Effectiveness of interventions to enhance healing of chronic ulcers of the foot in diabetes: a systematic review.

The outcome of management of diabetic foot ulcers remains a challenge, and there remains continuing uncertainty concerning optimal approaches to management. It is for these reasons that in 2008 and 2012, the International Working Group of the Diabetic Foot (IWGDF) working group on wound healing published systematic reviews of the evidence to inform protocols for routine care and to highlight areas, which should be considered for further study. The same working group has now updated this review by considering papers on the interventions to improve the healing of chronic ulcers published between June 2010 and June 2014. Methodological quality of selected studies was independently assessed by two reviewers using Scottish Intercollegiate Guidelines Network criteria. Selected studies fell into the following ten categories: sharp debridement and wound bed preparation with larvae or hydrotherapy; wound bed preparation using antiseptics, applications and dressing products; resection of the chronic wound; oxygen and other gases, compression or negative pressure therapy; products designed to correct aspects of wound biochemistry and cell biology associated with impaired wound healing; application of cells, including platelets and stem cells; bioengineered skin and skin grafts; electrical, electromagnetic, lasers, shockwaves and ultrasound and other systemic therapies, which did not fit in the aforementioned categories. Heterogeneity of studies prevented pooled analysis of results. Of the 2161 papers identified, 30 were selected for grading following full text review. The present report is an update of the earlier IWGDF systematic reviews, and the conclusion is similar: that with the possible exception of negative pressure wound therapy in post-operative wounds, there is little published evidence to justify the use of newer therapies. Analysis of the evidence continues to present difficulties in this field as controlled studies remain few and the majority continue to be of poor methodological quality.

Association of peripheral neuropathy with circulating advanced glycation end products, soluble receptor for advanced glycation end products and other risk factors in patients with type 2 diabetes.

BACKGROUND: The pathogenesis of diabetic peripheral neuropathy remains uncertain and nonenzymatic glycoxidation is one of the contributing mechanisms. The aim of this study was to assess the respective relationship of diabetic peripheral neuropathy with glycoxidation, compared with other identified risk factors, in patients with type 2 diabetes. METHODS: We included 198 patients with type 2 diabetes and high risk for vascular complications. Circulating concentrations of three advanced glycation end products (carboxymethyllysine, methyl-glyoxal-hydroimidazolone-1, pentosidine) and of their soluble receptor (sRAGE) were measured. Peripheral neuropathy was assessed by the neuropathy disability score and by the monofilament test and defined as either an abnormal monofilament test and/or a neuropathy disability score ≥6. Multivariate regression analyses were performed adjusting for potential confounding factors for neuropathy: age, gender, diabetes duration, current smoking, systolic blood pressure, waist circumference, height, peripheral arterial occlusive disease, glycated haemoglobin, estimated glomerular filtration rate and lipid profile. RESULTS: Prevalence of peripheral neuropathy was 20.7%. sRAGE and carboxymethyllysine were independently and positively associated with the presence of peripheral neuropathy. No significant association was found between peripheral neuropathy and methyl-glyoxal-hydroimidazolone-1 or pentosidine. Waist circumference, height and peripheral arterial occlusive disease were independently associated with peripheral neuropathy. CONCLUSIONS: Carboxymethyllysine and sRAGE were independently associated with peripheral neuropathy in patients with type 2 diabetes. Although the conclusions are limited by the absence of a healthy control population, this study confirms the relationship between advanced glycoxidation and diabetic peripheral neuropathy, independently of other risk factors.

Evaluation of a 5-day education programme in type 1 diabetes: achieving individual targets with a patient-centred approach.

AIMS: To evaluate if a single inpatient education training programme can achieve individualized therapeutic targets. METHODS: Patients with Type 1 diabetes participating in a flexible intensive therapy programme were consecutively included in a prospective monocentric study. They all participated in the same education programme which had a patient-centred approach. Before the intervention, patients were divided into three groups according to their main therapeutic target: Group 1, to decrease HbA1c concentration in patients with baseline HbA1c ≥ 58 mmol/mol (7.5%); Group 2, to improve quality of life and satisfaction with treatment in patients with baseline HbA1c < 58 mmol/mol (7.5%); and Group 3, to decrease the frequency of hypoglycaemic episodes in patients with severe or frequent hypoglycaemic episodes. Therapeutic targets were evaluated at 12 months. Quality of life and treatment satisfaction were evaluated with validated questionnaires completed at baseline and 6 months. RESULTS: In Group 1 (n = 74), the mean ± sd HbA1c concentration decreased from 75 ± 15 mmol/mol (9.0 ±1.4%) to 68 ±15 mmol/mol (8.4 ± 1.4%; P < 0.001), with 53% of patients experiencing a decrease in HbA1c concentration of at least 6 mmol/mol (0.5%), without weight gain or more frequent hypoglycaemia. In Group 2 (n = 12), patient satisfaction with treatment improved significantly (P < 0.0001). In Group 3 (n = 35), minor hypoglycaemia significantly decreased from a mean ± sd of 6.6 ± 4.7 to 3.2 ± 3.0 hypoglycaemic episodes/week (P < 0.001) and the incidence of severe hypoglycaemia dropped significantly from a mean ± sd of 2.31 ± 3.07 to 0.86 ± 2.46 episodes/patient/year (P < 0.001). CONCLUSIONS: Many patients with different needs, who attended the same flexible intensive therapy education programme, which had a patient-centred approach, were able to achieve their individual therapeutic targets.

