Autoantibodies to post-translationally modified type I and II collagen in Charcot neuroarthropathy in subjects with type 2 diabetes mellitus.

AIMS: Charcot neuroarthropathy (CN) is a disabling complication, culminating in bone destruction and involving joints and articular cartilage with high inflammatory environment. Its real pathogenesis is as yet unknown. In autoinflammatory diseases, such as rheumatoid arthritis, characterized by inflammation and joint involvement, autoantibodies against oxidative post-translationally modified (oxPTM) collagen type I (CI) and type II (CII) were detected. Therefore, the aim of our study was to assess the potential involvement of autoimmunity in charcot neuroarthropathy, investigating the presence of autoantibodies oxPTM-CI and oxPTM-CII, in participants with charcot neuroarthropathy. METHODS: In this case-control study, we enrolled 124 participants with type 2 diabetes mellitus (47 with charcot neuroarthropathy, 37 with diabetic peripheral neuropathy without charcot neuroarthropathy, and 40 with uncomplicated diabetes), and 32 healthy controls. The CI and CII were modified with ribose and other oxidant species, and the modifications were evaluated with sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Binding of sera from the participants was analyzed with enzyme-linked immunosorbent assay. RESULTS: Age, body mass index, waist and hip circumferences, and lipid profile were similar across the 4 groups, as well as glycated hemoglobin and duration of diabetes among people with diabetes. An increased binding to both native and all oxidation-modified forms of CII was found in participants with CN and diabetic neuropathy. Conversely, for CI, an aspecific increased reactivity was noted. CONCLUSIONS: Our results detected the presence of autoantibodies against oxidative post-translational modified collagen, particularly type 2 collagen, in participants with charcot neuroarthropathy and diabetic neuropathy, suggesting the possible involvement of autoimmunity. Further studies are required to understand the role of autoimmunity in the pathogenesis of charcot neuroarthropathy.

Bariatric surgery versus conventional medical therapy for type 2 diabetes.

BACKGROUND: Roux-en-Y gastric bypass and biliopancreatic diversion can markedly ameliorate diabetes in morbidly obese patients, often resulting in disease remission. Prospective, randomized trials comparing these procedures with medical therapy for the treatment of diabetes are needed. METHODS: In this single-center, nonblinded, randomized, controlled trial, 60 patients between the ages of 30 and 60 years with a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of 35 or more, a history of at least 5 years of diabetes, and a glycated hemoglobin level of 7.0% or more were randomly assigned to receive conventional medical therapy or undergo either gastric bypass or biliopancreatic diversion. The primary end point was the rate of diabetes remission at 2 years (defined as a fasting glucose level of <100 mg per deciliter [5.6 mmol per liter] and a glycated hemoglobin level of <6.5% in the absence of pharmacologic therapy). RESULTS: At 2 years, diabetes remission had occurred in no patients in the medical-therapy group versus 75% in the gastric-bypass group and 95% in the biliopancreatic-diversion group (P<0.001 for both comparisons). Age, sex, baseline BMI, duration of diabetes, and weight changes were not significant predictors of diabetes remission at 2 years or of improvement in glycemia at 1 and 3 months. At 2 years, the average baseline glycated hemoglobin level (8.65±1.45%) had decreased in all groups, but patients in the two surgical groups had the greatest degree of improvement (average glycated hemoglobin levels, 7.69±0.57% in the medical-therapy group, 6.35±1.42% in the gastric-bypass group, and 4.95±0.49% in the biliopancreatic-diversion group). CONCLUSIONS: In severely obese patients with type 2 diabetes, bariatric surgery resulted in better glucose control than did medical therapy. Preoperative BMI and weight loss did not predict the improvement in hyperglycemia after these procedures. (Funded by Catholic University of Rome; ClinicalTrials.gov number, NCT00888836.).

Platelet mean volume, distribution width, and count in type 2 diabetes, impaired fasting glucose, and metabolic syndrome: a meta-analysis.

