Matrix metalloproteinases and diabetic foot ulcers: the ratio of MMP-1 to TIMP-1 is a predictor of wound healing

Aims Matrix metalloproteinases (MMPs) play a major role in wound healing: they can degrade all components of the extracellular matrix. In diabetic foot ulcers there is an excess of MMPs and a decrease of the tissue inhibitors of MMPs (TIMPs). This imbalance is probably one cause of impaired healing. However, little is known about changes in MMPs during wound healing. Methods Sixteen patients with neuropathic diabetic foot ulcers participated. Wound fluid was collected regularly during the 12-week follow-up period, for measurement of MMP-1, MMP-2, MMP-8, MMP-9 and TIMP-1. Results were analysed by the degree of wound healing: good healers (defined by a reduction of at least 82% in initial wound surface at 4 weeks) and poor healers (reduction of less than 82% in wound surface at 4 weeks). Results In good healers, levels of MMP-8 and -9 secreted by inflammatory cells decreased earlier. The initial levels of MMP-1 were similar in good and poor healers (P = 0.1) but rose significantly at week 2 in good healers (P = 0.039). There was a significant correlation between a high ratio of MMP-1/TIMP-1 and good healing (r = 0.65, P = 0.008). Receiver Operator Curve (ROC) analysis showed that an MMP-1/TIMP-1 ratio of 0.39 best predicted wound healing (sensitivity = 71%, specificity = 87.5%). Conclusions A high level of MMP-1 seems essential to wound healing, while an excess of MMP-8 and -9 is deleterious, and could be a target for new topical treatments. The MMP-1/TIMP-1 ratio is a predictor of wound healing in diabetic foot ulcers.     

Topical application of the bee hive protectant propolis is well tolerated and improves human diabetic foot ulcer healing in a prospective feasibility study

AimsPropolis is a naturally occurring anti-inflammatory bee derived protectant resin. We have previously reported that topically applied propolis reduces inflammation and improves cutaneous ulcer healing in diabetic rodents. The aim of this study was to determine if propolis shows efficacy in a pilot study of human diabetic foot ulcer (DFU) healing and if it is well tolerated.MaterialsSerial consenting subjects (n = 24) with DFU ≥ 4 week's duration had topical propolis applied at each clinic review for 6 weeks. Post-debridement wound fluid was analyzed for viable bacterial count and pro-inflammatory MMP-9 activity. Ulcer healing data were compared with a matched control cohort of n = 84 with comparable DFU treated recently at the same center.ResultsUlcer area was reduced by a mean 41% in the propolis group compared with 16% in the control group at week 1 (P < 0.001), and by 63 vs. 44% at week 3, respectively (P < 0.05). In addition, 10 vs. 2% (P < 0.001), then 19 vs. 12% (P < 0.05) of propolis treated vs. control ulcers had fully healed by weeks 3 and 7, respectively. Post-debridement wound fluid active MMP-9 was significantly reduced, by 18.1 vs. 2.8% week 3 from baseline in propolis treated ulcers vs. controls (P < 0.001), as were bacterial counts (P < 0.001). No adverse effects from propolis were reported.ConclusionsTopical propolis is a well-tolerated therapy for wound healing and this pilot in human DFU indicates for the first time that it may enhance wound closure in this setting when applied weekly. A multi-site randomized controlled of topical propolis now appears to be warranted in diabetic foot ulcers.     

Efficacy of shock wave therapy on chronic diabetic foot ulcer: A single-blinded randomized controlled clinical trial

