in the leg not operated on (36.68 +/- 6.22 vs 33.64 +/- 7.30 m/s; P.05, Wilcoxon signed rank test). Transcutaneous oxygen tension increased in the revascularized extremity (mean [+/- SD] 40.62 +/- 24.76 vs 66.73 +/- 14.89 mm Hg) but remained unchanged in the leg not operated on (56.76 +/- 17.07 vs 62.00 +/- 15.66 mm Hg; P.05). Of the entire cohort, 5 patients died during the study period. Graft occlusion occurred in 10 (17%) of 59 extremities. Subset analysis disclosed that the preoperative transcutaneous oxygen tension was significantly higher in the successfully revascularized extremities (41.98 +/- 23.58 vs 24.10 +/- 21.50 mm Hg; P.001).Reversal of hypoxia halts the progression of diabetic neuropathy, lending further support to the role of hypoxia in the pathogenesis of nerve destruction in diabetes mellitus. Preoperative transcutaneous oxygen tension is lower in patients with bypass failure, but the severity of neuropathy does not affect the outcome of the operation.

Primary care of the diabetic patient with foot ulcer can be provided by medically or surgically trained practitioners. We have prospectively followed 90 sequential patients with newly developed foot ulcers from two major centers. One in the USA where the primary doctor was a podiatrist and one in Europe with a diabetologist. Thirty-four patients from Boston and 56 from Pisa (mean age, 55.6; range, 26-75 years; vs. 66.5; range, 35-94; P < 0.001), matched for sex, weight, type, duration of diabetes, renal impairment and retinopathy took part. Boston patients had more severe neuropathy, assessed with clinical examination utilizing a neuropathy disability score (NDS) (16 +/- 6 vs. 6 +/- 3 (mean +/- S.D.) P < 0.001) and vibration perception threshold (46 +/- 8 vs. 35 +/- 12 V: P < 0.001) while no difference existed in the number of patients with clinical infection, a history of lower extremity by-pass operation (6 (18%) vs. 3 (5%); P = NS) and in the size and the severity of the ulcer, according to the Wagner classification. Initial treatment was similar in both centers with emphasis on outpatient ulcer debridement, pressure relieving foot-wear and topical wound care. Hospitalization was needed in five (15%) Boston and 12 (21%) Pisa patients (P = NS) while surgery was performed on five (15%) Boston and 16 (29%) Pisa patients (P = NS). The in-hospital stay was similar in both centers (1.4 +/- 4.4 vs. 2.1 +/- 5.9 days; P = NS). The most common operations in both centers were incision, drainage and bone debridement. Ulcers healed in all patients but the amount of healing time was shorter in Boston patients (6.7 +/- 4.2 vs. 10.5 +/- 6.5 weeks; P < 0.02). We conclude that despite the differences in the two systems similar success rates were achieved in the two centers while a more surgically oriented strategy may have resulted in a slightly shorter healing time.

Untreated and long-lasting obstructive sleep apnea (OSA) may lead to important vascular abnormalities, including endothelial cell (EC) dysfunction, hypertension, and atherosclerosis. We observed a correlation between microcirculatory reactivity and endothelium-dependent release of nitric oxide in OSA patients. Therefore, we hypothesized that OSA affects (micro)vasculature and we aimed to identify vascular gene targets of OSA that could possibly serve as reliable biomarkers of severity of the disease and possibly of vascular risk. Using quantitative RT-PCR, we evaluated gene expression in skin biopsies of OSA patients, mouse aortas from animals exposed to 4-week intermittent hypoxia (IH; rapid oscillations in oxygen desaturation and reoxygenation), and human dermal microvascular (HMVEC) and coronary artery endothelial cells (HCAEC) cultured under IH. We demonstrate a significant upregulation of endothelial nitric oxide synthase (eNOS), tumor necrosis factor-alpha-induced protein 3 (TNFAIP3; A20), hypoxia-inducible factor 1 alpha (HIF-1α?? and vascular endothelial growth factor (VEGF) expression in skin biopsies obtained from OSA patients with severe nocturnal hypoxemia (nadir saturated oxygen levels [SaO2]