BACKGROUND: Platelet activation contributes to cardiovascular disease (CVD), the main complication of type 2 diabetes mellitus (T2DM) and pre-diabetic conditions. Mean platelet volume is an easy-to-measure platelet parameter that has been associated with CVD. We sought to assess mean platelet volume, platelet distribution width, and platelet count in T2DM, impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and metabolic syndrome. METHODS: Web-based literature search (PubMed, EMBASE, and Web of Science) of studies published in English through June 2014 was performed to select case-control and cross-sectional studies that reported data on mean platelet volume, platelet distribution width, or platelet count in cases (subjects with T2DM, IFG, IGT, or metabolic syndrome) and noncases. Descriptive and quantitative information was extracted, and within-study standardized mean difference was estimated from means and standard deviations. Standardized mean differences across studies were synthesized using a random random-effects model, and subgroup analyses were performed on pre-specified study-level characteristics. RESULTS: Thirty-nine studies were included. Compared with controls, mean platelet volume was significantly higher in T2DM (standardized mean difference, 95% confidence interval: 0.70, 0.50-0.91; N = 24,245), IFG (0.14, 0.02-0.26; N = 17,389) but not in metabolic syndrome (0.15, -0.24 to 0.55; N = 14,990). Platelet distribution width was wider in T2DM (0.93, 0.09-1.76; N = 471). Platelet count resulted higher in IFG (0.18, 0.12-0.24; N = 3960) and metabolic syndrome (0.39, 0.01-0.78; N = 4070). Only two studies included IGT. CONCLUSIONS: Available data suggest that T2DM subjects tend to have higher mean platelet volume and platelet distribution width values, but nondifferent platelet count as compared with subjects without T2DM. Whether and how these morphometric changes contribute to CVD of T2DM or can be used as CVD biomarker awaits further investigation.

Effect of proinflammatory gene polymorphisms on the risk of Alzheimer's disease.

BACKGROUND: A number of studies associate Alzheimer's disease (AD) with APOE polymorphism and alleles which favor the increased expression of immunological mediators such as cytokines or acute-phase proteins. OBJECTIVE: In this study we evaluated the distribution of a set of functionally important polymorphisms of genes encoding prototypical inflammatory molecules in individuals with AD. We also investigated whether a synergistic effect of these proinflammatory gene polymorphisms on the risk of AD could be hypothesized. METHODS: In a genetic association study that included 533 AD patients and 713 controls, the following gene polymorphisms were analyzed: C-reactive protein (CRP) 1059 G/C, interleukin 6 (IL6) -174 G/C, interleukin 1ß (IL1B) -31 T/C, tumor necrosis factor α (TNF-α) -308 G/A, macrophage migration inhibitory factor (MIF) -173 G/C, monocyte chemoattractant protein 1 (CCL2) -2518 A/G, intercellular adhesion molecule 1 (ICAM1) 469 E/K, E-selectin (SELE) Ser128Arg, macrophage inflammatory protein 1α (CCL3) -906 T/A, matrix metalloproteinase 3 (MMP3) -1171 5A/6A and matrix metalloproteinase 9 (MMP9) -1562 C/T. RESULTS: We found that IL6, IL1B, CCL2, CCL3, SELE, ICAM1, MMP3, and MMP9 gene polymorphisms were significantly and independently associated with AD. The association remained significant even after the Bonferroni correction. We also found that these proinflammatory polymorphisms were associated with different levels of risk for AD, depending on the number of high-risk genotypes concomitantly carried by a given individual. CONCLUSION: Proinflammatory genotypes might influence the development and progression of AD exerting a potential synergistic effect.

Severity of coronary atherosclerosis in patients with a first acute coronary event: a diabetes paradox.

