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We examined the effects of high-dosage vitamin E treatment over a 12-month period on the vascular reactivity of micro- and macrocirculation and left ventricular function in diabetic patients. Subjects (n = 89) were randomized to vitamin E (1,800 IU daily) or placebo and were followed for 12 months. High-resolution ultrasound images were used to measure the flow-mediated dilation (FMD; endothelium dependent) and nitroglycerin-induced dilation (NID; endothelium independent) of the brachial artery. Laser Doppler perfusion imaging was used to measure vascular reactivity in the forearm skin. Left ventricular function was evaluated using transthoracic echocardiogram. At the end of the 6-month period, a worsening in endothelium-dependent skin vasodilation (P = 0.02) and rise in endothelin levels (P = 0.01) were found in the vitamin E compared with the placebo group. At the end of the 12-month period, a worsening was observed in NID (P = 0.02) and a marginal worsening was seen in systolic blood pressure (P = 0.04) and FMD (P = 0.04) in the vitamin E compared with the placebo group. In addition C-reactive protein levels decreased marginally in the vitamin E compared with the placebo group (P = 0.05). No changes were observed in left ventricular function. We concluded that long-term treatment with 1,800 IU of vitamin E has no beneficial effects on endothelial or left ventricular function in diabetic patients. Because vitamin E–treated patients had a worsening in some vascular reactivity measurements when compared with control subjects, the use of high dosages of vitamin E cannot be recommended.

To evaluate the effect of local anesthesia on the skin vasodilation induced by the iontophoresis of sodium nitroprusside and heating.Skin vascular reactivity, in response to iontophoresis of sodium nitroprusside (SNP), was evaluated at the forearm and foot in 13 neuropathic diabetic (DN) and 11 nonneuropathic diabetic (D) patients and 9 healthy, nondiabetic subjects who served as controls (C). The direct (DI) and nerve axon reflex-related (N-V) vasodilation were measured by using two single-point laser Doppler probes. The vasodilation in response to local warming was also assessed. A topical anesthetic was applied on the contralateral forearm and foot and all the measurements were repeated.Dermal anesthesia resulted in a reduction of the direct vasodilation to SNP at the forearm [C: 58.1 +/- 16, D: 60.6 +/- 11%, and DN: 48.3 +/- 37% (postanesthesia percentage of reduction; mean +/- SEM), P0.01] and at the foot in all three groups (D: 38.5 +/- 12%, P0.01; C: 27.2 +/- 14% and DN: 11.3 +/- 17.5%, P=NS). The N-V related vasodilation was very low before and did not change after local anesthesia. The postanesthesia hyperemic response to warming was significantly reduced at low temperatures but did not change at 44 degrees C.The sodium nitroprusside-related vasodilation is reduced after local anesthesia in a similar way in healthy subjects and diabetic patients with and without neuropathy. The response to heating is also reduced at low temperatures. This indicates a stabilizing effect of local anesthesia on the smooth muscle cell.

The aim of this study was to assess the reliability of the laser Doppler perfusion imager (Lisca PIM 1.0; Lisca development, Linkoping, Sweden) for longitudinal analysis. We measured the skin blood flow under a biological zero condition at the forearm level in 84 patients enrolled in a 12 week prospective interventional trial. Since the biological zero is the background reading registered by the laser when blood flow has been occluded, any fluctuation of the measurements obtained under this condition can be attributable to the laser scanner’s variability rather than biological variation. After the blood flow of the arm was occluded and arrested by a pressure cuff, blood perfusion readings were taken before and after the iontophoresis of a 1% acetylcholine chloride solution and a 1% sodium nitroprusside solution at the beginning of the study and during the two follow-up visits. A total of 927 biological zero readings were recorded throughout the study. The coefficient of variation of these measurements was...