Hypoxia is considered to be one of the main aetiopathogenic factors of diabetic neuropathy. We have examined the effects of the reversal of hypoxia, achieved by revascularization, on peripheral nerve function in diabetic patients with or without clinical neuropathy. Fifty-six patients [mean age 62 (range 30-74) years, 44 (79%) males, 15 (27%) with insulin-dependent diabetes of 20 years (range 1-57) duration, and creatinine level 92.8 +/- 30.9 mumol/l (mean +/- SD)] were tested pre-operatively while 30 (54%) were reexamined at least 6 weeks post-operatively. At baseline the leg scheduled for operation showed worse measurements compared to the control leg when tested for Semmes-Weinstein monofilaments, peroneal motor conduction velocity (PMCV) (33.7 +/- 7.18 vs 35.7 +/- 6.09 m.s-1, p0.05) and transcutaneous oxygen tension (37.4 +/- 24.6 vs 52.0 +/- 21.5 mm Hg, p0.0001) while no differences were found in the vibration perception threshold and leg temperature. When baseline and post-operative measurements were later compared in the operated leg, no differences were noticed in the vibration perception threshold, PMCV and Semmes-Weinstein monofilaments but the transcutaneous oxygen tension increased significantly (32.7 +/- 27.1 vs 64.6 +/- 14.5 mm Hg, p0.001). No differences were noticed in any of the above parameters in the contralateral leg. No correlations were found between changes in transcutaneous oxygen tension and PMCV values measured at baseline and at the follow-up visit in either leg. Similar results were found when patients were stratified according to severity of neuropathy, ischaemia and the level of the bypass. We conclude that although there is greater impairment of nerve function in the more ischaemic leg, reversal of hypoxia does not result in any significant improvement of the nerve function measurements.

Limited joint mobility is common in diabetes and is related to high foot pressures and foot ulceration. We have examined the differences in joint mobility and foot pressures in four groups matched for age, sex, and duration of diabetes: 31 white diabetic, 33 white non-diabetic, 24 black diabetic, and 22 non-diabetic black subjects. Joint mobility was assessed using a goniometer at the fifth metacarpal, first metatarsal, and subtalar joints. In-shoe and without shoes foot pressures were measured using an F-Scan system. Neuropathy was evaluated using clinical symptoms (Neuropathy Symptom Score), signs (Neuropathy Disability Score), and Vibration Perception Threshold. There was no difference between white and black diabetic patients in Neuropathy Symptom Score, Neuropathy Disability Score, and Vibration Perception Threshold. Subtalar joint mobility was significantly reduced in white diabetic patients (22 +/- 7 degrees) compared to white controls (26 +/- 4 degrees, black diabetic patients (25 +/- 5 degrees), and black controls (29 +/- 7 degrees), and increased in black controls compared to white controls and black diabetic patients (level of statistical significance p < 0.05). Without shoes foot pressures were higher in white diabetic patients (8.31 +/- 400 kg cm-2) compared to white controls (6.81 +/- 2.31 kg cma2), black diabetic patients (6.2 +/- 2.53 kg cm-2) and black controls (5.00 +/- 1.24 kg cm-2) and lower in black controls compared to white and black diabetic patients (p < 0.05 in all cases). We conclude that racial differences exist in joint mobility and foot pressures between black and white subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

In a recent article by Desouza et al. (1), an improvement of brachial artery flow-mediated vasodilatation, a measurement indicating endothelium-dependent vasodilation, was reported with both acute and prolonged sildenafil treatment. No measurements of endothelium-independent vasodilation were performed. As the administration of sublingual nitroglycerin is mainly used to evaluate endothelium-independent vasodilation, it is understandable that possible side effects related to the concomitant use of sildenafil and nitroglycerine were the main reason for omitting this measurement. However, we believe that although the presented data are very interesting, they …