AIMS: We aimed to compare coronary artery disease (CAD) at the time of a first acute coronary syndrome (ACS) in type II diabetic and non-diabetic patients by coronary angiography and by optical coherence tomography (OCT). METHODS AND RESULTS: Two different patient populations with a first ACS were enrolled for the angiographic (167 patients) and the OCT (72 patients) substudy. Angiographic CAD severity was assessed by Bogaty, Gensini, and Sullivan scores, whereas collateral development towards the culprit vessel was assessed by the Rentrop score. Optical coherence tomography plaque features were evaluated at the site of the minimum lumen area (MLA) and of culprit segment. In the angiographic substudy, at multivariate analysis, diabetes was associated with both the stenosis score and the extent index (P = 0.001). Furthermore, well-developed collateral circulation (Rentrop 2-3) towards the culprit vessel was more frequent in diabetic than in non-diabetic patients (73% vs. 16%, P = 0.001). In the OCT substudy, at MLA site lipid quadrants were less and the lipid arc was smaller in diabetic than in non-diabetic patients (2.3 ± 1.3 vs. 3.0 ± 1.2; P = 0.03 and 198° ± 121° vs. 260° ± 118°; P = 0.03). Furthermore, the most calcified cross-section along the culprit segment had a greater number of calcified quadrants and a wider calcified arc in diabetic than in non-diabetic patients (1.7 ± 1.0 vs. 1.2 ± 0.9; P = 0.03 and 126° ± 95° vs. 81° ± 80°; P = 0.03). Superficial calcified nodules were more frequently found in diabetic than in non-diabetic patients (79 vs. 54%, P = 0.04). CONCLUSIONS: In spite of potent pro-inflammatory, pro-oxidant and pro-thrombotic stimuli operating in type II diabetes, diabetic patients exhibit substantially more severe coronary atherosclerosis than non-diabetic patients at the time of a first acute coronary event. Better collateral development towards the culprit vessel, a predominantly calcific plaque phenotype and, probably, yet unknown protective factors operating in diabetic patients may explain these intriguing paradoxical findings.

Nutrient infusion bypassing duodenum-jejunum improves insulin sensitivity in glucose-tolerant and diabetic obese subjects.

The mechanisms of type 2 diabetes remission after bariatric surgery is still not fully elucidated. In the present study, we tried to simulate the Roux-en-Y gastric bypass with a canonical or longer biliary limb by infusing a liquid formula diet into different intestinal sections. Nutrients (Nutrison Energy) were infused into mid- or proximal jejunum and duodenum during three successive days in 10 diabetic and 10 normal glucose-tolerant subjects. Plasma glucose, insulin, C-peptide, glucagon, incretins, and nonesterified fatty acids (NEFA) were measured before and up to 360 min following. Glucose rate of appearance (Ra) and insulin sensitivity (SI), secretion rate (ISR), and clearance were assessed by mathematical models. SI increased when nutrients were delivered in mid-jejunum vs. duodenum (SI × 104 min⁻¹·pM⁻¹: 1.11 ± 0.44 vs. 0.62 ± 0.22, P < 0.015, in controls and 0.79 ± 0.34 vs. 0.40 ± 0.20, P < 0.05, in diabetic subjects), whereas glucose Ra was not affected. In controls, Sensitivity of NEFA production was doubled in mid-jejunum vs. duodenum (2.80 ± 1.36 vs. 1.13 ± 0.78 × 106, P < 0.005) and insulin clearance increased in mid-jejunum vs. duodenum (2.05 ± 1.05 vs. 1.09 ± 0.38 l/min, P < 0.03). Bypass of duodenum and proximal jejunum by nutrients enhances insulin sensitivity, inhibits lipolysis, and increases insulin clearance. These results may further our knowledge of the effects of bariatric surgery on both insulin resistance and diabetes.

Association between TNFRSF11B gene polymorphisms and history of ischemic stroke in Italian diabetic patients.

