Undiagnosed and Untreated Peripheral Complications of Diabetes: Findings from a Pilot Study on Diabetes-Related Foot Diseases (DFD) in Patients with Glycemic Disorders.

BACKGROUND Diabetes-related foot disease (DFD) is a serious complication of diabetes, increasing the risk of amputation. Coimplications are preventable, but most diabetics do not receive proper screening and treatment, despite indications. This study was a pilot screening of diabetes-related foot disease in a group of people with glycemic disorders. MATERIAL AND METHODS We recruited 143 volunteers over 40 years of age. In the final analysis, we included 85 people diagnosed with glycemic disorders (diabetes or prediabetes), for whom we performed a total of 170 foot measurements. We screened for peripheral artery disease using: foot pulse, ankle-brachial index (manual and automatic), toe-brachial index, and transcutaneous oxygen pressure (TcPO2). To screen for diabetic peripheral neuropathy, we used indicators of loss of protective sensation: pressure perception and temperature perception, and plantar pressure distribution. RESULTS A history of diabetes was reported by 26 (30.6%) of the subjects. Disorders of at least 1 foot occurred in 20 (66.7%) subjects with diagnosed diabetes and in 10 (17%) subjects declaring no diabetes. Higher risk and DFD category were correlated with duration of diabetes (r=0.68, p=0.007), glycemic levels (r=0.56, p=0.001), age (r=0.57, p=0.007), and the presence of other diabetes complications. The best predictor of risk in DFD was manual ABI, p=0.001; followed by automatic ABI, p=0.006. CONCLUSIONS Our results showed that peripheral complications of diabetes, such as DFD, often remain undiagnosed and untreated despite the high risk of developing ulcers. There is a need for multi-center screening studies.

Wearable laser Doppler flowmetry for non-invasive assessment of diabetic foot microcirculation: methodological considerations and clinical implications.

Significance: Type 2 diabetes mellitus (T2DM) is a global health concern with significant implications for vascular health. The current evaluation methods cannot achieve effective, portable, and quantitative evaluation of foot microcirculation. Aim: We aim to use a wearable device laser Doppler flowmetry (LDF) to evaluate the foot microcirculation of T2DM patients at rest. Approach: Eleven T2DM patients and twelve healthy subjects participated in this study. The wearable LDF was used to measure the blood flows (BFs) for regions of the first metatarsal head (M1), fifth metatarsal head (M5), heel, and dorsal foot. Typical wavelet analysis was used to decompose the five individual control mechanisms: endothelial, neurogenic, myogenic, respiratory, and heart components. The mean BF and sample entropy (SE) were calculated, and the differences between diabetic patients and healthy adults and among the four regions were compared. Results: Diabetic patients showed significantly reduced mean BF in the neurogenic (p=0.044) and heart (p=0.001) components at the M1 and M5 regions (p=0.025) compared with healthy adults. Diabetic patients had significantly lower SE in the neurogenic (p=0.049) and myogenic (p=0.032) components at the M1 region, as well as in the endothelial (p<0.001) component at the M5 region and in the myogenic component at the dorsal foot (p=0.007), compared with healthy adults. The SE in the myogenic component at the dorsal foot was lower than at the M5 region (p=0.050) and heel area (p=0.041). Similarly, the SE in the heart component at the dorsal foot was lower than at the M5 region (p=0.017) and heel area (p=0.028) in diabetic patients. Conclusions: This study indicated the potential of using the novel wearable LDF device for tracking vascular complications and implementing targeted interventions in T2DM patients.

Treating chronic wounds in an acute care setting: the forgotten diagnosis.

BACKGROUND: Chronic wounds include lower extremity ulcers, diabetic foot ulcers, and pressure injuries, and can take months or years to heal. Wounds place a high burden on outpatient and inpatient care settings. This burden is expected to increase markedly in the United States as the population ages and with increased rates of diabetes, obesity, and COVID-19. PURPOSE: To articulate the effect of chronic, hard-to-heal wounds on acute care facilities, and how a few days of inpatient care can have a significant effect on the healing trajectory. METHODS: An expert panel of 7 members, all with extensive knowledge and experience in the assessment and treatment of chronic wounds in an acute care setting, was convened in March 2022. The panel discussed the role of hospitals as part of the longer-term healing pathway of chronic wounds. RESULTS: Chronic wounds have a significant effect on hospitals that includes unseen costs, bed occupancy, demands on bedside nurses, and wound complications that lead to extended stays or readmissions. A successful inpatient wound program offers appropriate identification of previously undiagnosed wounds, elevation of bedside care through simplified protocols, quickly and easily understood education and easy dressing selection, and comprehensive discharge planning with a multidisciplinary team for continuity of care and reduced risk of readmission. CONCLUSION: Hospitals can play a key role in the management of chronic wounds, thus reducing the effect on each facility and the wider care network.