OBJECTIVE To examine the differences in peripheral and autonomic nerve function measurements between diabetic patients without neuropathy (group 1, n = 38, mean age 50.9, range 29–71 years), with painless neuropathy (group 2, n = 32, mean age 49.2, range 30–71 years), and with painful neuropathy (group 3, n = 52, mean age 51.5, range 28–73 years). RESEARCH DESIGN AND METHODS The evaluation of neuropathy was based on clinical symptoms, signs, and quantitative sensory testing, including current perception threshold (CPT) with a neurometer and electrophysiology. RESULTS The Neuropathy Symptom Score and the Neuropathy Disability Score were higher in patients with painful neuropathy compared with patients with painless neuropathy (6.8 ± 2.7 vs. 0.5 ± 0.8 [mean ± SD], P < 0.0001, and 12.5 ± 6.2 vs. 8.6 ± 6.8, P < 0.01, respectively). In contrast, no differences were found in the quantitative sensory testing, including CPT measurements, the electrophysiological measurements, and the autonomic nerve system function tests in the two groups. Significant differences were found in all the above measurements when groups 2 and 3 were compared with diabetic patients without neuropathy (group 1). When all diabetic patients were considered as one group, significant correlations were found between CPT and the other peripheral nerve function assessments. In particular, peroneal nerve motor conduction velocity correlated with CPT at 2 kHz (r = −0.48, P < 0.001) and vibration perception threshold (r = −0.50, P < 0.001). CONCLUSIONS We conclude that no difference could be found in the function of small and large nerve fibers between painful and painless diabetic neuropathy using conventional tests currently used. The CPT evaluation failed to quantify painful symptoms, but it compared favorably with other quantitative sensory tests in quantifying peripheral neuropathy.

OBJECTIVE To assess the ability of vibration perception threshold (VPT) to predict the development of diabetic foot ulceration. RESEARCH DESIGN AND METHODS A prospective follow-up study of consecutive patients with vibration perception measured by biothesiometry from April 1988 to March 1989. Patients were stratified in various risk groups. RESULTS Patients with a VPT 25 V, odds ratio (OR) 7.99 (3.65–17.5, 95% confidence intervals), P < 0.01. The incidence of ulceration increased with duration of diabetes, but even with this effect removed, the excess of ulceration persisted, OR 6.82 (2.75–16.92), P < 0.01. CONCLUSIONS VPT is an effective predictor of the risk of foot ulceration in diabetes and therefore could be used to target foot-care education to those patients most likely to benefit and, thereby, possibly improve its effectiveness.

OBJECTIVE To examine the prevalence of painful symptoms in neuropathic patients with or without foot ulceration. It has been suggested that there are two clinical presentations of sensory diabetic neuropathy with little overlap: painful (acute or chronic) and painless with recurrent foot ulceration. RESEARCH DESIGN AND METHODS We examined three groups of diabetic patients matched for age and duration of diabetes–24 without neuropathy on clinical grounds (mean age 56.1 yr [range 38–76 yr], diabetes duration 12.6 yr [0.4–40 yr]), 30 with neuropathy (mean age 55.3 yr [range 21–73 yr], diabetes duration 17.3 yr [range 0.2–61 yr[), and 40 with neuropathic foot ulceration (mean age 58.1 yr [range 41–72 yr], diabetes duration 18.5 yr [range 1–46 yr])–and compared them with 20 healthy subjects (mean age 50 yr [range 37–69 yr]). For evaluation of neuropathy, the neuropathy symptom score, neuropathy disability score, and vibration perception threshold were measured. RESULTS No difference existed between the neuropathic and foot ulcer groups in the neuropathy symptom score (4.2 ± 3.9 [mean ± SD] vs. 2.5 ± 2.1, NS) and neuropathy disability score (15.1 ± 5.7 vs. 16.8 ± 6.1, NS), but the vibration perception threshold was lower in the neuropathic group (30.1 ± 13.4 vs. 40.5 ± 13.8 V, P < 0.001). Painful symptoms (neuropathy symptom score > 3), either in the past or during the time the study was conducted, had been experienced by none of the control subjects, 7 (29%) of the nonneuropathic group, 18 (60%) of the neuropathic group, and 17 (43%) of the foot ulcer group (NS for the last two groups), and were present at the time of examination in 13 (43%) of the neuropathic group and in 13 (33%) of the foot ulcer group (NS in all groups). Duration of symptoms was < 12 mo in 12 (40%) neuropathic and 15 (38%) foot ulcer patients (NS). CONCLUSIONS We conclude that painful symptoms are frequent in diabetic neuropathy, irrespective of the presence or absence of foot ulceration and that these symptoms can occur at any stage of the disease. These results suggest that there is a spectrum of neuropathic syndromes from the painful to the patients with foot ulceration, and that much overlap exists.

