Mechanisms involved in the development and healing of diabetic foot ulceration

We examined the role of vascular function and inflammation in the development and failure to heal diabetic foot ulcers (DFUs). We followed 104 diabetic patients for a period of 18.4 \ub1 10.8 months. At the beginning of the study, we evaluated vascular reactivity and serum inflammatory cytokines and growth factors. DFUs developed in 30 (29%) patients. DFU patients had more severe neuropathy, higher white blood cell count, and lower endothelium-dependent and -independent vasodilation in the macrocirculation. Complete ulcer healing was achieved in 16 (53%) patients, whereas 13 (47%) patients did not heal. There were no differences in the above parameters between the two groups, but patients whose ulcers failed to heal had higher tumor necrosis factor-\u3b1, monocyte chemoattractant protein-1, matrix metallopeptidase 9 (MMP-9), and fibroblast growth factor 2 serum levels when compared with those who healed. Skin biopsy analysis showed that compared with control subjects, diabetic patients had increased immune cell infiltration, expression of MMP-9, and protein tyrosine phosphatase-1B (PTP1B), which negatively regulates the signaling of insulin, leptin, and growth factors. We conclude that increased inflammation, expression of MMP-9, PTP1B, and aberrant growth factor levels are the main factors associated with failure to heal DFUs. Targeting these factors may prove helpful in the management of DFUs

Mechanisms Involved in the Development and Healing of Diabetic Foot Ulceration

We examined the role of vascular function and inflammation in the development and failure to heal diabetic foot ulcers (DFUs). We followed 104 diabetic patients for a period of 18.4 ± 10.8 months. At the beginning of the study, we evaluated vascular reactivity and serum inflammatory cytokines and growth factors. DFUs developed in 30 (29%) patients. DFU patients had more severe neuropathy, higher white blood cell count, and lower endothelium-dependent and -independent vasodilation in the macrocirculation. Complete ulcer healing was achieved in 16 (53%) patients, whereas 13 (47%) patients did not heal. There were no differences in the above parameters between the two groups, but patients whose ulcers failed to heal had higher tumor necrosis factor-α, monocyte chemoattractant protein-1, matrix metallopeptidase 9 (MMP-9), and fibroblast growth factor 2 serum levels when compared with those who healed. Skin biopsy analysis showed that compared with control subjects, diabetic patients had increased immune cell infiltration, expression of MMP-9, and protein tyrosine phosphatase-1B (PTP1B), which negatively regulates the signaling of insulin, leptin, and growth factors. We conclude that increased inflammation, expression of MMP-9, PTP1B, and aberrant growth factor levels are the main factors associated with failure to heal DFUs. Targeting these factors may prove helpful in the management of DFUs

One step closer to understanding the role of bacteria in diabetic foot ulcers: characterising the microbiome of ulcers

Background: The aim of this study was to characterise the microbiome of new and recurrent diabetic foot ulcers using 16S amplicon sequencing (16S AS), allowing the identification of a wider range of bacterial species that may be important in the development of chronicity in these debilitating wounds. Twenty patients not receiving antibiotics for the past three months were selected, with swabs taken from each individual for culture and 16S AS. DNA was isolated using a combination of bead beating and kit extraction. Samples were sequenced on the Illumina Hiseq 2500 platform. Results: Conventional laboratory culture showed positive growth from only 55 % of the patients, whereas 16S AS was positive for 75 % of the patients (41 unique genera, representing 82 different operational taxonomic units (OTU’s). S. aureus was isolated in 72 % of culture-positive samples, whereas the most commonly detected bacteria in all ulcers were Peptoniphilusspp., Anaerococcus spp. and Corynebacterium spp., with the addition of Staphylococcus spp. in new ulcers. The majority of OTU’s residing in both new and recurrent ulcers (over 67 %) were identified as facultative or strict anaerobic Gram-positive organisms. Principal component analysis (PCA) showed no difference in clustering between the two groups (new and recurrent ulcers). Conclusions: The abundance of anaerobic bacteria has important implications for treatment as it suggests that the microbiome of each ulcer “starts afresh” and that, although diverse, are not distinctly different from one another with respect to new or recurrent ulcers. Therefore, when considering antibiotic therapy the duration of current ulceration may be a more important consideration than a history of healed ulcer