Objectives. The role of tangential stress in neuropathic foot ulceration is yet unknown. The aim of this study was to investigate the tangential forces developed during gait by the whole foot and by selected subareas of it, namely the heel, the metatarsals and the hallux. Methods. 61 diabetic patients have been evaluated: 27 without neuropathy, 19 with neuropathy and 15 with previous neuropathic ulcer. The patients were compared with 21 healthy volunteers. A piezo-dynamometric platform was used to measure the three components of the ground reaction force under the total foot and the selected subareas. Results. A significant reduction was observed for the forward peak and the backward peak of the anteroposterior ground reaction force component measured under the whole foot. Patients with previous neuropathic ulcer showed a significant increase of the mediolateral stress under the metatarsals. Conclusions. Tangential stress is altered in diabetic neuropathic patients; the increased mediolateral component suggests that tangential stress could have a role in the high risk of recurrence observed in patients with previous ulceration. Relevance To assess the effectiveness of a non-invasive methodology for the estimation and the monitoring of significant alterations of the tangential stress with the increase of neuropathy.

Diabetes is often defined a “vascular disease” because of the early and extensive involvement of the vascular-tree observed in patients with diabetes and even in those at risk of developing diabetes. Both the micro- and macrocirculation are affected. Changes in the micro- and macrocirculation, both anatomical and functional, contribute to the development of diabetic neuropathy. On the other hand, the development of diabetic neuropathy also affects the vasodilatory capacity of the microcirculation. Thus, the interaction between changes in the vasculature and peripheral nerves is bidirectional and results in changes in both blood flow and neuronal function. The possible links between diabetic micro- and macrovascular alterations and nerve damage will be the focus of this chapter.

OBJECTIVE—To assess the ability of the 4-week healing rate to predict complete healing over a 12-week period in a large prospective multicenter trial of diabetic patients with foot ulceration. RESEARCH DESIGN AND METHODS—We examined the change in ulcer area over a 4-week period as a predictor of wound healing within 12 weeks in patients who were seen weekly in a prospective, randomized controlled trial. RESULTS—Wound area measurements at baseline and after 4 weeks were performed in 203 patients. The midpoint between the percentage area reduction from baseline at 4 weeks in patients healed versus those not healed at 12 weeks was found to be 53%. Subjects with a reduction in ulcer area greater than the 4-week median had a 12-week healing rate of 58%, whereas those with reduction in ulcer area less than the 4-week median had a healing rate of only 9% (P < 0.01). The absolute change in ulcer area at 4 weeks was significantly greater in healers versus nonhealers (1.5 vs. 0.8 cm2, P < 0.02). The percent change in wound area at 4 weeks in those who healed was 82% (95% CI 70–94), whereas in those who failed to heal, the percent change in wound area was 25% (15–35; P < 0.001). CONCLUSIONS—The percent change in foot ulcer area after 4 weeks of observation is a robust predictor of healing at 12 weeks. This simple tool may serve as a pivotal clinical decision point in the care of diabetic foot ulcers for early identification of patients who may not respond to standard care and may need additional treatment.

The aim of the present study was to examine the relationship among water diuresis-induced changes in renal oxygenation, endothelial function, and various metabolic parameters in type 2 diabetic patients and healthy subjects at risk of type 2 diabetes. Thirty-eight subjects with type 2 diabetes (D: age, 54 ± 10 years, mean ± SD, 24 men) and 7 healthy subjects with parental history of type 2 diabetes or with impaired glucose tolerance (IGT) (relatives [R]: age 46 ± 11 years, 4 men) were included. Laser Doppler imaging scanning was used to measure vasodilatation in the forearm skin in response to iontophoresis of 1% acetylcholine (Ach) and 1% sodium nitroprusside (SNP), and ultrasound was used to measure the flow-mediated dilation (FMD) and nitroglycerin-induced dilation (NID) in the brachial artery. Renal oxygenation was assessed by magnetic resonance imaging (MRI) before and during water diuresis. A decrease in the magnetic parameter R2∗ implies an increase in oxygenation. Renal medullary oxygenation did not improve with diuresis in either group (D: −0.5 ± 1.9, R: −0.4 ± 2.1, P = not significant [NS]). The renal cortical oxygenation showed a small, but statistically significant, improvement after diuresis in the 2 groups (D: −0.6 ± 1.1, R: −0.5 ± 0.5, P < .05). There were no correlations between the change in cortical R2∗ (R2∗ post-minus R2∗ prewater diuresis) and the micro- and macrovascular reactivity. The postdiuresis renal cortical R2∗ was negatively correlated with both the Ach- and SNP-induced skin vasodilation (% change over baseline)(r = −.40, P < .01 and r = − .39, P < .05, respectively), while no correlation existed with the FMD and NID. The baseline renal cortical oxygenation was also negatively correlated with the SNP-induced skin vasodilation (r = −.36, P < .05) and positively correlated with the fasting plasma glucose, total cholesterol, and vascular cell adhesion molecule (VCAM) concentrations (r = .34, P < .05, r = .31, P < .05 and r = .37, P < .05, respectively). These preliminary findings suggest an association between the kidney cortical oxygenation and the skin microvascular reactivity, glycemia, and lipidemia. Water diuresis failed to produce an improvement in renal medullary oxygenation in both patients with diabetes and subjects at risk for diabetes.