ObjectiveThis study was conducted to evaluate the efficacy of extracorporeal shock wave therapy (ESWT) on the healing rate, wound surface area and wound bed preparation in chronic diabetic foot ulcers (DFU).MethodsThirty eight patients with 45 chronic DFU were randomly assigned into; the ESWT-group (19 patients/24 ulcers) and the control-group (19 patients/21 ulcers). Blinded therapist measured wound surface area (WSA), the percentage of reduction in the WSA, rate of healing and wound bed preparation at baseline, after the end of the interventions (W8), and at 20-week follow-up (W20). The ESWT group received shock wave therapy twice per week for a total of eight treatments. Each ulcer was received ESWT at a frequency of 100 pulse/cm², and energy flux density of 0.11 mJ/cm². All patients received standardized wound care consisting of debridement, blood-glucose control agents, and footwear modification for pressure reduction.ResultsThe overall clinical results showed completely healed ulcers in 33.3% and 54% in ESWT-groups and 14.28% and 28.5% in the control group after intervention (W8), and at follow-up (W20) respectively. The average healing time was significantly lower (64.5 ± 8.06 days vs 81.17 ± 4.35 days, p < 0.05) in the ESWT-group compared with the control group.ConclusionESWT-treated ulcers had a significant reduction in wound size and median time required for ulcer healing, with no adverse reactions. So, the ESWT is advocated as an adjunctive therapy in chronic diabetic wound.     

Polymerase chain reaction–denaturing gradient gel electrophoresis (PCR–DGGE): A promising tool to diagnose bacterial infections in diabetic foot ulcers

AimThe diagnosis of diabetic foot infections is difficult due to limitations of conventional culture-based techniques. The objective of this study was to evaluate the contribution of denaturing gradient gel electrophoresis (DGGE) in the microbiological diagnosis of diabetic foot ulcers in comparison to conventional techniques, and also to evaluate the need to perform a biopsy sample for this diagnosis.MethodsTwenty diabetic patients (types 1 and 2) with foot ulcers (grades 1–4) were included. After debridement of their wounds, samples were taken in duplicate by surface swabbing and deep-tissue biopsy. The samples were analyzed by conventional culture and by a new molecular biology tool, DGGE technology.ResultsPolymerase chain reaction (PCR)–DGGE led to the identification of more bacteria than did conventional cultures (mean: 2.35 vs 0.80, respectively). In 11 cases, the technology detected pathogenic species not isolated by classical cultures. PCR–DGGE also identified significantly more pathogenic species at deep levels compared with species detected at superficial levels (87% vs 58%, respectively; P = 0.03). In 9/20 cases, pathogenic bacteria were detected only in deep samples, revealing the need to perform tissue biopsy sampling.ConclusionDGGE, achievable in 48 h, could be a useful technique for the bacteriological diagnosis of diabetic foot infections. It may help to identify pathogenic bacteria in deeply infected ulcers, thereby contributing to a more appropriate use of antibiotics.     

Assessment of risk factors in diabetic foot ulceration and their impact on the outcome of the disease

AimsThe current study aims to identify risk factors for diabetic foot ulcer and their impact on the outcome of the disease.MethodsThree hundred diabetic patients were enrolled in the study. One hundred eighty subjects with diabetic foot ulcer and 120 diabetic controls without foot lesions. All expected risk factors were studied in all patients and after a follow up period, patients with diabetic foot ulcer were classified into group A (patients with healed ulcers) and group B (patients with persistent ulcer or ended by amputation). The risk factors were reanalyzed in both groups to find out their impact on the outcome of the disease.ResultsThe following variables were significant factors for foot ulceration: Male gender (P = 0.009), previous foot ulcer (P = 0.003), peripheral vascular disease (P = 0.004), and peripheral neuropathy (P = 0.006). Also lack of frequent foot self-examination was independently related to foot ulcer risk. The outcome was related to longer diabetes duration (P = 0.004), poor glycaemic control (P = 0.006) and anaemia (P = 0.003) and presence of infection (P < 0.001).ConclusionsPeripheral vascular disease and peripheral neuropathy together with lack of foot self-examination, poor glycaemic control and anaemia are main significant risk factors for diabetic foot ulceration.     