Factors Influencing Wound Healing in Diabetic Foot Patients.

Background and objectives: Diabetic foot stands out as one of the most consequential and devastating complications of diabetes. Many factors, including VIPS (Vascular management, Infection management, Pressure relief, and Source of healing), influence the prognosis and treatment of diabetic foot patients. There are many studies on VIPS, but relatively few studies on "sources of healing". Nutrients that affect wound healing are known, but objective data in diabetic foot patients are insufficient. We hypothesized that "sources of healing" would have many effects on wound healing. The purpose of this study is to know the affecting factors related to the source of healing for diabetic foot patients. Materials and Methods: A retrospective review identified 46 consecutive patients who were admitted for diabetic foot management from July 2019 to April 2021 at our department. Several laboratory tests were performed for influencing factor evaluation. We checked serum levels of total protein, albumin, vitamin B, iron, zinc, magnesium, copper, Hb, HbA1c, HDL cholesterol, and LDL cholesterol. These values of diabetic foot patients were compared with normal values. Patients were divided into two groups based on wound healing rate, age, length of hospital stay, and sex, and the test values between the groups were compared. Results: Levels of albumin (37%) and Hb (89%) were low in the diabetic foot patients. As for trace elements, levels of iron (97%) and zinc (95%) were low in the patients, but levels of magnesium and copper were usually normal or high. There were no differences in demographic characteristics based on wound healing rate. However, when compared to normal adult values, diabetic foot patients in our data exhibited significantly lower levels of hemoglobin, total protein, albumin, iron, zinc, copper, and HDL cholesterol. When compared based on age and length of hospital stay, hemoglobin levels were significantly lower in both the older age group and the group with longer hospital stays. Conclusions: Serum levels of albumin, Hb, iron, and zinc were very low in most diabetic foot patients. These low values may have a negative relationship with wound healing. Nutrient replacements are necessary for wound healing in diabetic foot patients.

The Stress of Measuring Plantar Tissue Stress in People with Diabetes-Related Foot Ulcers: Biomechanical and Feasibility Findings from Two Prospective Cohort Studies.

Reducing high mechanical stress is imperative to heal diabetes-related foot ulcers. We explored the association of cumulative plantar tissue stress (CPTS) and plantar foot ulcer healing, and the feasibility of measuring CPTS, in two prospective cohort studies (Australia (AU) and The Netherlands (NL)). Both studies used multiple sensors to measure factors to determine CPTS: plantar pressures, weight-bearing activities, and adherence to offloading treatments, with thermal stress response also measured to estimate shear stress in the AU-study. The primary outcome was ulcer healing at 12 weeks. Twenty-five participants were recruited: 13 in the AU-study and 12 in the NL-study. CPTS data were complete for five participants (38%) at baseline and one (8%) during follow-up in the AU-study, and one (8%) at baseline and zero (0%) during follow-up in the NL-study. Reasons for low completion at baseline were technical issues (AU-study: 31%, NL-study: 50%), non-adherent participants (15% and 8%) or combinations (15% and 33%); and at follow-up refusal of participants (62% and 25%). These underpowered findings showed that CPTS was non-significantly lower in people who healed compared with non-healed people (457 [117; 727], 679 [312; 1327] MPa·s/day). Current feasibility of CPTS seems low, given technical challenges and non-adherence, which may reflect the burden of treating diabetes-related foot ulcers.

An observational study of the pH value during the healing process of diabetic foot ulcer.