We have investigated the effect of atorvastatin on the endothelial function of patients with diabetes and subjects at risk for type 2 diabetes in a 12-wk, prospective, randomized, placebo-controlled, double-blind clinical trial. The flow- mediated dilation (FMD; endothelium dependent) and nitroglycerin-induced dilation (endothelium independent) in the brachial artery and the vascular reactivity at the forearm skin were measured. FMD improved in the atorvastatin-treated, at-risk subjects [median (25-75 percentile), 7.2% (2.9-9.6%) at exit visit vs. 6.6% (2.9-9.5%) at baseline; P < 0.05]. A similar improvement of FMD was found in atorvastatin-treated diabetic patients [median (25-75 percentile), 5.6 (3.9-7.9) at exit visit vs. 4.2 (3.2-7.2) at baseline; P = 0.07]. No changes were observed in nitroglycerin-induced dilation and the microcirculation reactivity measurements in either group. In the at-risk group, there was a decrease in the C-reactive protein [median (25-75 percentile), 0.12 mg/dl (0.07-0.27 mg/dl) at exit visit vs. 0.24 mg/dl (0.07-0.35 mg/dl) at baseline; P < 0.05] and TNF alpha [median (25-75 percentile), 2.6 pg/ml (1.8-4.1 pg/ml) at exit visit vs. 4.4 pg/ml (3.6-6.0 pg/ml) at baseline; P < 0.05] in the atorvastatin-treated patients, whereas in the diabetes group, a decrease in endothelin-1 (mean +/- SD, 0.97 +/- 0.29 pg/ml at exit visit vs. 1.19 +/- 0.42 pg/ml at baseline; P < 0.05) and plasminogen activator inhibitor-1 [median (25-75 percentile), 18 ng/ml (9-24 ng/ml) at exit visit vs. 27 ng/ml (7-41 ng/ml) at baseline; P < 0.05] were observed. We conclude that atorvastatin improves endothelial function and decreases levels of markers of endothelial activation and inflammation.

OBJECTIVE—Endothelial dysfunction has been reported in type 2 diabetic patients and in obese subjects with insulin resistance syndrome (IRS). This study evaluates the effects of weight reduction and exercise on vascular reactivity of the macro- and the microcirculation in obese subjects with IRS. RESEARCH DESIGN AND METHODS—We studied 24 obese subjects (9 men and 15 women, age 49.3 ± 1.9 years, BMI 36.7 ± 0.94 kg/m2, mean ± SEM) with IRS at baseline and after 6 months of weight reduction and exercise. Brachial artery flow-mediated dilation (FMD) and response to sublingual glyceryltrinitrate (GTN) were assessed by high-resolution ultrasound. Microvascular reactivity was evaluated by the laser-Doppler perfusion imaging after iontophoresis of acetylcholine and sodium nitroprusside. We also measured plasma levels of soluble intercellular adhesion molecule (sICAM), vascular adhesion molecule, von Willebrand factor, plasminogen activator inhibitor-1 (PAI-1) antigen, and tissue plasminogen activator antigen. RESULTS—This intervention resulted in 6.6 ± 1% reduction in body weight (P < 0.001) and significant improvement of insulin sensitivity index (2.9 ± 0.36 vs. 1.9 ± 0.33 [10−4 · min−1 · (μU ml−1)], P < 0.001). FMD significantly improved (12.9 ± 1.2% vs. 7.9 ± 1.0%, P < 0.001), whereas response to GTN and microvascular reactivity did not change. Similar observations were seen when the subjects were subclassified according to their glucose tolerance to normal glucose tolerance, impaired glucose tolerance, and type 2 diabetes. sICAM and PAI-1 significantly decreased (251.3 ± 7.7 vs. 265.6 ± 9.3 ng/ml, P = 0.018 and 36.2 ± 3.6 vs. 48.6 ± 3.9 ng/ml, P = 0.001, respectively). The relationship between percentage weight reduction and improved FMD was linear (R2 = 0.47, P = 0.001). CONCLUSIONS—We conclude that 6 months of weight reduction and exercise improve macrovascular endothelial function and reduces selective markers of endothelial activation and coagulation in obese subjects with IRS regardless of the degree of glucose tolerance.