Exercise ameliorates serum MMP-9 and TIMP-2 levels in patients with type 2 diabetes

AimThis study assessed the impact of regular exercise on inflammatory markers (high-sensitivity C-reactive protein [hsCRP], fibrinogen), and matrix metalloproteinases (MMPs) and their inhibitors (TIMPs), in patients with type 2 diabetes mellitus (T2DM).PatientsFifty overweight patients with T2DM were randomly assigned to two groups: (A) an exercise group (EXG, n = 25), with self-controlled exercise for at least 150 min/week and one additional supervised exercise session/week; and (B) a control group (COG, n = 25), with no exercise instructions. All participants were taking oral antidiabetic drugs, and none had diabetic complications. Clinical parameters, exercise capacity (VO_2peak), ventilatory threshold (VT), insulinresistance indices (fasting insulin, HOMA-IR, HOMA%S), hsCRP, fibrinogen, MMP-2, MMP-9, TIMP-1 and TIMP-2 were assessed at baseline and after 16 weeks.ResultsNo significant changes were found in body mass index, waist/hip ratio, insulin-resistance indices, MMP-2 and TIMP-1 throughout the study in either group (P > 0.05). Compared with controls, the EXG showed a significant decrease in systolic and mean blood pressure, total and LDL cholesterol, and HbA_1c (P < 0.05). Also, exercise significantly suppressed levels of fibrinogen (P = 0.047), hsCRP (P = 0.041) and MMP-9 (P = 0.028), and the MMP-9-to-TIMP-1 ratio (P = 0.038), whereas VO_2peak (P = 0.011), VT (P = 0.008) and plasma TIMP-2 levels (P = 0.022) were considerably upregulated in the EXG vs. COG. Standard multiple-regression analyses revealed that MMP-9 changes were independently associated with fibrinogen and HbA_1c changes, while fibrinogen changes independently predicted TIMP-2 alterations with exercise.ConclusionMostly self-controlled exercise of moderate intensity ameliorated serum levels of pro- and anti-atherogenic markers in patients with T2DM, with no effects on body weight. These data offer further insight into the cardioprotective mechanisms of exercise in patients with T2DM.     

MMP-9 in atrial remodeling in patients with atrial fibrillation

IntroductionAtrial fibrillation (AF) is the most common arrhythmia and is associated with significant morbidity and mortality. The impact of matrix metalloproteinases (MMPs) on structural atrial remodeling and sustainment of AF in patients with persistent and permanent AF is unresolved.ObjectivesThe aim was to evaluate MMP-9 and its tissue inhibitor-1 (TIMP-1) as markers of atrial remodeling in patients with persistent AF (PAF) who underwent electrical cardioversion (ECV) and in patients with permanent AF (continuous AF, CAF).Patients and methodsPlasma levels of MMP-9 and TIMP-1, clinical findings, and echocardiographic parameters were evaluated in 39 patients with AF and in 14 controls with sinus rhythm.ResultsThe concentrations of MMP-9 were significantly higher in patients with PAF and CAF compared to controls. There was a significant increase of MMP-9 after ECV in the persistent AF group. The values of TIMP-1 were not significantly different between the groups. In patients with AF, MMP-9 levels were positively related to posterior wall thickness of the LV (r = 0.356, P = 0.049) and body mass index (r = 0.367, P = 0.046).ConclusionElevated levels of MMP-9 were related to the occurrence and maintenance of AF. This suggests that MMP-9 can be a marker of atrial remodeling in patients with AF. Regulation of the extracellular collagen matrix might be a potential therapeutic target in AF.     

Serum levels of MMP-9 and TIMP-1 in primary hypertension and effect of antihypertensive treatment

BackgroundMatrix metalloproteinases, a family of proteolytic enzymes are thought to be involved in extracellular matrix accumulation during development of hypertensive target organ disease. The present study was designed to compare hypertensive patients with normotensive individuals with respect to serum levels of matrix metalloproteinase (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)-1 and to search for the effect of antihypertensive treatment on the serum enzyme levels.MethodsThirty-three patients with stage 1 primary hypertension and sixteen age- and sexmatched control subjects were enrolled into the study. Serum MMP-9 and TIMP-1 levels were assessed in the hypertensive group before and after a 3-month-antihypertensive treatment (candesartan 8 mg/day to 17 patients and lisinopril 10 mg/day to 16 patients).ResultsPre-treatment serum MMP-9 levels were higher in the hypertensive group (p = 0.309) while serum TIMP-1 levels were lower (p = 0.296). Serum MMP-9 levels were decreased (p < 0.001) and TIMP-1 levels were increased (p = 0.022) after the antihypertensive treatment.ConclusionsIn hypertensive patients, increased MMP-9 activity could result in increased degradation of elastin relative to collagen and non-elasticity, while decreased TIMP-1 activity could lead to accumulation of poorly cross-linked, immature and unstable fibril degradation products, which result in misdirected deposition of collagen. Our study is important for revealing the role of the MMP enzyme system in the pathogenesis of hypertensive target organ disease.     