OBJECTIVE: In this study, we evaluated the pH (potential of hydrogen) value of diabetic foot ulcers and explored the relationship between the pH value and infection, sinus formation, stasis dermatitis, and the process of healing. METHODS: From October 2022 to June 2023, 99 patients with 106 diabetic foot ulcers were selected. Diabetic foot ulcers were treated in a standardized manner by a professional team. The pH value, area, PUSH (Pressure Ulcer Scale for Healing) score, and the degree of infection of the wounds were compared before and after the treatment. RESULTS: The baseline wound pH value in 76.4% of the patients was in the alkaline range and was closely related to the degree of infection (P < 0.05). As the ulcers healed, the pH decreased. For moderately and severely infected diabetic foot ulcers, each unit decrease in pH was associated with a decrease in the PUSH score of approximately 4.6 points (P < 0.05). The pH values of wounds with surrounding ecchymosis dermatitis were significantly higher than those of wounds without ecchymosis dermatitis (P < 0.05). The pH value of the wound with a sinus tract was higher. After treatment, there was no significant difference in pH value between the patients with and without sinus tracts (P < 0.05). CONCLUSIONS: The measurement of pH value is efficient and simple, and the patient suffers no discomfort in the process. The change in pH helps predict the healing process of diabetic foot ulcers and quickly identify whether there are key factors such as infection and ischemia in the wound. It is suggested that dynamic pH monitoring be included in the whole course evaluation and intervention strategy development of diabetic foot.

Proximal Arterial Inflow Revascularization Improves Pedal Arch Quality and Its Impact on Ischemic Diabetic Foot Ulcer Healing.

BACKGROUND: Arterial perfusion is a key factor in diabetic foot ulcer (DFU) healing. Although it is associated with pedal arch patency, not all patients are amenable to pedal artery angioplasty. This study aims to determine the impact of angiographic improvement of the pedal arch quality after proximal arterial inflow revascularization (PAIR) and its association with wound healing. METHODS: One hundred and fifty diabetic patients with tissue loss in 163 limbs who had digital subtraction angiography were studied. Cox regression analysis was used to determine independent predictors of wound healing. Wound healing rates in association with pedal arch patency were calculated by Kaplan-Meier analysis. RESULTS: End-stage renal disease, minor amputation, and complete pedal arch patency were significant independent predictors of wound healing following PAIR with hazard ratios for failure: 3.02 (P = 0.008), 0.54 (P = 0.023), and 0.40 (P = 0.039), respectively. The prevalence of complete pedal arches increased by 24.1% with successful intervention (P < 0.001). The overall rates of wound healing at 6, 12, and 24 months were 36%, 64%, and 72%, respectively. The wound healing rate at 1 year in patients with a complete pedal arch was 73% compared to 45% in those with an absent pedal arch (P = 0.017). CONCLUSIONS: PAIR increases complete pedal arch patency, a significant predictor of wound healing in DFU.

What Are Diabetic Foot Ulcers?

This JAMA Patient Page describes diabetic foot ulcers and their evaluation and treatment.

Microenvironment-Based Diabetic Foot Ulcer Nanomedicine.

Diabetic foot ulcers (DFU), one of the most serious complications of diabetes, are essentially chronic, nonhealing wounds caused by diabetic neuropathy, vascular disease, and bacterial infection. Given its pathogenesis, the DFU microenvironment is rather complicated and characterized by hyperglycemia, ischemia, hypoxia, hyperinflammation, and persistent infection. However, the current clinical therapies for DFU are dissatisfactory, which drives researchers to turn attention to advanced nanotechnology to address DFU therapeutic bottlenecks. In the last decade, a large number of multifunctional nanosystems based on the microenvironment of DFU have been developed with positive effects in DFU therapy, forming a novel concept of "DFU nanomedicine". However, a systematic overview of DFU nanomedicine is still unavailable in the literature. This review summarizes the microenvironmental characteristics of DFU, presents the main progress of wound healing, and summaries the state-of-the-art therapeutic strategies for DFU. Furthermore, the main challenges and future perspectives in this field are discussed and prospected, aiming to fuel and foster the development of DFU nanomedicines successfully.

Terahertz imaging demonstrates its diagnostic potential and reveals a relationship between cutaneous dehydration and neuropathy for diabetic foot syndrome patients.