Osteoprotegerin (OPG) is a secretory glycoprotein that belongs to the tumor necrosis factor receptor family and plays a role in atherosclerosis. The present study aimed to evaluate whether OPG gene (TNFRSF11B) polymorphisms are involved in ischemic stroke in an Italian population with diabetes. Participants in a retrospective case-control study included 364 diabetic patients (180 males, 184 females) with history of ischemic stroke and 492 diabetic subjects without history of ischemic stroke (252 males, 240 females). The T245G, T950C, and G1181C polymorphisms of the OPG gene were analyzed by polymerase chain reaction and restriction fragment length polymorphism. We found that the T245G, T950C, and G1181C gene polymorphisms of the OPG gene were significantly (34.1 vs. 9.5 %, P < 0.0001; 30.8 vs. 6.3 %, P < 0.0001 and 26.4 vs. 11.6 % P < 0.0001, respectively) and independently (adjusted OR 5.15 [3.46-7.68], OR 6.63 [4.26-10.31], and OR 3.03 [2.04-4.50], respectively) associated with history of ischemic stroke. We also found that these three polymorphisms act synergistically in patients with stroke history. The TNFRSF11B gene polymorphisms studied are associated with history of ischemic stroke and synergistic effects between these genotypes might be potential markers for cerebrovascular disorders.

Oxidative stress in diabetes: implications for vascular and other complications.

In recent decades, oxidative stress has become a focus of interest in most biomedical disciplines and many types of clinical research. Increasing evidence shows that oxidative stress is associated with the pathogenesis of diabetes, obesity, cancer, ageing, inflammation, neurodegenerative disorders, hypertension, apoptosis, cardiovascular diseases, and heart failure. Based on these studies, an emerging concept is that oxidative stress is the "final common pathway" through which the risk factors for several diseases exert their deleterious effects. Oxidative stress causes a complex dysregulation of cell metabolism and cell-cell homeostasis; in particular, oxidative stress plays a key role in the pathogenesis of insulin resistance and ß-cell dysfunction. These are the two most relevant mechanisms in the pathophysiology of type 2 diabetes and its vascular complications, the leading cause of death in diabetic patients.

Reduced respiratory muscle strength and endurance in type 2 diabetes mellitus.

BACKGROUND: A restrictive lung function pattern is frequently observed in patients with diabetes mellitus (DM) and has been related to respiratory muscle dysfunction in type 1 DM or in mixed population. We aimed to verify whether such a relationship applies also to type 2 DM patients. METHODS: The respiratory muscle function was explored in 75 non-smoking patients with type 2 DM without pulmonary or cardiac diseases and compared with that of 40 healthy non-smoking control subjects matched by age and sex. Maximal inspiratory and expiratory pressures (MIP, MEP) and maximum voluntary ventilation (MVV), which reflect respiratory muscle strength and endurance, respectively, were measured, and a complete respiratory function assessment was recorded. RESULTS: Patients were in stable metabolic conditions and had, on average, normal total lung capacity and diffusing lung capacity for carbon monoxide. However, MIP and MVV were significantly reduced in comparison with those of control subjects. Both MIP/MEP and MVV significantly correlated with lung volumes and diffusing lung capacity for carbon monoxide. The multiple regression analysis identified age (beta coefficient = -0.238, p = 0.046), glycated haemoglobin (beta coefficient = -0.245, p = 0.047) and total lung capacity (beta coefficient = 0.430, p = 0.016) as independent correlates of MIP, whereas male sex (beta coefficient = 0.423, p = 0.004) and diabetic complications (beta coefficient = -0.248, p = 0.044) were independent correlates of MVV. CONCLUSIONS: In type 2 DM, respiratory muscle strength was reduced and significantly related to lung volumes and quality of metabolic control, whereas impaired endurance of respiratory muscles prevailed in patients with microvascular complications.

Expansion of CD4+CD28null T-lymphocytes in diabetic patients: exploring new pathogenetic mechanisms of increased cardiovascular risk in diabetes mellitus.

