Phenotyping animal models of diabetic neuropathy: a consensus statement of the diabetic neuropathy study group of the EASD (Neurodiab).

NIDDK, JDRF, and the Diabetic Neuropathy Study Group of EASD sponsored a meeting to explore the current status of animal models of diabetic peripheral neuropathy. The goal of the workshop was to develop a set of consensus criteria for the phenotyping of rodent models of diabetic neuropathy. The discussion was divided into five areas: (1) status of commonly used rodent models of diabetes, (2) nerve structure, (3) electrophysiological assessments of nerve function, (4) behavioral assessments of nerve function, and (5) the role of biomarkers in disease phenotyping. Participants discussed the current understanding of each area, gold standards (if applicable) for assessments of function, improvements of existing techniques, and utility of known and exploratory biomarkers. The research opportunities in each area were outlined, providing a possible roadmap for future studies. The meeting concluded with a discussion on the merits and limitations of a unified approach to phenotyping rodent models of diabetic neuropathy and a consensus formed on the definition of the minimum criteria required for establishing the presence of the disease. A neuropathy phenotype in rodents was defined as the presence of statistically different values between diabetic and control animals in 2 of 3 assessments (nocifensive behavior, nerve conduction velocities, or nerve structure). The participants propose that this framework would allow different research groups to compare and share data, with an emphasis on data targeted toward the therapeutic efficacy of drug interventions.

Pilot study of the effects of bariatric surgery and continuous positive airway pressure treatment on vascular function in obese subjects with obstructive sleep apnoea.

BACKGROUND: The mechanisms by which obesity and obstructive sleep apnoea (OSA) may contribute to endothelial dysfunction are unclear. AIMS: We sought to follow up a sample of obese subjects undergoing either bariatric surgery or continuous positive airway pressure (CPAP) therapy to treat OSA. We hypothesised improved vascular function with both therapeutic approaches, consistent with a reversible OSA effect on the circulation. METHODS: Twenty-seven obese (BMI ≥30 kg/m(2)) subjects with OSA underwent either bariatric surgery without CPAP (n = 12, median BMI 43.7 kg/m(2) IQR 9.4) or CPAP (n = 15, median BMI 33.8 kg/m(2) IQR 6.6). Polysomnography and vascular testing (flow-mediated dilation of the brachial artery measured with high-resolution ultrasound, endothelium-dependent change in skin blood flow measured with laser Doppler flowmetry, and arterial stiffness measured with applanation tonometry) took place at baseline and after 6 months. RESULTS: Both groups showed significant improvements in the apnoea-hypopnea index and overnight oxygen saturation. Endothelium-dependent microvascular reactivity was 45.6% (IQR 37.5) at baseline in the CPAP group, which increased to 69.1% (IQR 62.3) post-treatment (P < 0.05). No significant changes were observed in the surgery group, despite significant weight loss (post-surgery BMI 32.7 kg/m2 IQR 8.6 (P < 0.01); no change in BMI was observed in the CPAP group. There were no significant changes in brachial artery flow-mediated dilation in either group. CONCLUSIONS: This pilot study demonstrates that 6 months of CPAP may be sufficient to improve endothelium-dependent microvascular reactivity, while substantial surgically induced weight loss did not result in improvements. Further research should be directed towards comparative effectiveness trials using these novel surrogate outcomes, as well as hard cardiovascular outcomes.

Small fibre neuropathy: role in the diagnosis of diabetic sensorimotor polyneuropathy.

Small fibres constitute 70-90% of peripheral nerve fibres and regulate several key functions such as tissue blood flow, temperature and pain perception as well as sweating, all of which are highly relevant to the clinical presentation and adverse outcomes associated with foot ulcerations in patients with diabetes. Recent studies demonstrated significant abnormalities in the small fibres in subjects with impaired glucose tolerance and diabetes, despite normal electrophysiology, suggesting that the earliest nerve fibre damage is to the small fibres. Unfortunately, guidelines and consensus statements focus on large fibres and continue to advocate electrophysiology as a diagnostic modality and as a primary end point for the assessment of therapeutic benefit. (In part, this reflects the difficulties in quantifying small fibre dysfunction and damage.) We have therefore critically assessed currently available techniques that measure small fibre dysfunction in diabetic neuropathy, using quantitative sensory and sudomotor testing. We have assessed the role of identifying structural damage by quantifying intraepidermal nerve fibre density in skin biopsies and corneal nerve morphology using corneal confocal microscopy. Finally, we propose a definition for diabetic neuropathy that incorporates small fibre damage.