OBJECTIVES—Secondary to peripheral neuropathy, plantar hyperpressure is a proven risk factor for foot ulceration. But limited joint mobility (LJM) and soft tissue abnormalities may also contribute. The aim of this study was to evaluate the relationships among thickness of plantar fascia, mobility of the metatarso-phalangeal joint, and forces expressed under the metatarsal heads. RESEARCH DESIGN AND METHODS—We evaluated 61 diabetic patients: 27 without neuropathy (D group), 19 with neuropathy (DN group), and 15 with previous neuropathic foot ulceration (DNPU group). We also examined 21 control subjects (C). Ultrasound evaluation was performed with a high resolution 8- to 10-MHz linear array (Toshiba Tosbee SSA 240). The foot loading pattern was evaluated with a piezo-dynamometric platform. First metatarso-phalangeal joint mobility was assessed with a mechanic goniometer. RESULTS—Diabetic patients presented increased thickness of plantar fascia (D 2.9 ± 1.2 mm, DN 3.0 ± 0.8 mm, DNPU 3.1 ± 1.0 mm, and C 2.0 ± 0.5.mm; P < 0.05), and significantly reduced motion range at the metatarso-phalangeal joint (D 54.0 ± 29.4°, DN 54.9 ± 17.2°, DNPU 46.8 ± 20.7°, and C 100.0 ± 10.0°; P < 0.05). The evaluation of foot-floor interaction under the metatarsal heads showed increased vertical forces in DN and DNPU and increased medio-lateral forces in DNPU. An inverse correlation was found between the thickness of plantar fascia and metatarso-phalangeal joint mobility (r = −0.53). The thickness of plantar fascia was directly correlated with vertical forces under the metatarsal heads (r = 0.52). CONCLUSIONS—In diabetic patients, soft tissue involvement may contribute to the increase of vertical forces under the metatarsal heads. Changes in the structure of plantar fascia may also influence the mobility of the first metatarso-phalangeal joint.

To evaluate the role of the C-nociceptive nerve fibers in nerve axon reflex-related vasodilation.Skin vascular reactivity, in response to iontophoresis of acetylcholine and sodium nitroprusside, was evaluated at both the forearm and the foot levels in 13 diabetic neuropathic (DN),11 nonneuropathic (D), and 9 healthy control (C) subjects. The total and nerve axon reflex-related vasodilation were measured by two single-point laser probes. A topical anesthetic was applied on the contralateral forearm and foot, and all the measurements were repeated.Dermal anesthesia resulted in a reduction of the nerve axon reflex-related vasodilation at the forearm in all three groups (C 70.7 +/- 12%, D 59.7 +/- 7%, and DN 73.5 +/- 14%; percentage of reduction over preanesthesia response, mean +/- SEM; p0.001) and at the foot in the two nonneuropathic groups (C 74 +/- 10% and D 68.9 +/- 9%; p0.001 versus before anesthesia). This reduction was absent at the foot of the neuropathic patients (DN -4 +/- 21%; p = NS versus before anesthesia). A correlation was found between the nerve axon reflex-related response and measurements of nerve function (neuropathy disability score, r = -0.425, p0.017; vibration perception threshold, r = -0.527, p0.002; Semmes-Weinstein monofilament perception, r = -0.619, p0.001).The nerve axon reflex-related vasodilation is directly related to the function of the C-nociceptive fibers and is significantly associated with other nerve function measurements. As this is an objective measurement, it has the potential to be used as an alternative to currently employed techniques to evaluate small-fiber function.