Diabetic foot syndrome, a long term consequence of Diabetes Mellitus, is the most common cause of non-traumatic amputations. Around 8% of the world population suffers from diabetes, 15% of diabetic patients present a diabetic foot ulcer which leads to amputation in 2.5% of the cases. There is no objective method for the early diagnosis and prevention of the syndrome and its consequences. We test terahertz imaging, which is capable of mapping the cutaneous hydration, for the evaluation of the diabetic foot deterioration as an early diagnostic test as well as ulcers prevention and tracking tool. Furthermore, the analysis of our terahertz measurements combined with neurological and vascular assessment of the patients indicates that the dehydration is mainly related to the peripheral neuropathy without a significant vascular cause.

Worldwide Research Trends on Diabetic Foot Ulcers (2004-2020): Suggestions for Researchers.

OBJECTIVES: Diabetic foot ulcer (DFU) is one of the devastating complications of diabetes. It has high mortality and disability rates. The number of research articles on DFUs has increased. This study was designed to explore the global trends and research hotspots of DFUs to benefit researchers in shaping future research directions. METHODS: Literatures relating to DFU from 2004 to 2020 were retrieved from the Science Citation Index Expanded (SCI-expanded) of Web of Science Core Collection (WoSCC). The current status of DFU research (including publications, journals, the performances of relevant countries, institutions, and authors and the research trends and hotspots of DFU) was analyzed with the WoSCC. VOSviewer v1.6.10.0 was utilised for cocitation, coauthorship, cooccurrence analyses, and bibliographic coupling. RESULTS: A total of 5869 publications on DFUs were retrieved. We performed a longitudinal review of publications over 17 years: 4500 articles and 865 review articles on DFUs published from 2004 to 2020 were analyzed. The total citation was 107,296. The USA (n = 1866), England (n = 606), and China (n = 599) were the three largest contributors. The University of Washington had the greatest number of publications within this time period (n = 103), and it had the most cooperative units and was in the core position in all research institutions, followed by the University of Manchester (n = 94) and the University of Miami (n = 92). Armstrong DG (91/1.69%) and Lavery LA (55/1.19%) should be regarded as scholars who have made outstanding contributions. The top journal with the greatest total link strength was Diabetes Care. Analysis showed that the global research hotspots of DFU focused on lower limb amputation, diabetic foot infection, and treatment and management of DFU. Studies on osteomyelitis, wound therapy and management, multidisciplinary integration and mechanism of DFUs, and its related diseases are the research fronts that should be closely watched in the future. CONCLUSIONS: This study revealed the current research status and hotspots in the domain of DFU over the past 17 years, which can help researchers to further pinpoint potential perspectives on hot topics and research frontiers.

Acceptance of illness, quality of life and nutritional status of patients after lower limb amputation due to diabetes mellitus.

INTRODUCTION: Diabetes mellitus is one of the most common chronic diseases with a high number of sufferers worldwide. Diabetic neuropathy and diabetic angiopathy lead to serious infectious complications which are very difficult to combat and may finally lead to the amputation of a lower limb. The aim of the study was to evaluate the quality of life, the level of acceptance of the illness and the nutritional status of patients after lower limb amputation due to diabetes. METHODS: Ninety-nine patients (23 men and 76 women) were enrolled into the study. They had all undergone lower limb amputation due to diabetic foot and were treated in the Department of General and Oncological Surgery. The following questionnaires were used: the WHO Quality of Life-BREF (WHOQOL-BREF), the Mini Nutritional Assessment (MNA), the Acceptance of Illness Scale (AIS) and the anonymous specific socio-demographic characteristics questionnaire. RESULTS: The diabetes-related amputees were revealed to have a higher QoL within the social domain (mean score 64.48), an intermediate QoL - within the environmental domain (mean score 63.04) and the mental domain (mean score 59.61), and a lower QoL - within physical (somatic) domain (mean score 54.69). There was no statistical correlation between genders or between all the domains of QoL (P > 0.05). The mean MNA score was 22.66, which means that patients were at risk of malnutrition. There were statistical differences between women and men as regards nutritional status (P = 0.034). The mean AIS score was 27.65 (27.09 women and 29.48 men), which means that the respondents accept their disease. There was no statistical correlation between gender and the acceptance of the disease (P = 0.288). There was not statistical correlation between age and QoL (P > 0.05). There were statistical differences between age and nutritional status (P < 0.05), and between age and acceptance of the illness (P = 0.044). CONCLUSIONS: The better the quality of life was in all the domains, the better the level of acceptance of illness was. The less malnourished the patient was, the better their quality of life was in all the domains.