Air pollution and inflammation in type 2 diabetes: a mechanism for susceptibility.

BACKGROUND: Particulate air pollution has been associated with several adverse cardiovascular health outcomes, and people with diabetes may be especially vulnerable. One potential pathway is inflammation and endothelial dysfunction-processes in which cell adhesion molecules and inflammatory markers play important roles. AIM: To examine whether plasma levels of soluble intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and von Willebrand factor (vWF) were associated with particle exposure in 92 Boston area residents with type 2 diabetes. METHODS: Daily average ambient levels of air pollution (fine particles (PM2.5), black carbon (BC) and sulphates) were measured approximately 500 m from the patient examination site and evaluated for associations with ICAM-1, VCAM-1 and vWF. Linear regressions were fit to plasma levels of ICAM-1, VCAM-1 and vWF, with the particulate pollutant index, apparent temperature, season, age, race, sex, glycosylated haemoglobin, cholesterol, smoking history and body mass index as predictors. RESULTS: Air pollutant exposure measures showed consistently positive point estimates of association with the inflammatory markers. Among participants not taking statins and those with a history of smoking, associations between PM(2.5), BC and VCAM-1 were particularly strong. CONCLUSIONS: These results corroborate evidence suggesting that inflammatory mechanisms may explain the increased risk of air pollution-associated cardiovascular events among those with diabetes.

Validation of the nerve axon reflex for the assessment of small nerve fibre dysfunction.

OBJECTIVE: To validate nerve-axon reflex-related vasodilatation as an objective method to evaluate C-nociceptive fibre function by comparing it with the standard diagnostic criteria. METHODS: Neuropathy was evaluated in 41 patients with diabetes (26 men and 15 women) without peripheral vascular disease by assessing the Neuropathy Symptom Score, the Neuropathy Disability Score (NDS), the vibration perception threshold (VPT), the heat detection threshold (HDT), nerve conduction parameters and standard cardiovascular tests. The neurovascular response to 1% acetylcholine (Ach) iontophoresis was measured at the forearm and at both feet by laser flowmetry. An age-matched and sex-matched control group of 10 healthy people was also included. RESULTS: Significant correlations were observed between the neurovascular response at the foot and HDT (r(s) = -0.658; p<0.0001), NDS (r(s) = -0.665; p<0.0001), VPT (r(s) = -0.548; p = 0.0005), tibial nerve conduction velocity (r(s) = 0.631; p = 0.0002), sural nerve amplitude (r(s) = 0.581; p = 0.0002) and autonomic function tests. According to the NDS, in patients with diabetes who had mild, moderate or severe neuropathy, a significantly lower neurovascular response was seen at the foot than in patients without neuropathy and controls. A neurovascular response <50% was found to be highly sensitive (90%), with a good specificity (74%), in identifying patients with diabetic neuropathy. CONCLUSION: Small-fibre dysfunction can be diagnosed reliably with neurovascular response assessment. This response is already reduced in the early stages of peripheral neuropathy, supporting the hypothesis that small-fibre impairment is an early event in the natural history of diabetic neuropathy.

Microcirculation of the diabetic foot.

Studies over the last decade have revealed impairment of the microcirculation in the diabetic foot. Endothelial dysfunction along with derangements in numerous biochemical pathways has been implicated as causes of microcirculation impairment. Additionally, reduction or absence of the nerve-axon reflex renders the diabetic foot unable to mount a vasodilatory response under conditions of stress, such as injury or infection and makes it functionally ischemic even in the presence of satisfactory blood flow under normal conditions. Furthermore, these changes appear to be directly related to the presence of diabetic neuropathy. These alterations in the diabetic microcirculation may explain the poor wound healing commonly observed in diabetes.

Role of C-nociceptive fibers in the nerve axon reflex-related vasodilation in diabetes.

OBJECTIVE: To evaluate the role of the C-nociceptive nerve fibers in nerve axon reflex-related vasodilation. METHODS: 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. RESULTS: 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; p < 0.001) and at the foot in the two nonneuropathic groups (C 74 +/- 10% and D 68.9 +/- 9%; p < 0.001 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, p < 0.017; vibration perception threshold, r = -0.527, p < 0.002; Semmes-Weinstein monofilament perception, r = -0.619, p < 0.001). CONCLUSION: 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.