Η οξεία επίδραση της υπερομοκυστεϊναιμίας που προκαλείται μετά τη λήψη μεθειονίνης σε ασθενείς με σακχαρώδη διαβήτη τύπου 2

High plasma levels of homocysteine (Hcy) affect endothelial function in non-diabetic subjects. However, the effect of hyperohomo-cysteinemia on endothelium-dependent (EDV) and in arterial stiffness in subjects with type 2 diabetes (T2DM) is not clearly known. Aim: The aim of this study was to examine the effect of acute hyperhomocysteinaemia on endothelial function and on arterial stiffness in subjects with T2DM. Patients-Methods: We examined the effect of L-methionine load (0.1g/Kg) vs water load in a crossover study, on EDV and on arterial stiffness in 30 patients with T2DM (mean age 58.7 ± 7.6 years, mean diabetes duration 7.0 years, without evidence of macroangiopathy). EDV was calculated as the percentage change of the brachial artery diameter, as compared with the baseline values, after occlusion of the brachial artery. Arterial stiffness was assessed by estimating the Augmentation index using a validated device (Sphygmocore). Measurements were performed in the fasting state and at 1st, 2nd and 3rd hour after the water or methionine load. Results: Water administration resulted in no change in total Hcy while methionine administration resulted in an increase of 143% in plasma total Hcy at 3rd hour. EDV - expressed as area under the curve (AUC) through the experiment - was significantly lower after methionine than after water load (14.5 ± 6.1 vs. 24.8 ± 9.2 % ? h, respectively, P<0.001). Augmentation index was significantly higher after the methionine than after the water load (AUC: 176.9 ± 36.4 vs. 156.7 ± 48.1 mm Hg ? h, respectively, P=0.03). Conclusions: Acute hyperhomocysteinemia impaires EDV and increases arterial stiffness in patients with type 2 diabetes. This effect is probably mediated by the adverse metabolic effects of hyperhomocysteinemia, resulting mainly in a reduction of NO bioavailability.