AIMS: Diabetes mellitus (DM) is associated with high incidence of first and recurrent cardiovascular events, especially acute coronary syndromes (ACSs); however, the mechanisms involved are still unknown. We sought to investigate the role of CD4(+)CD28(null)T-lymphocytes, a rare long-lived subset of T-lymphocytes with proatherogenic and plaque-destabilizing properties, in the increased cardiovascular risk associated with DM. METHODS AND RESULTS: CD4(+)CD28(null)T-cell frequency was analysed by flow-cytometry in 60 DM patients without overt cardiovascular disease (cDM), in 166 ACS patients with or without DM (ACS/DM+, n= 51 and ACS/DM-, n= 115), and in 60 healthy individuals. The incidence of cardiovascular events (death, myocardial infarction, unstable angina) was assessed at 36 months follow-up. CD4+CD28(null)T-cell frequency (median, range) was higher in ACS/DM+ (12.7%, 0.1-48) vs. ACS/DM- (3.9%, 0.2-35), cDM (3.1%, 0.3-22.4), and controls (1.5%, 0.1-9.1) (P< 0.001 for all comparisons). Notably, cDM patients had significantly higher CD4+CD28(null)T-cell frequency than controls (P= 0.001). Glycosylated haemoglobin A(1c) was the only parameter independently associated with CD4+CD28(null)T-cells in cDM. The 36-month event-free survival was significantly lower in cDM patients with CD4+CD28(null)T-cells ≥4% (90th percentile of normal distribution) than in those with CD4+CD28(null)T-cells <4% (P= 0.039). Among ACS patients, the 36-month event-free survival was the lowest in those with DM and CD4+CD28(null)T-cells ≥4% and highest in those without DM and CD4+CD28(null)T-cells <4% (P< 0.001), being intermediate in those with only one of these features. CONCLUSIONS: In DM patients, CD4+CD28(null)T-cells are expanded and are associated with poor glycaemic control; they also correlate with the occurrence of a first cardiovascular event and with a worse outcome after an ACS.

Assessment of the genetic effects of polymorphisms in the osteoprotegerin gene, TNFRSF11B, on serum osteoprotegerin levels and carotid plaque vulnerability.

BACKGROUND AND PURPOSE: Osteoprotegerin (OPG) is a secretory glycoprotein which belongs to the tumor necrosis factor receptor family. Various mechanisms have been suggested by which calcification might alter atherosclerotic plaque stability, but the significance of this intimal calcification is controversial. High concentrations of OPG have been associated with the presence of vascular and cardiovascular diseases. This study was designed to assess the association between gene polymorphisms of the OPG gene (TNFRSF11B), the serum OPG level, and plaque stability in patients with carotid atherosclerosis. METHODS: We studied 177 patients with internal carotid artery stenosis who underwent carotid endarterectomy and also 303 controls. Carotid endarterectomy samples removed from patients were assessed by immunohistochemistry. Concentrations of OPG were measured and gene polymorphisms were examined by polymerase chain reaction and restriction enzyme analysis and were compared, initially between patients with carotid atherosclerosis and controls, and subsequently between stable and unstable carotid plaques. RESULTS: We found that the GG genotype of the T245G polymorphism, the CC genotype of the T950C polymorphism, and the CC genotype of the G1181C polymorphism were significantly higher in patients with carotid plaque than in controls (21.5% versus 10.9% , P<0.01; 15.8% versus 7.6%, P<0.01; and 20.3% versus 10.9%, P<0.01, respectively) and that these polymorphisms were associated with high serum OPG levels (4.02 [3.07] versus 2.94 [1.81] pmol/L; P<0.01), which were significantly higher in patients with unstable atherosclerotic plaques (5.86 [4.02] versus 3.53 [1.87] pmol/L; P<0.01). CONCLUSIONS: The TNFRSF11B gene polymorphisms studied are associated with high serum OPG levels and might be potential markers for plaque instability.

Inflammation-related effects of adjuvant influenza A vaccination on platelet activation and cardiac autonomic function.