Geographic variation in Medicare spending and mortality for diabetic patients with foot ulcers and amputations

AimsThe purpose of this study was to identify the presence or absence of geographic variation in Medicare spending and mortality rates for diabetic patients with foot ulcers (DFU) and lower extremity amputations (LEA).MethodsDiabetic beneficiaries with foot ulcers (n=682,887) and lower extremity amputations (n=151,752) were enrolled in Medicare Parts A and B during the calendar year 2007. We used ordinary least squares (OLS) regression to explain geographic variation in per capita Medicare spending and one-year mortality rates.ResultsHealth care spending and mortality rates varied considerably across the nation for our two patient cohorts. However, higher spending was not associated with a statistically significant reduction in one-year patient mortality (P= .12 for DFU, P= .20 for LEA). Macrovascular complications for amputees were more common in parts of the country with higher mortality rates (P< .001), but this association was not observed for our foot ulcer cohort (P= .12). In contrast, macrovascular complications were associated with increased per capita spending for beneficiaries with foot ulcers (P= .01). Rates of hospital admission were also associated with higher per capita spending and increased mortality rates for individuals with foot ulcers (P< .001 for health spending and mortality) and lower extremity amputations (P< .001 for health spending, P= .01 for mortality).ConclusionsGeographic variation in Medicare spending and mortality rates for diabetic patients with foot ulcers and amputations is associated with regional differences in the utilization of inpatient services and the prevalence of macrovascular complications.     

Effect of foot-ankle flexibility and resistance exercise in the secondary prevention of plantar foot diabetic ulcer

AimsThe study aimed to evaluate the effects of foot-ankle flexibility and resistance exercises on the recurrence rate of plantar foot diabetic ulcers, HbA1c levels, diabetic neuropathy examination (DNE) scores, ankle brachial index (ABI), and walking speed within 12 and 24 weeks.MethodsWe conducted a double-blind randomized clinical trial. Fifty patients with recently healed plantar foot diabetic ulcers were randomized to an intervention group that performed foot-ankle flexibility and resistance exercise three times a week in their home (n = 25) or a control group (n = 25). Both groups were given foot care education. Outcomes were assessed at plantar foot diabetic ulcer recurrence or at 12 and 24 weeks whichever came first. Outcome measures included plantar foot diabetic ulcer recurrence, changes of HbA1c levels, DNE scores, ankle brachial index ABI, and walking speed.ResultsThere were significant difference between groups in ulcer recurrence at either 12 weeks (intervention 8%, control 68%, RR 0.288; 95% CI 0.156–0.534, P = 0.000) within 12 weeks.or 24 weeks (intervention 16%, control 72%, RR 0.222; 95% CI 0.088–0.564, P = 0.000).). There were significant differences in the DNE score delta (P = 0.000) and walking speed delta (P = 0.000), but there were no significant differences in the HbA1c delta and ABI delta between groups at either 12 or 24 weeks.ConclusionsFoot-ankle flexibility and resistance exercises can reduce the recurrence of plantar foot diabetic ulcer incidence and improve diabetic neuropathy and walking speed.Clinical trial number: NCT04624516     

25-Hydroxyvitamin D [25(OH)D] levels and diabetic foot ulcer: Is there any relationship?