Οι αυξημένες συγκεντρώσεις της ομοκυστεΐνης είναι γνωστό ότι προκαλούν δυσλειτουργία του ενδοθηλίου σε άτομα χωρίς διαβήτη βλάπτοντας την ενδοθηλιοεξαρτώμενη αγγειοδιαστολή. Επιπλέον οι χρονίως αυξημένες συγκεντρώσεις της ομοκυστεΐνης έχουν συνδεθεί με αυξημένο κίνδυνο για καρδιαγγειακά επεισόδια. Δεν υπάρχουν όμως στοιχεία για τη δράση της οξείας υπερομοκυστεϊναιμίας στην ενδοθηλιοεξαρτώμενη αγγειοδιαστολή ούτε στην αρτηριακή σκλήρυνση σε ασθενείς με διαβήτη τύπου 2. Σκοπός: Σκοπός της παρούσας διατριβής ήταν να εξετάσει την επίδραση της οξείας υπερομοκυστεϊναιμίας που προκλήθηκε μετά από τη χορήγηση μεθειονίνης στην ενδοθηλιοεξαρτώμενη αγγειοδιαστολή αλλά και στην αρτηριακή σκλήρυνση σε ασθενείς με διαβήτη τύπου 2. Ασθενείς - Μέθοδοι : Μελετήθηκε η επίδραση της φόρτισης από του στόματος με μεθειονίνη (0.1g/Kg) σε συσχέτιση με τη χορήγηση ύδατος στην ενδοθηλιοεξαρτώμενη αγγειοδιαστολή και στην αρτηριακή σκλήρυνση σε 30 ασθενείς με διαβήτη τύπου 2 (μέση ηλικία 58.7 ± 7.6 έτη, μέση διάρκεια διαβήτη 7.0 έτη) που δεν είχαν κλινικά έκδηλη μακροαγγειοπάθεια. Η ενδοθηλιοεξαρτώμενη αγγειοδιαστολή υπολογίστηκε ως η επί τοις εκατό μεταβολή της διαμέτρου της βραχιονίου αρτηρίας μετά από ισχαιμική περίδεση σε σχέση με τη βασική κατάσταση. Η αρτηριακή σκλήρυνση εκφράστηκε με το δείκτη ενίσχυσης του σφυγμικού κύματος (Augmentation index) με τη χρήση πιστοποιημένης συσκευής (Sphygmocore). Οι μετρήσεις έγιναν σε κατάσταση νηστείας και την 1η , 2η , και 3η ώρα μετά από τη λήψη ύδατος ή μεθειονίνης. Αποτελέσματα: Η χορήγηση ύδατος δεν προκάλεσε σημαντική αλλαγή στις συγκεντρώσεις της ολικής ομοκυστεΐνης πλάσματος ενώ η χορήγηση μεθειονίνης είχε ως αποτέλεσμα την αύξηση της ολικής ομοκυστεΐνης πλάσματος κατά 143% την 3η ώρα. Η ενδοθηλιοεξαρτώμενη αγγειοδιαστολή κατά τη διάρκεια του πειράματος εκφραζόμενη ως το εμβαδόν των τιμών της καμπύλης (Area under the Curve, AUC) παρουσίασε στατιστικά σημαντική ελάττωση μετά από τη λήψη της μεθειονίνης σε σχέση με τη λήψη ύδατος ( AUC: 14.5 ± 6.1 έναντι 24.8 ± 9.2 % , αντίστοιχα, P<0.001). Ο δείκτης ενίσχυσης του σφυγμικού κύματος παρουσίασε στατιστικά σημαντική αύξηση μετά από τη λήψη μεθειονίνης σε σχέση με τη λήψη ύδατος. (AUC: 176.9 ± 36.4 έναντι 156.7 ± 48.1 mm Hg ? h, αντίστοιχα, P=0.03). Συμπέρασμα: Η οξεία υπερομοκυστεϊναιμία όχι μόνο παραβλάπτει την ενδοθηλιοεξαρτώμενη αγγειοδιαστολή, αλλά, επιπλέον, αυξάνει και την αρτηριακή σκλήρυνση (μειώνει την αρτηριακή ελαστικότητα) σε ασθενείς με διαβήτη τύπου 2. Η βλαπτική αυτή επίδραση πιθανότατα οφείλεται στην ελάττωση της βιοδιαθεσιμότητας του μονοξειδίου του αζώτου στο ενδοθήλιο