Twenty diabetic patients with neuropathy underwent clinical and neurophysiological evaluation together with a detailed morphometric assessment of capillary pathology in endoneurial and epineurial microvascular beds of the sural nerve. Morphological data were compared with ten non-diabetic control subjects. There were no significant differences in control subjects between basement membrane area, endothelial cell area, endothelial cell profile number or luminal area of endoneurial when compared with epineurial capillaries. In contrast, when compared with epineurial capillaries, endoneurial capillaries from diabetic patients demonstrated a significant increase in basement membrane (p

Background: Accelerated atherosclerosis is the leading cause of morbidity and mortality in diabetic patients. Hyperglycemia is a recognized independent risk factor for heightened atherogenesis in diabetes mellitus (DM). However, our understanding of the mechanisms underlying glucose damage to the vasculature remains incomplete. Methodology/Principal Findings: High glucose and hyperglycemia reduced upregulation of the NF-kB inhibitory and atheroprotective protein A20 in human coronary endothelial (EC) and smooth muscle cell (SMC) cultures challenged with Tumor Necrosis Factor alpha (TNF), aortae of diabetic mice following Lipopolysaccharide (LPS) injection used as an inflammatory insult and in failed vein-grafts of diabetic patients. Decreased vascular expression of A20 did not relate to defective transcription, as A20 mRNA levels were similar or even higher in EC/SMC cultured in high glucose, in vessels of diabetic C57BL/6 and FBV/N mice, and in failed vein grafts of diabetic patients, when compared to controls. Rather, decreased A20 expression correlated with post-translational O-Glucosamine-N-Acetylation (O-GlcNAcylation) and ubiquitination of A20, targeting it for proteasomal degradation. Restoring A20 levels by inhibiting O-GlcNAcylation, blocking proteasome activity, or overexpressing A20, blocked upregulation of the receptor for advanced glycation endproducts (RAGE) and phosphorylation of PKCbII, two prime atherogenic signals triggered by high glucose in EC/SMC. A20 gene transfer to the aortic arch of diabetic ApoE null mice that develop accelerated atherosclerosis, attenuated vascular expression of RAGE and phospho-PKCbII, significantly reducing atherosclerosis. Conclusions: High glucose/hyperglycemia regulate vascular A20 expression via O-GlcNAcylation-dependent ubiquitination and proteasomal degradation. This could be key to the pathogenesis of accelerated atherosclerosis in diabetes. Citation: Shrikhande GV, Scali ST, da Silva CG, Damrauer SM, Csizmadia E, et al. (2010) O-Glycosylation Regulates Ubiquitination and Degradation of the Anti

Transcutaneous oxygen, laser Doppler flowmetry, peroneal nerve motor conduction velocity and skin temperature were assessed in both legs of 34 diabetic patients, who had a mean age of 41 (range 29–77) years, and diabetes duration of 21 (3–34) years. Transcutaneous oxygen significantly correlated with peroneal nerve motor conduction velocity (r=0.59 p

Microvascular factors have been implicated in the pathogenesis of human diabetic neuropathy. The extent of microangiopathy was assessed in 15 diabetic patients with clinically mild neuropathy and compared with eight age matched control subjects. Endoneurial capillary density was reduced (p less than 0.04) and correlated significantly with reduced myelinated fibre density (p less than 0.01). Both basement membrane area (p less than 0.0001) and endothelial cell profile number per capillary (p less than 0.002) were significantly increased in diabetic patients and correlated significantly with both neurophysiological and neuropathological measures of neuropathic severity. There was no evidence of endothelial cell hypertrophy as assessed by either cross sectional endothelial cell area or a reduction in luminal size. Furthermore, the percentage of closed vessels did not differ between diabetic patients and control subjects and failed to relate to measures of neuropathic severity. It was concluded that microvascular abnormalities are prominent in patients with clinically mild human diabetic neuropathy, and that these data provide further support for the role of endoneurial capillary disease in the development of this condition.

We agree with Schestatsky and his colleagues that additional techniques, including quantitative sensory testing, laser-evoked potentials, or contact heat-evoked potentials as well as intraepidermal nerve …

Aldose reductase activity can be measured in the neutrophil and it has been proposed that this may be a marker for risk of complications in diabetes. We have studied aldose reductase activity in neutrophil, nerve, and lens in diabetic patients undergoing sural nerve biopsy or cataract extraction. A correlation was demonstrated between lens and neutrophil aldose reductase activity (r = 0.53, p = 0.01) but no correlations were demonstrated between nerve aldose reductase activities and nerve morphometry, nerve function or neutrophil aldose reductase activity. No significant difference was found between neutrophil aldose reductase activities in groups of patients with severe neuropathy, or cataract, or no complications (24 (interquartile range 16-32) vs 24 (16-40) vs 24 (16-40) nmol NADPH min-1 10(8)-cells-1). In a group of 56 Type 1 diabetic patients screened within 6 years of diagnosis, multiple regression analysis failed to show any relationship between neutrophil aldose reductase activity and abnormalities of neurophysiological function. These results suggest that neutrophil aldose reductase activity cannot be used as a marker for the development of cataract or neuropathy in diabetes.