AimsIn recent years, there has been an effort to understand possible roles of 25(OH)D, including its role in the immune system particularly on T cell medicated immunity, pancreatic insulin secretion and insulin action. 25(OH)D stimulates the cell differentiation and reduces cell proliferation, which is essential for cell growth and wound healing. However, data on the association between low level of plasma 25(OH)D and diabetic foot syndrome are scarce.Materials and MethodsCirculating plasma levels of 25(OH)D were measured in diabetic patients with ulcer (n = 162) and without ulcer (n = 162) in a prospective cohort hospital based study.ResultsOf these patients, 85.1% had type 2 diabetes. Subjects with diabetic foot ulcer showed lower median plasma level of 25(OH)D [6.3(4.2–11.1) vs 28.0(21.4–37.0)] ng/ml after adjusting the age and BMI. Regardless of the low levels of 25(OH)D in cases and controls, it was associated with neuropathy, sex (female), duration of ulcer healing, and smoking status and independent of confounding factors, including BMI (kg/m²), A1c (%), hypertension, nephropathy, foot ulcer, retinopathy, CAD, PAD, HDL-C (mg/dl) and LDL-C (mg/dl). The factors which predict the risk of developing ulcer independent of 25(OH)D status were A1c (>6.9%) [OR 4.37; RR 1.77], HDL-C (<40 mg/dl) [OR 1.16; RR 1.07], LDL-C (>100 mg/dl) [OR 1.07; RR 1.03], triglycerides (>200 mg/dl) [OR 1.40; RR 1.19], neuropathy [OR 6.88; RR 3.12], retinopathy [OR 3.34; RR 1.91], hypertension [OR 1.64; RR 1.28], nephropathy [OR 3.12; RR 1.87] and smoking [OR 4.53; RR 2.99] using odds and risk ratios.ConclusionIt is not clear whether the suppression of delayed wound healing seen during 25(OH)D deficiency is due to the secondary effect or is a direct action of vitamin D on certain components of the immune system. Long-term randomized trials are needed to see the impact of vitamin D supplementation on the outcome of diabetic foot patients.     

Characteristics and management of diabetic patients hospitalized for myocardial infarction in France

AimThe objective of this study was to compare the management of diabetic and non-diabetic patients before, during and after hospitalization for myocardial infarction (MI).MethodsHospital admissions for MI in France from January to June 2006 were obtained from the national hospital-discharge database and merged with data on medications, 6 months before and after hospitalization of patients covered by the general health insurance scheme. Diabetic patients were identified by having at least two refunds for antidiabetic medications 6 months before the index hospitalization. Results comparing diabetic and non-diabetic patients were adjusted for age and gender.ResultsOf the 14,007 patients included in the study, 2545 were diabetic (18.2%). Before hospital admission, diabetic patients more frequently received secondary cardiovascular preventative medications (12.7% vs 4.2%; P < 0.0001) and stent implants (4.2% vs 2.2%; P < 0.0001) than did non-diabetic patients. During hospitalization and the following month, angioplasty (56.1% vs 61.7%; P = 0.0001) and stent implantation (53.3% vs 59.3%; P < 0.0001) were less frequently performed in diabetic patients and only coronary angiography was done in similar proportions of diabetic and non-diabetic patients (16.7% vs 15.2%). In addition, during the 6 months after hospitalization, diabetic vs non-diabetic patients had more admissions for cardiovascular reasons (36.9% vs 29.5%; P < 0.0001) and were prescribed more secondary preventative medications (65.9% vs 61.7%; P < 0.0001). They were also more frequently treated with insulin only (19.6% 6 months before vs 27.2% 6 months after) or oral antidiabetic drugs (14.6% vs 19.7%, respectively) than were non-diabetics.ConclusionFrench diabetic patients subsequent to MI undergo fewer angioplasty procedures than do non-diabetic patients. After the acute stage, secondary preventative medications are used more often, with a marked rise in the use of insulin.     