Clinical utility in the treatment of type 2 diabetes with the saxagliptin/metformin fixed combination

Fixed-dose combination (FDC) products represent a widely accepted approach to type 2 diabetes treatment, given that monotherapies sometimes fail to meet the treatment-targets obtaining a sustained reduction in micro-and macrovascular complications. Saxagliptin (SAXA)/metformin (MET) FDC tablets can be used either alone or in combination with glyburide, thiazolidinediones, or insulin. It has been proven that the SAXA/MET combination leads to a significant improvement in glycemic control compared to placebo in patients with type 2 diabetes that is inadequately controlled with MET alone. In addition, this FDC has been proven to be safe for people with diabetes mellitus and established cardiovascular disease, elderly patients, and patients with impaired renal function (&gt;30 mL/minute), with dosage modification. Patient compliance, adherence, and persistence to the therapeutic regimen has been shown to be very good, while the titration of each compound according to the patient’s profile is easy, given the availability of different formulations. The SAXA/MET FDC is a patient-friendly, dosage-flexible, and hypoglycemia-safe regimen with very few adverse events and a neutral or even favorable effect on body weight. It achieves significant glycosylated hemoglobin A(1c) reduction helping the patient to achieve his/her individual glycemic goals

The renal effects of SGLT2 inhibitors and a mini-review of the literature

Sodium-glucose linked transporter 2 (SGLT2) inhibitors are a new and promising class of antidiabetic agents which target renal tubular glucose reabsorption. Their action is based on the blockage of SGLT2 sodium-glucose cotransporters that are located at the luminal membrane of tubular cells of the proximal convoluted tubule, inducing glucosuria. It has been proven that they significantly reduce glycated hemoglobin (HbA1c), along with fasting and postprandial plasma glucose in patients with type 2 diabetes mellitus (T2DM). The glucosuria-induced caloric loss as well as the osmotic diuresis significantly decrease body weight and blood pressure, respectively. Given that SGLT2 inhibitors do not interfere with insulin action and secretion, their efficacy is sustained despite the progressive β-cell failure in T2DM. They are well tolerated, with a low risk of hypoglycemia. Their most frequent adverse events are minor: genital and urinal tract infections. Recently, it was demonstrated that empagliflozin presents a significant cardioprotective effect. Although the SGLT2 inhibitors’ efficacy is affected by renal function, new data have been presented that some SGLT2 inhibitors, even in mild and moderate renal impairment, induce significant HbA1c reduction. Moreover, recent data indicate that SGLT2 inhibition has a beneficial renoprotective effect. The role of this review paper is to explore the current evidence on the renal effects of SGLT2 inhibitors

Pulse Wave Analysis by Applanation Tonometry for the Measurement of Arterial Stiffness

The aim of our study was to investigate the association between pulse wave velocity (PWV) and pulse wave analysis (PWA)-derived measurements for the evaluation of arterial stiffness. A total of 20 (7 male and 13 female) healthy, non-smoking individuals, with mean age 31 ± 12years were included. PWV and PWA measurements were performed using a SphygmoCor apparatus (Atcor Medical Blood Pressure Analysis System, Sydney Australia). PWV significantly correlated with all central aortic haemodynamic parameters, especially with pulse pressure (PP) (p < 0.0001), augmentation index corrected for 75 pulses/min (AI75) (p = 0.035) and augmentation pressure (AP) (p = 0.005). Male subjects presented significantly higher PWV compared with females (p = 0.03), while there were no differences in PP, AP and AI75. In conclusion, PWA is strongly correlated with PWV as a method for the evaluation of arterial stiffness

Validation of the Greek Version of the Diabetes Management Self-Efficacy Scale (GR-DMSES)

Self-efficacy has been found to have a direct relation with self-care in diabetes. Several tools have been developed and used for evaluating self-efficacy of diabetic patients, the most widely used being the Diabetes Management Self-Efficacy Scale (DMSES). The aim of the present study was to translate, culturally adapt, and validate the Greek DMSES (GR-DMSES) in order for it to be used in the ATTICA pilot study of the SmartCare EU-funded project. Using standard procedures, the original version of DMSES was translated and culturally adapted into Greek. Content validity was assessed by an expert panel with the calculation of a content validity index of the overall scale. I convenient sample was recruited to complete the questionnaire. Psychometric testing of the produced instrument included internal consistency test (Cronbach&apos;s alpha), construct validity (factor analysis), and stability (intraclass correlation coefficient). One hundred and sixteen patients, aged 36-86 years, with type 2 diabetes (T2D) participated in the study. There were no items excluded from the original scale after the content validity procedure. The coefficient Cronbach&apos;s alpha for the internal consistency was 0.93 and the intraclass correlation coefficient for the stability with a 5-week time interval was 0.87 (P &lt; 0.001). Factor analysis yielded four factors related to diet, medical therapy, medication and feet check, and physical activity. The findings supported that the GR-DMSES was reliable and valid in measuring self-efficacy related to diabetes self-management, thus providing a quick and easy-to-use tool for health professionals dealing with Greek adults with T2D