A Comprehensive Review of the Pathogenesis, Diagnosis, and Management of Diabetic Foot Infections.

GENERAL PURPOSE: To review an approach to diabetic foot infections (DFIs), including acute osteomyelitis, while also discussing current practices and the challenges in diagnosis and management. TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care. LEARNING OBJECTIVES/OUTCOMES: After participating in this educational activity, the participant will1. Identify the risk factors for developing DFIs.2. Outline diagnostic techniques for assessing DFIs.3. Select the assessment techniques that support a diagnosis of osteomyelitis.4. Choose the appropriate pharmacologic and nonpharmacologic treatment options for patients who have DFIs. ABSTRACT: Diabetic foot ulcers result from a combination of peripheral neuropathy, vascular compromise, and repetitive trauma. Approximately 50% of individuals with diabetic foot ulcers will develop a diabetic foot infection (DFI), and 20% of individuals with a DFI will develop osteomyelitis. Herein, the authors review an approach to DFIs including acute osteomyelitis and discuss current practices and challenges in diagnosis and management.The diagnosis of a skin and soft tissue DFI is based on clinical criteria. A bone biopsy is considered the criterion standard for diagnosis of osteomyelitis; however, biopsy is not always feasible or available. Consequently, diagnosis can be made using a combination of clinical, biochemical, and radiographic findings. X-ray is the recommended imaging modality for initial evaluation; however, because of its lower relative sensitivity, advanced imaging may be used when clinical suspicion remains after negative initial testing.The microbiology of skin and soft tissue DFIs and osteomyelitis is similar. Staphylococcus aureus and other Gram-positive cocci are the most common pathogens identified. Deep cultures are preferred in both DFI and osteomyelitis to identify the etiologic pathogens implicated for targeted antimicrobial therapy. Management also requires a multidisciplinary approach. Surgical debridement in those with deep or severe infections is necessary, and surgical resection of infected bone is curative in cases of osteomyelitis. Finally, appropriate wound care is critical, and management of predisposing factors, such as peripheral neuropathy, peripheral arterial disease, tinea, and edema, aids in recovery and prevention.

Ginsenoside Rg1 promoted the wound healing in diabetic foot ulcers via miR-489-3p/Sirt1 axis.

PURPOSE: Diabetic foot ulcers (DFUs) are common complications of high severity for diabetes. Ginsenoside Rg1 (Rg1) has the potential for diabetes and cardiovascular diseases therapy. This research aimed at exploring the regulation of Rg1 on DFUs treatment and the underlying mechanism. METHODS: Human umbilical vein endothelial cells (HUVECs) incubated with high-glucose culture medium were established for induction of diabetes model. The MTT assay, Annexin V/PI assay and oxidative stress detection were carried out on high-glucose-induced HUVECs. Dual-luciferase reporter assay was performed to prove the interaction of miR-489-3p and Sirt1. DFUs model was established to determine the efficiency of Rg1 and miR-489-3p in wound closure of DFUs in vivo. RESULTS: Rg1 promoted cell proliferation, migration and angiogenesis, and reduced cell apoptosis in high-glucose-induced HUVECs. Knockdown of miR-489-3p alleviated the high-glucose-induced damage to HUVECs, while overexpression of miR-489-3p attenuated the protection effects of Rg1. Overexpression Sirt1 promoted wound healing in DFUs and Sirt1 was a direct target of miR-489-3p. In addition, animal experiments demonstrated that Rg1 promoted wound closure by regulating miR-489-3p/Sirt1 axis. CONCLUSIONS: Rg1 alleviated the DFUs by increasing Sirt1 expression via miR-489-3p downregulation and promoting activation of PI3K/AKT/eNOS signaling.

The Design of Individual Orthopedic Insoles for the Patients with Diabetic Foot Using Integral Curves to Describe the Plantar Over-Pressure Areas.