OBJECTIVE—Diabetic neuropathic patients show a peculiar loading pattern of the foot, which led us to hypothesize that a substantial modification exists in their deambulatory strategy. The aim of the present study was to support this hypothesis by quantifying the changes of the loading patterns and by monitoring the excursion of center of pressure (COP) during gait. RESEARCH DESIGN AND METHODS—A total of 21 healthy volunteers (C) and 61 diabetic patients were evaluated: 27 diabetic subjects without neuropathy (D), 19 with neuropathy (DN), and 15 with previous neuropathic ulcer (DPU). A piezo-dynamometric platform was used to record the foot-to-floor interaction by measuring loading time and the instantaneous COP position during the stance phase of gait. RESULTS—Loading time was significantly longer in neuropathic patients than in control subjects (DPU: 816.8 ± 150 ms; DN: 828.6 ± 152 ms; D: 766.5 ± 89.9 ms; C: 723.7 ± 65.7 ms; P < 0.05). COP excursion along the medio-lateral axis of the foot clearly decreased from C to DPU groups (C: 6.41 ± 0.1 cm; D: 4.88 ± 0.2 cm; DN: 4.57 ± 0.1 cm; DPU: 3.36 ± 0.1 cm; P < 0.05) as well as COP excursion along the longitudinal axis for the DPU group only (C: 26.6 ± 1 cm; D: 26.9 ± 1 cm; DN: 27.2 ± 1 cm; DPU: 24.2 ± 1 cm; P < 0.05). COP integrals were significantly reduced for all pathological classes (DPU: 14.2 ± 8 cm2; DN: 25.8 ± 6 cm2; D: 27.7 ± 3 cm2; C: 38.6 ± 6 cm2; P < 0.05). CONCLUSIONS—The accurate quantification of loading patterns and of COP excursions and integrals highlights changes of foot-to-floor interaction in diabetic neuropathic patients. The decreased medio-lateral and longitudinal COP excursions and corresponding changes of loading times and patterns support our hypothesis that a change in the walking strategy of diabetic patients with peripheral neuropathy does occur.

OBJECTIVE—We have previously demonstrated that high plantar pressures can predict foot ulceration in diabetic patients. The aim of the present study was to evaluate both the relationship between forefoot and rearfoot plantar pressure in diabetic patients with different degrees of peripheral neuropathy and their role in ulcer development. RESEARCH DESIGN AND METHODS—Diabetic patients of a 30-month prospective study were classified according to the neuropathy disability score: scores of 0, 1–5, 6–16, and 17–28 are defined as absent (n = 20), mild (n = 66), moderate (n = 95), and severe (n = 57) neuropathy, respectively. The F-Scan mat system was used to measure dynamic plantar pressures. The peak pressures under the forefoot and the rearfoot were selectively measured for each foot, and the forefoot-to-rearfoot ratio (F/R ratio) was calculated. RESULTS—Foot ulcers developed in 73 (19%) feet. The peak pressures were increased in the forefoot of the severe and moderate neuropathic groups compared with the mild neuropathic and nonneuropathic groups (6.2 ± 4.5 and 3.8 ± 2.7 vs. 3.0 ± 2.1 and 3.3 ± 2.1 kg/cm2 [mean ± SD], respectively; P < 0.0001). The rearfoot pressures were also higher in the severe and moderate neuropathic groups compared with the mild neuropathic and nonneuropathic groups (3.2 ± 2.0 and 3.2 ± 1.9 vs. 2.5 ± 1.3 and 2.3 ± 1.0, respectively; P < 0.0001). The F/R ratio was increased only in the severe group compared with the moderate and mild neuropathic and nonneuropathic groups (2.3 ± 2.4 vs. 1.5 ± 1.2, 1.3 ± 0.9, and 1.6 ± 1.0, respectively; P < 0.0001). In a logistic regression analysis, both forefoot pressure (odds ratio 1.19 [95% CI 1.11–1.28], P < 0.0001) and the F/R ratio (1.37 [1.16–1.61], P < 0.0001) were related to risk of foot ulceration, whereas rearfoot pressure was not. CONCLUSIONS—Both the rearfoot and forefoot pressures are increased in the diabetic neuropathic foot, whereas the F/R ratio is increased only in severe diabetic neuropathy, indicating an imbalance in pressure distribution with increasing degrees of neuropathy. This may lend further evidence toward the concept that equinus develops in the latest stages of peripheral neuropathy and may play an important role in the etiology of diabetic foot ulceration.