Influence of peripheral vascular calcification on efficiency of screening tests for peripheral arterial occlusive disease in diabetes--a cross-sectional study.

AIMS: Pulse palpation and ankle brachial index are recommended to screen for peripheral arterial occlusive disease in people with diabetes. However, vascular calcification can be associated with false negative tests (arteriopathy present despite normal screening tests). We therefore studied the impact of peripheral vascular calcification on the performance of these tests. METHODS: This cross-sectional study included 200 people with diabetes at high risk of cardiovascular disease. The main exclusion factor was an estimated glomerular filtration rate < 30 ml/min. Peripheral arterial occlusive disease was diagnosed by colour duplex ultrasonography and peripheral vascular calcification scored by computed tomography scan. We measured sensitivity, specificity, predictive values, accuracy and likelihood ratios of pulse palpation and ankle brachial index, and looked for the impact of calcification on false negative tests (arteriopathy present despite normal screening tests). RESULTS: Ankle brachial index alone had poor sensitivity and negative predictive value and high negative likelihood ratio. Pulse palpation had higher sensitivity and negative predictive value. An abnormal pulse palpation, defined by weak or missing pulses, combined with an abnormal ankle brachial index, had the highest sensitivity and negative predictive value (92.3 and 89.8%, respectively). Vascular calcification score was higher in patients with false negative tests, for both pulse palpation and ankle brachial index (P < 0.0001 for all). Ankle systolic blood pressure was higher in patients with false negative tests for pulse palpation (P = 0.004). CONCLUSIONS: Below-knee vascular calcification gave a high rate of false negative results for ankle brachial index. Refined pulse palpation combined with ankle brachial index remained the best strategy to screen for peripheral arteriopathy.

Influence of peripheral arterial occlusive disease on the Neuropad(®) test performance in patients with diabetes.

AIMS: The specificity of the Neuropad(®) test to screen for peripheral neuropathy is moderate, but this test has several advantages, such as self-use, educative value and good sensitivity. Use of the Neuropad is usually contra-indicated in the presence of peripheral arterial occlusive disease, a condition associated with skin dryness. The aim of this study was to assess the influence of peripheral arterial occlusive disease on the performance of the Neuropad for screening peripheral neuropathy, and to compare it with the monofilament test. METHODS: We included 200 patients with diabetes. Peripheral neuropathy was defined by a neuropathy disability score ≥ 6. The Neuropad was determined as normal or abnormal at 10 and 20 min, respectively, and its performance was compared in patients with and without peripheral arterial occlusive disease diagnosed by colour duplex ultrasonography. The performances of the Neuropad and of the monofilament test were compared. RESULTS: Prevalences of peripheral neuropathy and of peripheral arterial occlusive disease were 15.8 and 44%, respectively. At 10 min, sensitivity and negative predictive value were high (93.8 and 95.1%), while specificity and positive predictive value were poor (23.2 and 18.9%). The Neuropad performance was not significantly different between patients with and without arteriopathy. Between 10 and 20 min, there was significant loss of sensitivity and gain in specificity. The Neuropad at 10 min was more sensitive but less specific than the monofilament test. CONCLUSIONS: The reliability of the Neuropad is not significantly different in the presence or absence of peripheral arterial occlusive disease.

A systematic review of interventions to enhance the healing of chronic ulcers of the foot in diabetes.