Identification of over-pressure areas in the plantar side of the foot in patients with diabetic foot and reduction of plantar pressure play a major role in clinical practice. The use of individual orthopedic insoles is essential to reduce the over-pressure. The aim of the present study is to mark the over-pressure areas of the plantar part of the foot on a pedogram and describe them with high accuracy using a mathematical research method. The locally over-pressured areas with calluses formed due to repeated injuries were identified on the patients' pedograms. The geometric shapes of the over-pressure areas were described by means of the integral curves of the solutions to Dirichlet singular boundary differential equations. Based on the mathematical algorithm describing those curves, the computer programs were developed. The individual orthopedic insoles were produced on a computer numerical control milling machine considering the locally over-pressured areas. The ethylene vinyl acetate polymers of different degrees of hardness were used to produce the individual orthopedic insoles. For the over-pressure areas, a soft material with a hardness of 20 Shore A was used, which reduces the pressure on the plantar side of the foot and increases the contact area. A relatively hard material with a hardness of 40 Shore A was used as the main frame, which imparts the stability of shape to the insole and increases its wear life. The individual orthopedic insoles produced by means of such technology effectively reduce the pressure on the plantar side of the foot and protect the foot from mechanical damage, which is important for the treatment of the diabetic foot.

Associations between Nutrients and Foot Ulceration in Diabetes: A Systematic Review.

We reviewed the literature to evaluate potential associations between vitamins, nutrients, nutritional status or nutritional interventions and presence or healing of foot ulceration in diabetes. Embase, Medline, PubMed, and the Cochrane Library were searched for studies published prior to September 2020. We assessed eligible studies for the association between nutritional status or interventions and foot ulcers. Fifteen studies met the inclusion criteria and were included in this review. Overall, there is a correlation between poor nutritional status and the presence of foot ulceration or a delay in healing. However, there is not enough data to reach conclusions about whether the relationships are causal or only association. Further research is required to test whether any forms of nutritional supplementation improve foot ulcer healing.

Assessment of heart rate variability (HRV) in subjects with type 2 diabetes mellitus with and without diabetic foot: correlations with endothelial dysfunction indices and markers of adipo-inflammatory dysfunction.

BACKGROUND: Some studies have suggested that patients with diabetes and foot complications have worse cardiovascular and cerebrovascular risk profiles, higher degrees of endothelial dysfunction and arterial stiffness and a higher inflammatory background than patients with diabetes without diabetic foot complications. Patients with diabetes mellitus have an alteration in the sympathovagal balance as assessed by means of heart rate variability (HRV) analysis, which is also related to the presence of endothelial dysfunction. Other studies suggest a possible role of inflammation coexisting with the alteration in the sympathovagal balance in favor of the atherosclerotic process in a mixed population of healthy subjects of middle and advanced age. AIMS: The aim of this study was to evaluate the degree of alteration of sympathovagal balance, assessed by HRV analysis, in a cohort of patients with diabetes mellitus with diabetic foot and in control subjects without diabetic foot compared with a population of healthy subjects and the possible correlation of HRV parameters with inflammatory markers and endothelial dysfunction indices. METHODS: We enrolled all patients with diabetic ulcerative lesions of the lower limb in the Internal Medicine with Stroke Care ward and of the diabetic foot outpatient clinic of P. Giaccone University Hospital of Palermo between September 2019 and July 2020. 4-h ECG Holter was performed. The following time domain HRV measures were analyzed: average heart rate, square root of the mean of successive differences of NN (RMSSD), standard deviation or square root of the variance (SD), and standard deviation of the means of the NN intervals calculated over a five-minute period (SDANN/5 min). The LF/HF ratio was calculated, reactive hyperemia was evaluated by endo-PAT, and serum levels of vaspine and omentin-1 were assessed by blood sample collection. RESULTS: 63 patients with diabetic foot, 30 patients with diabetes and without ulcerative complications and 30 patients without diabetes were enrolled. Patients with diabetic ulcers showed lower mean diastolic blood pressure values than healthy controls, lower MMSE scores corrected for age, lower serum levels of omentin-1, lower RHI values, higher body weight values and comparable body height values, HF% and LF/HF ratio values. We also reported a negative correlation between the RHI value and HRV indices and the expression of increased parasympathetic activity (RMSDD and HF%) in subjects with diabetic foot and a statistically significant positive correlation with the LF/HF ratio and the expression of the sympathovagal balance. DISCUSSION: Patients with diabetic foot show a higher degree of activation of the parasympathetic system, expressed by the increase in HF values, and a lower LF/HF ratio. Our findings may corroborate the issue that a parasympathetic dysfunction may have a possible additive role in the pathogenesis of other vascular complications in subjects with diabetic foot.