Patients’ clinical charecteristics and predictors for diabetic foot amputation

IntroductionMedical and surgical treatment options are available for patients with diabetic foot ulcers. In more severe cases, amputation decisions are determined by patient comorbidities, performance, imaging studies, and clinical examination results. However, an objective indicator that predicts how this amputation process will end has not yet been clarified. This study identifiies clinical characteristics that can be predictors of the need for diabetic foot amputation among patients.MethodsIn this retrospective observational study, a total of 400 patients with type 2 diabetes who were over the age of 18 and possessed diabetic foot ulcers were examined. The clinical, radiological, and scintigraphic profiles of these patients including age, gender, duration of diabetes, smoking history, previous diabetic foot amputation, presence of hypertension (HT), coronary artery disease (CAD), peripheral artery disease (PAD), cerebrovascular disease, cardiovascular disease, retinopathy, neuropathy and nephropathy were analyzed.ResultsOf the 400 patients with diabetic foot ulcers, 143 (35.75%) underwent foot amputation. Moreover, the frequency of proteinuria in amputees was significantly higher than in non-amputees (p < 0,05). Amputees also exhibited significantly longer smoking histories (p < 0,001), and the frequency of reamputation was significantly higher in those who possesed histories of previous amputation (p = 0.038). After multivariate analysis PAD presence and previous diabetic ulcer history were the significant factors to determine the amputation decision.ConclusionThe following patient characteristics were determined as being effective for predicting the need for amputation: male sex, CAD, PAD, HT, proteinuria, ulcers with Wagner Stages 4–5, smoking histories, previous diabetic ulcer histories, and previous amputation histories. The specificity of the model with these variables was determined as 86% in the patients who did not need amputation. Significant determinants were peripheral artery disease presence and diabetic foot ulcer history. Still, further and more extensive research with higher numbers of patients is necessary for determining more precisely the need for amputation.     

Direct costs and outcomes for inpatients with diabetes mellitus and foot ulcers in a developing country: The experience of the public health system of Brazil

AimsAnalyze the care received by hospitalized patients with diabetes mellitus and foot ulcers in Brazil, taking into account clinical and economic aspects.MethodsA cohort prospective study of 109 patients with diabetes hospitalized primarily for foot ulcers covered exclusively by the Brazilian public health system. All patients had type 2 diabetes mellitus, the staff at the hospitals has no specific training in the care of diabetic foot and study patients did not have access to multidisciplinary teams or rehabilitation facilities, characterizing a non-organized set.ResultsPatients had chronic infected deep ulcers with little or no prior access to a specialized foot clinic before the hospitalization. Forty-three (39%) patients were discharged with primary healing and 52 (48%) were healed with amputation. Fourteen (13%) patients died during hospitalization. Only five (4.6%) patients received reconstructive vascular procedures. Direct cost per patient varied between US$ 324.3 and US$ 5628.4 (1533.0 ± 1029.3). The total cost for the 109 hospitalizations was US$ 167,097.4.ConclusionsIn this non-organized set, inpatient care for diabetic foot in the public health system of Brazil is related to high costs and bad outcomes.     

Link between nasal carriage of Staphylococcus aureus and infected diabetic foot ulcers

AimsNasal carriage of Staphylococcus aureus in diabetic patients may be a risk factor for diabetic foot lesion infections. The aims of this study were to compare the genotypic profiles of S. aureus strains isolated from nares and diabetic foot ulcers (DFUs) using microarray technology.MethodsPatients were included if they were admitted for diabetic foot infection (DFI) at any of three diabetology departments of Montpellier and Nîmes University Hospitals between 1 September 2010 to 30 June 2012. All S. aureus isolates were analyzed using oligonucleotides arrays; S. aureus resistance and virulence genes were determined and each isolate was affiliated to a clonal complex.ResultsThe prevalence of S. aureus nasal carriage among the 276 included patients was 39.5% (n = 109), while 36.6% (n = 101) had S. aureus at both sites (nares and foot wounds) and, of these patients, 65.3% of patients harboured the same strain at both sites. In addition, the spread of the methicillin-resistant S. aureus (MRSA) ST398 clone in DFI and its tropism for bone were also further confirmed.ConclusionThese findings appear to provide new arguments in favour of the systematic detection of nasal S. aureus carriage to anticipate the management of DFI.     