BACKGROUND: Inflammation, platelet reactivity and cardiac autonomic dysfunction increase the risk of cardiovascular events, but the relationships between these prognostic markers are poorly defined. In this study, we investigated the effect of an inflammatory stimulus (influenza A vaccine) on platelet activation and cardiac autonomic function. METHODS: We measured serum C-reactive protein (CRP) and interleukin-6 levels, monocyte-platelet aggregates (MPAs) and monocyte/platelet receptor expression before and after adjuvant influenza A vaccination in 28 patients with type II diabetes (mean age 62.1 ± 8 years, 18 men). Twenty-four-hour Holter electrocardiogram was recorded 24 h before and after vaccination; heart rate variability (HRV) was assessed as a measure of cardiac autonomic function. RESULTS: Inflammatory cytokines, MPA formation and monocyte/platelet receptor expression increased after vaccination. CRP was 2.6 ± 2.8 and 7.1 ± 5.7 mg L⁻¹ 48 h before and after vaccination, respectively (P < 0.0001). HRV parameters decreased after vaccination compared to baseline, with very low-frequency amplitude showing the most significant change (34.6 ± 11.8 and 31.0 ± 10.2 ms 48 h before and after vaccination, respectively; P = 0.002). A significant correlation was found between percentage changes in CRP levels and in most HRV variables, with the most significant correlations between changes in CRP levels and changes in standard deviation of all normal RR intervals (r = 0.43; P = 0.02). CONCLUSIONS: Together with an inflammatory reaction, influenza A vaccine induced platelet activation and sympathovagal imbalance towards adrenergic predominance. Significant correlations were found between CRP levels and HRV parameters, suggesting a pathophysiological link between inflammation and cardiac autonomic regulation. The vaccine-related platelet activation and cardiac autonomic dysfunction may transiently increase the risk of cardiovascular events.

Glycaemic variability affects ischaemia-induced angiogenesis in diabetic mice.

The aim of the present study was to investigate the role of GV (glycaemic variability) in diabetic vascular complications and to explore the molecular pathways modulated by glycaemic 'swings'. We developed a murine model. A total of 30 diabetic mice received once daily basal insulin administration plus two oral boluses of glucose solution (GV group, named 'V') and 30 diabetic mice received once daily basal insulin plus two oral boluses of saline solution (stable hyperglycaemia group, named 'S') for a period of 30 days. Glycaemia was measured eight times daily to detect GV. Finally, postischaemic vascularization, induced by hindlimb ischaemia 30 days after diabetes onset, was evaluated. We found that GV was significantly different between S and V groups, whereas no significant difference in the mean glycaemic values was detected. Laser Doppler perfusion imaging and histological analyses revealed that the ischaemia-induced angiogenesis was significantly impaired in V mice compared with S group, after ischaemic injury. In addition, immunostaining and Western blot analyses revealed that impaired angiogenic response in V mice occurred in association with reduced VEGF (vascular endothelial growth factor) production and decreased eNOS (endothelial nitric oxide synthase) and Akt (also called protein kinase B) phosphorylation. In conclusion, we describe a murine model of GV. GV causes an impairment of ischaemia-induced angiogenesis in diabetes, likely to be independent of changes in average blood glucose levels, and this impaired collateral vessel formation is associated with an alteration of the VEGF pathway.

Intestinal permeability in cirrhotic patients with and without spontaneous bacterial peritonitis: is the ring closed?