Sural nerve fibre pathology in diabetic patients with mild neuropathy: relationship to pain, quantitative sensory testing and peripheral nerve electrophysiology.

Nerve fibre pathology is poorly described in diabetic patients with mild neuropathy and has not been adequately related to clinical evaluation, quantitative sensory examination and neurophysiology. Sural nerve myelinated and unmyelinated fibre pathology was morphometrically quantified and related to the presence of pain and conventional measures of neuropathic severity in 15 diabetic patients with mild neuropathy and 14 control subjects. Diabetic patients demonstrated a significant (P < 0.01) reduction in myelinated fibre density, but no change in fibre/axonal area, or g-ratio, compared to control subjects. Unmyelinated fibre degeneration was evidenced by an increase in the percentage of unassociated Schwann cell profiles (P < 0.0001) and a reduction in axon density (P < 0.0008) in diabetic patients. This was associated with a significant reduction in unmyelinated axon diameter (P < 0.001) with a shift of the size frequency distribution to the left (P < 0.02). Neurophysiology, quantitative sensory testing and nerve fibre pathology failed to differentiate diabetic patients with painful and painless neuropathy and failed to correlate with any measure of unmyelinated fibre pathology.

Graftskin, a human skin equivalent, is effective in the management of noninfected neuropathic diabetic foot ulcers: a prospective randomized multicenter clinical trial.

OBJECTIVE: We assessed in a randomized prospective trial the effectiveness of Graftskin, a living skin equivalent, in treating noninfected nonischemic chronic plantar diabetic foot ulcers. RESEARCH DESIGN AND METHODS: In 24 centers in the U.S., 208 patients were randomly assigned to ulcer treatment either with Graftskin (112 patients) or saline-moistened gauze (96 patients, control group). Standard state-of-the-art adjunctive therapy, which included extensive surgical debridement and adequate foot off-loading, was provided in both groups. Graftskin was applied at the beginning of the study and weekly thereafter for a maximum of 4 weeks (maximum of five applications) or earlier if complete healing occurred. The major outcome of complete wound healing was assessed by intention to treat at the 12-week follow-up visit. RESULTS: At the 12-week follow-up visit, 63 (56%) Graftskin-treated patients achieved complete wound healing compared with 36 (38%) in the control group (P = 0.0042). The Kaplan-Meier median time to complete closure was 65 days for Graftskin, significantly lower than the 90 days observed in the control group (P = 0.0026). The odds ratio for complete healing for a Graftskin-treated ulcer compared with a control-treated ulcer was 2.14 (95% CI 1.23-3.74). The rate of adverse reactions was similar between the two groups with the exception of osteomyelitis and lower-limb amputations, both of which were less frequent in the Graftskin group. CONCLUSIONS: Application of Graftskin for a maximum of 4 weeks results in a higher healing rate when compared with state-of-the-art currently available treatment and is not associated with any significant side effects. Graftskin may be a very useful adjunct for the management of diabetic foot ulcers that are resistant to the currently available standard of care.

Contribution of nerve-axon reflex-related vasodilation to the total skin vasodilation in diabetic patients with and without neuropathy.

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.

Screening techniques to identify people at high risk for diabetic foot ulceration: a prospective multicenter trial.

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.

The effect of hormonal replacement therapy on the vascular reactivity and endothelial function of healthy individuals and individuals with type 2 diabetes.