A Chinese 2-herb formula (NF3) promotes hindlimb ischemia-induced neovascularization and wound healing of diabetic rats

Diabetic foot ulcer is closely associated with peripheral vascular disease. Enhancement of tissue oxidative stress, reduction of nitric oxide (NO) and angiogenic growth factors, and abnormal matrix metalloproteinase (MMP) activity are pathophysiological factors in post-ischemic neovascularization and diabetic wound healing. Our previous study demonstrated that the Chinese 2-herb formula, NF3, showed significant wound healing effects on diabetic foot ulcer rats. A novel rat diabetic foot ulcer with hindlimb ischemia model was established in order to strengthen our claims on the diabetic wound healing and post-ischemic neovascularization effects of NF3. Our results demonstrate that NF3 can significantly reduce the wound area of the diabetic foot ulcer rat with hindlimb ischemia by 21.6% (p < 0.05) compared with the control group. In addition, flow cytometric analysis revealed that NF3 could boost circulating EPC levels for local wound vessel incorporation. Immunohistochemical analysis showed that NF3 could significantly augment blood vessel density, VEGF and eNOS expression, and attenuate tissue oxidative stress of ischemic muscles (p < 0.001). NF3 significantly stimulated MMP activity involved in angiogenesis. Our study shows, for the first time, the beneficial effects of NF3 in wound healing and post-ischemic neovascularization in diabetes.     

Prospective study of matrix metalloproteinase-9 and risk of myocardial infarction and stroke in older men and women

ObjectivesThe endopeptidase matrix metalloproteinase-9 (MMP-9) is implicated in atherosclerotic plaque rupture. We investigate prospective associations between MMP-9 and MI or stroke in an older general population cohort, accounting for established and novel cardiovascular risk factors.MethodsBaseline serum MMP-9 was measured in incident MI (n = 368) and stroke (n = 299) cases and two controls per case, ‘nested’ in prospective studies of 4252 men and 4286 women aged 60–79 years, sampled from General Practices in Britain in 1998–2000, with 7-year follow-up for fatal and non-fatal MI and stroke.ResultsGeometric mean MMP-9 was 528 ng/mL (IQR 397, 743) in MI cases compared to 501 ng/mL (IQR 370, 743) in controls, p = 0.10. Participants in the top compared to bottom third of MMP-9 levels had an age-adjusted odds ratio for MI of 1.53 (95% CI 1.09, 2.13), which attenuated to 1.18 (95% CI 0.81, 1.70) after adjustment for established and novel cardiovascular risk factors. There was weak evidence that OR differed according to pre-existing CVD; the OR for MI in 187 participants with pre-existing CVD was 2.20 (1.04, 4.64) and 1.24 (0.84, 1.82) in 715 participants without (LR test for interaction p = 0.06). Geometric mean MMP-9 levels were higher in stroke cases than controls; 522 ng/mL (IQR 363, 673) vs 487 (IQR 393, 704), p = 0.045; however adjustments similarly attenuated the associations.ConclusionsWhile serum MMP-9 is univariately associated with risk of MI and stroke, it is not a strong independent risk marker for either.     

Nocturnal activity of 11β-hydroxy steroid dehydrogenase type 1 is increased in type 1 diabetic children

AimThe objective of this study was to investigate low-grade inflammation in children with type 1 diabetes (T1D) and its association with cortisol levels as well as its bioavailability through 11β-hydroxy steroid dehydrogenase type 1 (11β-HSD1) activity.MethodsChildren with T1D (n = 45) and their non-diabetic siblings (n = 28) participated in the study. Interleukin-6 (IL-6) and high-sensitivity C-reactive protein (CRPhs) were measured between 1400 and 1800 h. Glucocorticoid metabolites were measured in the first morning urine on clinic day and 11β-HSD1 activity was estimated by tetrahydrocortisol/tetrahydrocortisone (THF/THE) ratio.ResultsDiabetic patients presented with an increased THF/THE ratio compared with controls (median: 0.68 [range: 0.45–1.18] vs 0.45 [0.27–0.98], respectively; P < 10^–3). There was no difference between diabetic patients and controls for IL-6 (0.6 ng/mL [0.6–6.8] vs 0.6 [0.6–2.2], respectively; P = 0.43) and CRPhs (0.4 mg/L [0–7.4] vs 0.3 [0–8.2]; P = 0.26, respectively). When adjusted for age, gender and BMI, the THF/THE ratio was significantly associated with CRPhs (β = 0.32, P = 0.02) in diabetic patients, but not in controls.ConclusionLow-grade inflammation assessed by plasma CRPhs and IL-6 concentrations was not detectable in our cohort of T1D children. Nocturnal 11β-HSD1 activity was increased and associated with plasma CRPhs concentration in diabetic patients. These results may be explained by either a direct or inflammation-mediated effect of the relative hepatic lack of insulin due to subcutaneous insulin therapy.     