OBJECTIVES: Impaired intestinal permeability (IP) may have a role in the pathogenesis of ascites and in spontaneous bacterial peritonitis (SBP) in patients with liver cirrhosis (LC). The aim of this study was to assess IP in LC patients with respect to healthy controls. METHODS: IP was evaluated by the (51)Cr-ethylenediaminetetraacetic acid ((51)Cr-EDTA) permeability test in 52 LC patients and in 48 sex- and age-matched controls. The presence of (51)Cr-EDTA was also evaluated in ascitic fluid after therapeutic paracentesis in all LC patients with ascites. RESULTS: An altered IP was found in 45% of LC patients compared with 4% of controls (P<0.00001). IP impairment was significantly associated with Child-Pugh status (75% of Child C patients vs. 39% of Child B and 22% of Child A patients), with the presence of ascites (60% in ascitic patients vs. 31% in nonascitic patients), and with a history of SBP (100% of patients with SBP vs. 50% of those without SBP). (51)Cr-EDTA was present in all ascitic samples obtained from patients with SBP compared with 22% of patients without SBP. CONCLUSIONS: IP derangement was a common finding in LC, especially in patients with more advanced disease (presence of ascites and history of SBP). The presence of (51)Cr-EDTA in ascites in patients with SBP suggests an altered permeability of splancnic vessels and/or peritoneal membranes. Further studies are required to assess (51)Cr-EDTA urine and ascite cutoffs to set up SBP preventive strategies.

COX-1 sensitivity and thromboxane A2 production in type 1 and type 2 diabetic patients under chronic aspirin treatment.

AIMS: Although aspirin treatment is useful in reducing ischaemic events in diabetic patients, recent studies suggest that it is less effective when compared with non-diabetics (ND). We sought to evaluate COX-1 sensitivity and thromboxane A(2) (TxA(2)) production in type 1 (T1DM) and type 2 diabetic (T2DM) patients under chronic aspirin treatment, and also evaluate the association between thromboxane A(2) (TxA(2)) production and markers of inflammation and metabolic control, such as high-sensitivity C-reactive protein, fasting blood glucose, and haemoglobin A1c (HbA1c). METHODS AND RESULTS: Agonist-induced platelet aggregation (PA) and TxB(2), a stable metabolite of TxA(2), production, serum TxB(2), and platelet COX-1 and COX-2 expression were studied in T2DM patients, T1DM patients, and high-risk ND subjects, all receiving a low dose of aspirin. TxB(2) formation was studied in platelets treated in vitro with aspirin alone or with a COX-2 inhibitor (NS-398). PA, collagen-induced TxB(2) production, and serum TxB(2) were higher in T1DM and T2DM patients than in ND subjects. TxB(2) production was reduced in diabetic patients by in vitro treatment with aspirin. COX-2 was expressed in all diabetic patients but only in 46% of ND patients. In diabetic patients significant correlations were observed between TxB(2) production and both fasting plasma glucose and HbA1c. CONCLUSION: COX-1 sensitivity and TxB(2) production is similarly reduced in both T1DM and T2DM patients under chronic aspirin treatment. The association between TxB(2) production and either fasting plasma glucose and HbA1c levels suggests that in diabetic patients hyperglycaemia is a determinant of the reduced platelet sensitivity to aspirin.

Pioglitazone enhances collateral blood flow in ischemic hindlimb of diabetic mice through an Akt-dependent VEGF-mediated mechanism, regardless of PPARgamma stimulation.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is commonly associated with both microvascular and macrovascular complications and a strong correlation exists between glycaemic control and the incidence and progression of vascular complications. Pioglitazone, a Peroxisome proliferator-activated receptor-gamma (PPARgamma) ligand indicated for therapy of type T2DM, induces vascular effects that seem to occur independently of glucose lowering. METHODS: By using a hindlimb ischemia murine model, in this study we have found that pioglitazone restores the blood flow recovery and capillary density in ischemic muscle of diabetic mice and that this process is associated with increased expression of Vascular Endothelial Growth Factor (VEGF). Importantly, these beneficial effects are abrogated when endogenous Akt is inhibited; furthermore, the direct activation of PPARgamma, with its selective agonist GW1929, does not restore blood flow recovery and capillary density. Finally, an important collateral vessel growth is obtained with combined treatment with pioglitazone and selective PPARgamma inhibitor GW9662. CONCLUSION: These data demonstrate that Akt-VEGF pathway is essential for ischemia-induced angiogenic effect of pioglitazone and that pioglitazone exerts this effect via a PPARgamma independent manner.