The outcome of management of diabetic foot ulcers is poor, and there is continuing uncertainty concerning optimal approaches to management. It was for these reasons that in 2006 the International Working Group of the Diabetic Foot (IWGDF) working group on wound healing undertook a systematic review of the evidence to inform protocols for routine care and to highlight areas which should be considered for further study. The same working group has now updated this review by considering papers on the interventions to improve the healing of chronic ulcers published between December 2006 and June 2010. Methodological quality of selected studies was independently assessed by two reviewers using Scottish Intercollegiate Guidelines Network criteria. Selected studies fell into the following ten categories: sharp debridement and wound bed preparation with larvae and hydrotherapy; wound bed preparation using antiseptics, applications and dressing products; resection of the chronic wound; hyperbaric oxygen therapy (HBOT); compression or negative pressure therapy; products designed to correct aspects of wound biochemistry and cell biology associated with impaired wound healing; application of cells, including platelets and stem cells; bioengineered skin and skin grafts; electrical, electromagnetic, lasers, shockwaves and ultrasound; other systemic therapies which did not fit in the above categories. Heterogeneity of studies prevented pooled analysis of results. Of the 1322 papers identified, 43 were selected for grading following full text review. The present report is an update of the earlier IWGDF systematic review, but the conclusion is similar: that with the exception of HBOT and, possibly, negative pressure wound therapy, there is little published evidence to justify the use of newer therapies. This echoes the conclusion of a recent Cochrane review and the systematic review undertaken by the National Institute for Health and Clinical Excellence Guidelines Committee in the UK. Analysis of evidence presents considerable difficulties in this field particularly as controlled studies are few and the majority are of poor methodological quality.

Pregnant type 1 diabetes women with rises in C-peptide display higher levels of regulatory T cells: A pilot study.

AIM: During pregnancy of type 1 diabetes (T1D) women, a C peptide rise has been described, which mechanism is unclear. In T1D, a defect of regulatory T cells (Tregs) and its major controlling cytokine, interleukin-2 (IL2), is observed. METHODS: Evolution of clinical, immunological (Treg (CD4+CD25hiCD127-/loFoxp3+ measured by flow cytometry and IL2 measured by luminex xMAP technology) and diabetes parameters (insulin dose per day, HbA1C, glycaemia, C peptide) was evaluated in 13 T1D women during the three trimesters of pregnancy and post-partum (PP, within 6 months) in a monocentric pilot study. Immunological parameters were compared with those of a healthy pregnant cohort (QuTe). RESULTS: An improvement of beta cell function (C peptide rise and/or a decrease of insulin dose-adjusted A1c index that estimate individual exogenous insulin need) was observed in seven women (group 1) whereas the six others (group 2) did not display any positive response to pregnancy. A higher level of Tregs and IL2 was observed in group 1 compared to group 2 during pregnancy and at PP for Tregs level. However, compared to the healthy cohort, T1D women displayed a Treg deficiency CONCLUSION: This pilot study highlights that higher level of Tregs and IL2 seem to allow improvement of endogenous insulin secretion of T1D women during pregnancy.

Five-year mortality in patients with diabetic foot ulcer during 2009-2010 was lower than expected.

AIM: Mortality rates are decreasing in patients with diabetes. However, as this observation also concerns patients with diabetic foot ulcer (DFU), additional data are needed. For this reason, our study evaluated the 5-year mortality rate in patients with DFU during 2009-2010 and identified risk factors associated with mortality. METHODS: Consecutive patients who attended a clinic for new DFU during 2009-2010 were followed until healing and at 1 year. Data on mortality were collected at year 5. Multivariate Cox proportional-hazards model was used to identify mortality risk factors. RESULTS: A total of 347 patients were included: mean age was 65±12 years, diabetes duration was 16 [10; 27] years; 13% were on dialysis; and 7% had an organ transplant. At 5 years, 49 patients (14%) were considered lost to follow-up. Total mortality rate at 5 years was 35%, and 16% in patients with neuropathy. On multivariate analyses, mortality was positively associated with: age [hazard ratio (HR): 1.05 (1.03-1.07), P<0.0001]; duration of diabetes [HR: 1.02 (1.001-1.03], P=0.03]; PEDIS perfusion grade 2 vs. 1 [HR: 2.35 (1.28-4.29), P=0.006)]; PEDIS perfusion grade 3 vs. 1 [HR: 3.14 (1.58-6.24), P=0.001); and ulcer duration at year 1 [HR 2.09 (1.35-3.22), P=0.0009]. CONCLUSION: Mortality rates were not as high as expected despite the large number of comorbidities, suggesting that progress has been made in the health management of these patients. In particular, patients with neuropathic foot ulcer had a survival rate of 84% at 5 years.

Factors associated with oral health-related quality of life in patients with diabetes.

BACKGROUND: Oral pathologies are prevalent in diabetes, and they may affect the quality of life and patient's perception of their oral health. The aim of this study was to investigate the factors associated with oral health-related quality of life of patients with diabetes. METHODS: A cross sectional study was conducted involving 316 patients visiting a hospital diabetic unit. Sociodemographic, oral and medical care data were recorded, and a General Oral Health Assessment Index (GOHAI) questionnaire was completed. A multivariable analysis was performed. RESULTS: Of the 316 study participants, 61.7% had type 2 diabetes (T2DM) and 20.5% had poorly controlled diabetes. Forty-five percent had at least one oral complication, 55% had visited a dentist within the past year and 67% reported having poor oral health and 281 answered the GOHAI questionnaire. A low GOHAI score (≤50) was obtained for 24.6% of the patients and was associated with T2DM, poorer oral health, dry mouth sensation and use of a removable prosthesis. CONCLUSIONS: Oral health status was poorer and had a negative effect on the quality of life among patients with T2DM, possibly contributing to poorly balanced nutrition.