Switching fibrate to statin in type 2 diabetic patients: Consequences on lipid profile

Interest of statins in terms of morbid-mortality reduction in primary and secondary prevention in type 2 diabetic patients has broadly been proven in recent studies, while evidence for fibrates preventive effect is considerably weaker. HMGCoA reductase inhibitors are known to decrease low density lipoprotein cholesterol (LDL C) in a greater extension than triglycerides (TG). In type 2 diabetic patients, the dyslipidemic profile is commonly associated with reduced high-density lipoproteins (HDL C), increased TG and normal or mildly elevated LDL C.Patients and methodsType 2 diabetic outpatients (n = 45) treated with fibrate with or without history of cardiovascular disease were included. Mean age was 57.7 ± 13.2 yr, sex ratio was 16/39 (F/M), and BMI was 29.3 ± 4.4 kg/m². Non-inclusion criteria were TG ≥ 3.5 g/L and intolerance to statins or a combined lowering lipid therapy. Serum lipid profile, HbA_1c and creatin kinase (CK) were assessed under treatment with fibrate, then after a 3-month wash-out period, and after a 6-month treatment with a low dose of atorvastatin (10 mg/day).ResultsAfter a 3-month wash-out period, total cholesterol (TC) was 1.98 ± 0.31 g/L (m ± SD), TG 1.63 ± 1.09 g/L, HDL C 0.46 ± 0.12 g/L, and LDL C 1.22 ± 0.31 g/L. Comparing lipid profile with atorvastatin vs fibrate, we observed a significant decrease in TC and LDL C (1.56 vs 1.79 g/L P = 0.001, and 0.84 vs 1.09 g/L, P = 0.001, respectively). No significant difference between treatments was observed for TG (1.35 vs 1.17 g/L, P = 0.06), and HDL C (0.44 vs 0.48 g/L, P = 0.15). When treated with atorvastatin, 90% of patients achieved a LDL C < 1 g/L, compared to 51% when treated with fibrate (P = 0.001). HbA_1c remained about 7.6 ± 1.5%, and CK in the normal range.ConclusionIn well-controlled type 2 diabetic patients previously treated with fibrate, short-term (6 months) treatment with low-dose atorvastatin (10 mg/day) improves TC and LDL C levels, without any alteration in TG and HDL C levels.     

Diabetes-related foot ulcers and associated factors: Results from the Nord-Trøndelag Health Survey (HUNT3) (2006–2008)

AimTo determine the proportion of people with diabetes reporting a history of foot ulcer and investigate associated factors and healing time in the Nord-Trøndelag Health Survey (HUNT3), Norway.MethodsIn 2006–2008, all inhabitants in Nord-Trøndelag County aged ≥ 20 years were invited to take part in this population-based study; 54% (n = 50,807) attended. In participants reporting to have diabetes we examined the relationships between foot ulcers requiring more than 3 weeks to heal (DFU) and sociodemographic, lifestyle and clinical variables using logistic regression analysis.ResultsAmong participants with diabetes, 7.4% (95% confidence interval (CI) 6.2%–8.6%) reported a DFU. The median healing time was 6.0 weeks. In the final model, factors associated with a DFU were age ≥ 75 years (odds ratio (OR) 2.3, 95% CI 1.4–3.7), male sex (OR 2.0, 95% CI 1.3–3.1), waist circumference ≥ 102 cm (men) or 88 cm (women) (OR 1.95, 95% CI 1.2–3.2), insulin use (OR 2.1, 95% CI 1.3–3.4) and any macrovascular complication (OR 1.8, 95% CI 1.1–2.8).ConclusionsThe proportion of people with diabetes reporting a DFU was 7.4%, associated factors were age ≥ 75 years, male sex, waist circumference ≥ 102 cm (men) or 88 cm (women), insulin use and any macrovascular complication. The median healing time was 6 weeks.