According to the American Diabetes Association, 7% of the general population and 21% of people over the age of 60 are afflicted with diabetes in the US. One of the most outward and debilitating complications of diabetes is the development of chronic non-healing foot ulcerations, occurring in 15% of diabetics. In its most unfavorable course, diabetic foot ulceration (DFU) leads to amputation in 14–24% of afflicted individuals and is the leading cause of non-traumatic lower-extremity amputation in the US. The national economic burden of DFU and amputation is correspondingly staggering, estimated near US$11 billion in 2001. Traditionally, ischemia, neuropathy, trauma, and infection were considered the culprits of the recurring chronic wound. More recently, diabetic impairment of the cutaneous wound-healing process has been recognized as a major contributor to the failure to heal, and wound healing has been appreciated as yet another biological system hindered by the metabolic, vascular, neurological, and inflammatory alterations present in both type 1 and type 2 diabetes.

The Neurometer is a variable constant current sine wave stimulator, and has recently been proposed as a simple non-invasive and quantitative measure of peripheral nerve function. The device is portable and battery operated; assessment of upper and lower extremities takes only a few min, in contrast to conventional assessment techniques. In order to assess its potential in the quantification of diabetic neuropathy, detection thresholds for constant current electric sine wave stimulation were measured at three different frequencies in different sites in 31 healthy control subjects and 90 diabetic patients with and without neuropathy. The device provides good discrimination between neuropathic and non-neuropathic groups (p less than 0.001) and is quick and easy to use. Comparisons with results of conventional tests of nerve function show that high frequency detection thresholds correlate best with tests of large fibre function (r = 0.42-0.69, p less than 0.001), and low frequency detection thresholds correlate with tests of small fibre function (r = 0.34-0.46, p less than 0.005). It is concluded that the device may be a simple and comprehensive way of assessing peripheral nerve function.

Purpose: Endothelial dysfunction is associated with atheromatosis and is a common finding with diabetes. We have studied the effects of acute hyperglycemia on the endothelium-dependent vasodilatation of both the microcirculation and the macrocirculation of healthy subjects. Because of the presence of endothelial dysfunction with diabetes, we hypothesize that acute hyperglycemia causes impaired endothelial-dependent responses. Methods: Twenty healthy subjects (15 men, 5 women) with a mean age of 32.3 years (range, 23 to 49 years) were examined during fasting conditions and at 1 hour after the ingestion of 75 g of glucose. The endothelium-dependent vasodilatation of the brachial artery, a conduit vessel, was evaluated with high-resolution ultrasound scan to measure the changes in the vessel diameter induced with reactive hyperemia. In the microcirculation, the endothelial function was assessed by measuring the changes in the erythrocyte flux after the acetylcholine iontophoresis. Results: The brachial artery endothelium-dependent dilatation was greater during fasting as compared with the response after the glucose load was administered (11.7% [8.3 to 14.3] vs 4.2% [1.5 to 9.6]; P < .001; median, first, and third quartile). Both peak and average blood flow velocities during the hyperemic response were higher after the administration of the glucose load as compared with the fasting period (P < .05), but no changes were found in the blood flow volume. During fasting, microcirculatory endothelial-dependent vasodilatation was also significantly greater than the response after the administration of the glucose load (1293% [591 to 1856] vs 863% [385 to 1180]; P < .01). Conclusions: In healthy subjects, the ingestion of a glucose load impairs the endothelial-dependent vasodilation in both the microcirculation and the macrocirculation. Because impairment of endothelial responses is associated with the early changes of atherosclerosis, it is possible that prolonged hyperglycemia and endothelial dysfunction may lead to the early and accelerated atherosclerosis of diabetes. Further studies are necessary to examine the long-term effects of hyperglycemia. (J Vasc Surg 1998;28:687-94.)