Glycemic risk factors of diabetic vascular complications: the role of glycemic variability.

Achieving adequate targets relatively to all risk factors is considered a standard of care for patients with diabetes mellitus. To date, current guidelines underline the importance of the 'glucose triad' (post-prandial glucose, fasting plasma glucose and glycated haemoglobin) as the three glycemic factors that should be controlled in diabetes care; however, several literature data show that optimizing glycemic control needs achieving a control of glycemic variations. The objective of the present work is reviewing biological and clinical data supporting the role of glycemic variability, its measurement and relationship with the three other well-known glycemic risk factors and evidencing the areas that need further investigation. At last, we propose a simple model that summarizes the 'glucose triad' plus the 'new' risk factor glycemic variability (the 'Pyramid of the Risk').

Charcot Neuroarthropathy: From the Laboratory to the Bedside.

BACKGROUND: The diabetic Charcot foot syndrome is a serious and potentially limbthreatening lower-extremity complication of diabetes. INTRODUCTION: The present review provides a concise account of the advances made over the last twentyfive years in understanding the pathogenesis and management of Charcot neuroarthropathy (CN). METHODS: In this study, the widely known pathogenetic mechanisms underpinning CN are brought into focus, particularly the role of RANKL/RANK/OPG system and advanced glycation end production in the pathogenesis of CN. Furthermore, other potential triggering factors, namely nitric oxide, endothelial dysfunction, macro calcifications and body weight that influence CN have also been discussed. RESULTS: The wide range of diagnostic tools available to clinicians for accurate staging of this pathology has been examined, particularly radiological and nuclear medicine imaging. Additionally, the difficult differential diagnosis between osteomyelitis and CN is also elucidated. CONCLUSION: The review concludes with the comprehensive summary of the major promising therapeutic strategies, including conservative treatment involving orthopedic devices, pharmacological approach, and the most common surgical techniques currently employed in the diagnosis and treatment of this acute disease.

Taurine in women with a history of gestational diabetes.

Taurine is the most abundant amino acid in the human body and seems to play an important role in increasing glucose-mediated insulin secretion, as well as in programming beta-cell maturation during the prenatal life in utero. To test the hypothesis that plasma taurine is related to glucose tolerance, insulin sensitivity and insulin secretion in subjects with history of beta-cell dysfunction such as women with history of gestational diabetes (GDM), we studied 72 non-diabetic women with history of GDM (n=43), impaired glucose tolerance (IGT; n=7), and normal glucose tolerance (NGT; n=22) as previously classified by a 100g-3h-OGTT performed between the 24th and the 28th gestational week. Insulin sensitivity (ISIogtt, calculated through Matsuda-DeFronzo index) and a proxy for insulin secretion (basal plasma C-peptide/fasting plasma glucose; CP/glucose) were measured during and after pregnancy. Plasma taurine was measured after a median period of 6 years (2-11 years) from index pregnancy, when glucose tolerance was retested by a 75 g-2h-OGTT. Plasma taurine was significantly lower in women who had experienced GDM and was unrelated to ISIogtt. Moreover, plasma taurine was inversely related to previous gestational area-under-curve of glucose and directly related to post-gestational CP/glucose, as well to CP/glucose measured during pregnancy (p<0.05 for both). The relative risk of altered glucose metabolism during previous pregnancies (IGT+GDM) was higher as plasma taurine decreased, even after adjusting for age, time-lag from pregnancy, body mass index and family history of diabetes (OR: 0.980; CI 95%: 0.963-0.999, p=0.003). In conclusion plasma taurine seems to be a fair marker of altered glucose metabolism during past pregnancies in women with antecedent GDM and appears to be inversely related to the previous as well as to the actual insulin secretion in these subjects.