Estrogens protect healthy women from cardiovascular disease. However, epidemiological data suggest that women with diabetes are denied the cardioprotection associated with estrogens. Whether or not hormonal replacement therapy (HRT) confers cardiovascular benefits in postmenopausal women with diabetes is not known. The aim of this study was to examine the effects of HRT on the microvascular reactivity and endothelial function of individuals with and without diabetes. We studied the following groups of individuals: premenopausal healthy women [n = 28, age 41 +/- 8 yr (mean +/- SD)], premenopausal women with type 2 diabetes (n = 16, age 43 +/- 6 yr); postmenopausal healthy women (n = 12, age 57 +/- 4 yr), postmenopausal women with diabetes (n = 17, age 62 +/- 5 yr); postmenopausal healthy women on HRT (n = 13, age 51 +/- 5 yr), postmenopausal women with diabetes on HRT (n = 11, age 57 +/- 7 yr). We used laser Doppler flowmetry to measure forearm cutaneous vasodilatation in response to iontophoresis of 1% acetylcholine (endothelium dependent) and 1% sodium nitroprusside (endothelium independent). The endothelium-dependent vasodilation was significantly higher in premenopausal healthy women (180 +/- 67%; increase over baseline) compared to premenopausal diabetic women (87 +/- 41%; P < 0.001). endothelium-dependent vasodilation was also higher in postmenopausal healthy women on HRT (143 +/- 52) compared with postmenopausal diabetic women on HRT (86 +/- 61), postmenopausal healthy women without HRT (104 +/- 43), and postmenopausal diabetic women without HRT (74 +/- 28; P < 0.001). A similar pattern of responses was observed in the endothelium-independent vasodilation (premenopausal healthy women, 126 +/- 56; premenopausal diabetic women, 88 +/- 26; postmenopausal healthy women on HRT, 121 +/- 37; postmenopausal diabetic women on HRT, 88 +/- 41; postmenopausal healthy women without HRT, 84 +/- 36; and postmenopausal diabetic women without HRT, 73 +/- 36; P < 0.001). Soluble intercellular adhesion molecule (sICAM) was also measured among all the women with diabetes. Premenopausal women with diabetes (248.9 +/- 56 ng/ml) and postmenopausal women with diabetes on HRT (257.7 +/- 49 ng/ml) had lower sICAM levels compared with the postmenopausal diabetic women without HRT (346.4 +/- 149 ng/ml; P < 0.05). We conclude that menopausal status and type 2 diabetes are associated with impaired microvascular reactivity. HRT substantially improves microvascular reactivity in postmenopausal healthy women. In contrast, the effect of HRT on the microvascular reactivity of postmenopausal diabetic women is less apparent. However, the use of HRT among women with diabetes is associated with lower sICAM levels, suggesting an attenuation in endothelial activation.

Soluble intercellular adhesion molecule, vascular cell adhesion molecule, and impaired microvascular reactivity are early markers of vasculopathy in type 2 diabetic individuals without microalbuminuria.

OBJECTIVE: Using von Willebrand Factor (vWF) as a marker of endothelial function, previous studies have shown that the development of microalbuminuria is associated with the onset of endothelial dysfunction in individuals with type 2 diabetes. We tested the hypothesis that endothelial dysfunction is already evident in normoalbuminuric individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: We used laser Doppler imaging scanning to measure vasodilation in the forearm skin in response to iontophoresis of 1% acetylcholine (endothelium-dependent) and 1% sodium nitroprusside (endothelium-independent). Multiple indicators of endothelial function--soluble intercellular adhesion molecule (sICAM), soluble vascular cell adhesion molecule (sVCAM), vWF, and microvascular reactivity--were measured in 20 healthy control subjects, 45 normoalbuminuric (urinary albumin/creatinine ratio < 30 micrograms/mg) individuals with type 2 diabetes, and 14 microalbuminuric (urinary albumin/creatinine ratio between 30 and 300 micrograms/mg) individuals with type 2 diabetes. RESULTS: Serum sICAM and sVCAM levels were elevated in the normoalbuminuric (305 +/- 120, 851 +/- 284 ng/ml) and microalbuminuric (300 +/- 89, 845 +/- 252 ng/ml) individuals with diabetes when compared with the healthy control subjects (213 +/- 58, 661 +/- 176 ng/ml) (P < 0.01). Furthermore, the microvascular endothelium-dependent and -independent vasodilation was reduced in the normoalbuminuric (76 +/- 44, 70 +/- 33) (percent increase in perfusion over baseline) and microalbuminuric (74 +/- 41, 73 +/- 28) individuals with diabetes compared with healthy control subjects (126 +/- 67, 120 +/- 47) (P < 0.05). In contrast, plasma vWF was elevated only in the microalbuminuric individuals with diabetes (129 +/- 35%) compared with the normoalbuminuric individuals with diabetes (110 +/- 34) and healthy control subjects (111.3 +/- 39) (P < 0.05). On stepwise multivariate analysis, fasting blood glucose was the most important contributing factor to the variation in microvascular reactivity and sVCAM, whereas insulin resistance (by homeostasis model assessment) was the most important contributing factor to the variation in sICAM. Addition of all clinical and biochemical measures explained only 15-22% of the variation in sICAM, sVCAM, and microvascular reactivity. CONCLUSIONS: Multiple markers of endothelial dysfunction were evident in normoalbuminuric individuals with type 2 diabetes. The pathogenic process of vasculopathy in type 2 diabetes occurs early and may be operative before the development of microalbuminuria.

Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes.

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.

Endothelium-dependent vasodilatation is impaired in both microcirculation and macrocirculation during acute hyperglycemia.

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.

Role of neuropathy and high foot pressures in diabetic foot ulceration.

OBJECTIVE: High plantar foot pressures in association with peripheral neuropathy have been ascertained to be important risk factors for ulceration in the diabetic foot. Most studies investigating these parameters have been limited by their size and the homogeneity of study subjects. The objective of this study was therefore to ascertain the risk of ulceration associated with high foot pressures and peripheral neuropathy in a large and diverse diabetic population. RESEARCH DESIGN AND METHODS: We studied a cross-sectional group of 251 diabetic patients of Caucasian (group C) (n=121), black (group B) (n=36), and Hispanic (group H) (n=94) racial origins with an overall age of 58.5+/-12.5 years (range 20-83). There was an equal distribution of men and women across the entire study population. All patients underwent a complete medical history and lower extremity evaluation for neuropathy and foot pressures. Neuropathic parameters were dichotomized (0/1) into two high-risk variables: patients with a vibration perception threshold (VPT) > or =25 V were categorized as HiVPT (n=132) and those with Semmes-Weinstein monofilament tests > or =5.07 were classified as HiSWF (n=190). The mean dynamic foot pressures of three footsteps were measured using the F-scan mat system with patients walking without shoes. Maximum plantar pressures were dichotomized into a high-pressure variable (Pmax6) indicating those subjects with pressures > or =6 kg/cm2 (n=96). A total of 99 patients had a current or prior history of ulceration at baseline. RESULTS: Joint mobility was significantly greater in the Hispanic cohort compared with the other groups at the first metatarsal-phalangeal joint (C 67+/-23 degrees, B 69+/-23 degrees, H 82+/-23 degrees, P=0.000), while the subtalar joint mobility was reduced in the Caucasian group (C 21+/-8 degrees, B 26+/-7 degrees, H 27+/-11 degrees, P=0.000). Maximum plantar foot pressures were significantly higher in the Caucasian group (C 6.7+/-2.9 kg/cm2, B 5.7+/-2.8 kg/cm2, H 4.4+/-1.9 kg/cm2, P=0.000). Univariate logistic regression for Pmax6 on the history of ulceration yielded an odds ratio (OR) of 3.9 (P=0.000). For HiVPT, the OR was 11.7 (P=0.000), and for HiSWF the OR was 9.6 (P=0.000). Controlling for age, diabetes duration, sex, and race (all P < 0.05), multivariate logistic regression yielded the following significant associations with ulceration: Pmax6 (OR=2.1, P=0.002), HiVPT (OR=4.4, P=0.000), and HiSWF (OR=4.1, P=0.000). CONCLUSIONS: We conclude that both high foot pressures (> or =6 kg/cm2) and neuropathy are independently associated with ulceration in a diverse diabetic population, with the latter having the greater magnitude of effect. In black and Hispanic diabetic patients especially, joint mobility and plantar pressures are less predictive of ulceration than in Caucasians.

Evaluation of a collagen-alginate wound dressing in the management of diabetic foot ulcers.

Efficacy and safety of a collagen-alginate topical wound dressing (FIBRACOL Collagen-Alginate Wound Dressing) in the treatment of diabetic foot ulcers was compared with that of regular gauze moistened with normal saline. Seventy-five patients with foot ulcers were assigned randomly in a 2:1 ratio to the collagen-alginate test dressing or the gauze dressing. At the end of the study, the mean percent reduction of the wound area was 80.6% +/- 6% in the collagen-alginate dressing group and 61.1% +/- 26% in the gauze dressing group (p = .4692). Thirty-nine (78%) patients treated with the collagen-alginate dressing achieved > or = 75% wound area reduction, compared with 15 (60%) of gauze-treated patients. Complete healing was achieved in 24 (48%) of the collagen-alginate dressing group and 9 (36%) of the gauze dressing group. Wound size, when averaged over the 8-week period and with the duration of the ulcer taken into account, was reduced significantly in the collagen-alginate dressing group, as compared with the gauze dressing group (df = 1, p = .0049). It is concluded that the collagen-alginate test dressing is as or more effective and safe as the currently used treatment.