Lower-extremity arterial revascularization: Is there any evidence for diabetic foot ulcer-healing?

The presence of peripheral arterial disease (PAD) is an important consideration in the management of diabetic foot ulcers. Indeed, arteriopathy is a major factor in delayed healing and the increased risk of amputation. Revascularization is commonly performed in patients with critical limb ischaemia (CLI) and diabetic foot ulcer (DFU), but also in patients with less severe arteriopathy. The ulcer-healing rate obtained after revascularization ranges from 46% to 91% at 1 year and appears to be improved compared to patients without revascularization. However, in those studies, healing was often a secondary criterion, and there was no description of the initial wound or its management. Furthermore, specific alterations associated with diabetes, such as microcirculation disorders, abnormal angiogenesis and glycation of proteins, can alter healing and the benefits of revascularization. In this review, critical assessment of data from the literature was performed on the relationship between PAD, revascularization and healing of DFUs. Also, the impact of diabetes on the effectiveness of revascularization was analyzed and potential new therapeutic targets described.

Coping and distress as predictors of glycemic control in diabetes.

This study attempts to identify the relative contribution of coping styles (task-, emotion-oriented and avoidance) and anxiety and diabetes-related distress to glycemic control in IDDM (Insulin Dependent Diabetes Mellitus) patients. Recent research suggests that coping and distress may as well be determinants as consequences of certain characteristics of the illness and subject. This points to the need to control some of these variables in diabetic research. Ninety seven IDDM patients from an outpatient unit were included. Measures were self-report questionnaires (CISS, STAI-Y, PAID) and biological data (HbA1C i.e. metabolic control). When potential confounds were controlled for (current age, age at onset, gender, presence of complication), three main predictors of metabolic control could be isolated through hierarchical regression analysis: (1) presence of complications; (2) task-oriented coping style; and (3) diabetes-related distress. Three steps were included in predictors: illness and subject variables (step 1); coping styles (step 2); and negative emotions (step 3). Each step contributed to a significant increase in variance. Emotion-oriented coping style appeared as redundant with distress measures. Results suggest that the relations between psychological predictors and metabolic control would be closer in women. These results partly replicate other findings, and advocate for a better consideration of emotional factors in the prediction of blood glucose control in this disease.

Interleukin-2 and type 1 diabetes: new therapeutic perspectives.

A new sort of CD4+T cells, so-called regulatory T cells (Tregs), has been described in 1996. Tregs are suggested to have an important function consisting in controlling autoimmune reactions. In humans, absence of Tregs induces the IPEX syndrome characterized by the presence of several autoimmune diseases. These cells depend on interleukin-2 (IL-2) for proliferating and controlling the T effector cells (Teff) reaction, but they do not have the capacity to produce IL-2. In type 1 diabetes (T1DM), a hypothesis is that a lack of IL-2 in pancreas could prevent Tregs action and lead to beta cells destruction. In NOD mice, low dose IL-2 treatment at the initial time of diabetes can rescue insulin secretion by restoring proteins expression that are necessary for Tregs regulatory function in the pancreas. Using low doses instead of high doses IL-2 prevents Teff activation which also depends on IL-2. These results led to conduct a dose-effect trial in human T1DM. This trial aimed at determining the therapeutic condition, which induces Tregs activation without major side effects, in a therapeutic perspective to recover insulin secretion at the apparition of diabetes.

Painful diabetic neuropathy: diagnosis and management.

The prevalence of painful diabetic peripheral neuropathy (PDN) is about 20% in patients with type 2 diabetes and 5% in those with type 1. Patients should be systematically questioned concerning suggestive symptoms, as they are not usually volunteers. As PDN is due to small-fibre injury, the 10 g monofilament pressure test as well as the standard electrophysiological procedures may be normal. Diagnosis is based on clinical findings: type of pain (burning discomfort, electric shock-like sensation, aching coldness in the lower limbs); time of occurrence (mostly at rest and at night); and abnormal sensations (such as tingling or numbness). The DN4 questionnaire is an easy-to-use validated diagnostic tool. Three classes of drugs are of equal value in treating PDN: tricyclic antidepressants; anticonvulsants; and selective serotonin-reuptake inhibitors. These compounds may be prescribed as first-line therapy following pain assessment using a visual analogue scale. If the initial drug at its maximum tolerated dose does not lead to a decrease in pain of at least 30%, another drug class should be prescribed; if the pain is decreased by 30% but remains greater than 3/10, a drug from a different class may be given in association.