Association of the systemic immuno-inflammation index, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio with diabetic microvascular complications.

Background: The systemic immuno-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) are widely used and have been shown to be predictive indicators of various diseases. Diabetic nephropathy (DN), retinopathy (DR), and peripheral neuropathy (DPN) are the most prominent and common microvascular complications, which have seriously negative impacts on patients, families, and society. Exploring the associations with these three indicators and diabetic microvascular complications are the main purpose. Methods: There were 1058 individuals with type 2 diabetes mellitus (T2DM) in this retrospective cross-sectional study. SII, NLR, and PLR were calculated. The diseases were diagnosed by endocrinologists. Logistic regression and subgroup analysis were applied to evaluate the association between SII, NLP, and PLR and diabetic microvascular complications. Results: SII, NLR, and PLR were significantly associated with the risk of DN [odds ratios (ORs): 1.52, 1.71, and 1.60, respectively] and DR [ORs: 1.57, 1.79, and 1.55, respectively] by multivariate logistic regression. When NLR ≥2.66, the OR was significantly higher for the risk of DPN (OR: 1.985, 95% confidence interval: 1.29-3.05). Subgroup analysis showed no significant positive associations across different demographics and comorbidities, including sex, age, hypertension, HbA1c (glycated hemoglobin), and dyslipidemia. Conclusion: This study found a positive relationship between NLR and DN, DR, and DPN. In contrast, SII and PLR were found to be only associated with DN and DR. Therefore, for the diagnosis of diabetic microvascular complications, SII, NLR and PLR are highly valuable.

What Makes Wounds Chronic.

Chronic wounds present a unique therapeutic challenge to heal. Chronic wounds are colonized with bacteria and the presence of a biofilm that further inhibits the normal wound healing processes, and are locked into a very damaging proinflammatory response. The treatment of chronic wounds requires a coordinated approach, including debridement of devitalized tissue, minimizing bacteria and biofilm, control of inflammation, and the use of specialized dressings to address the specific aspects of the particular nonhealing ulcer.

Serum Levels of Antibodies to Advanced Glycation End Products in Patients with Type 2 Diabetes Mellitus and Hypertension.

BACKGROUND AND AIMS: Proteins containing advanced glycation end products are highly immunogenic and anti-advanced glycation end products antibodies (anti-AGEs antibodies) are found in the sera of diabetics. MATERIALS AND METHODS: Enzyme-linked immunosorbent assay (ELISA) was used for measuring levels of anti-advanced glycation end products antibodies in sera of 93 patients with type 2 diabetes mellitus and arterial hypertension (mean age 61.4±11.3 years, diabetes duration 9.88±3.12 years; hypertension duration 9.28±4.98). These values were compared to serum anti-AGEs antibodies in 42 age and sex matched controls. Diabetics were divided in two groups according to presence or absence of microangiopathy, group 1 (n=67) and group 2 (n=26), respectively. RESULTS: Serum levels of anti-AGEs antibodies in patients with type 2 diabetes mellitus and arterial hypertension were statistically significantly higher than those in the control group (1.39±0.39 vs. 1.05±0.32), (p<0.05). Group 1 showed significantly higher levels of anti-AGEs antibodies than those of healthy controls (1.53±0.14 vs. 1.05±0.32), (p<0.01). Anti-AGEs antibodies levels were higher in patients with microvascular complications than these in patients without complications. Anti-AGEs antibodies correlate with diastolic blood pressure (r=0.26, p=0.05) and body mass index (r=0.37, p=0.03). We found significantly higher percentage of positive patients for anti-AGEs antibodies (mean+2SD) in group 1 than in group 2. CONCLUSION: Determining the levels of serum anti-AGEs antibodies can help physicians make early diagnosis and prognosis of the severity of late diabetic complications in hypertensive patients.

Platelet activation and immune response in diabetic microangiopathy.

BACKGROUND: Diabetes can lead to serious pathological changes in the microvascular system, which in turn leads to functional damage of related tissues that affects the quality of life of patients. The mechanism of microcirculation disturbance in diabetes is not well understood; however, the inflammatory damage and dysgenesis of blood vessels based on oxidative and hyperosmotic stress is considered to be a key factor. In addition, with in-depth studies of platelet function, the study of platelet inflammatory function has become popular in recent years. OBJECTIVE: The present manuscript reviews the new knowledge of platelet immune inflammatory function and the mechanism of diabetic microangiopathy, and emphasizes the relationship between them. CONCLUSION: The nuclear factor-κB (NF-κB) pathway has always been regarded as a typical pro-inflammatory signaling pathway in different nucleated cells, and NF-κB is also expressed in platelets. Although the signaling pathway of NF-κB in platelets is not completely understood, numerous studies have confirmed its function in platelet immune inflammation. The signaling pathway of the development of diabetic microangiopathy is partially cross-linked with the platelet NF-κB pathway. In addition, platelets can release various chemokines to aggravate vascular endothelial cell injury, indicating that platelets may serve a key role in the mechanism of diabetic microangiopathy.

Allicin alleviates inflammation of diabetic macroangiopathy via the Nrf2 and NF-kB pathway.

As diabetic macroangiopathy is becoming increasingly prevalent, it is urgent to explore preventive and therapeutic drugs and study the mechanism. Diabetic mice were induced by intraperitoneal injection of streptozotocin (STZ)for five consecutive days. Diabetic mice were divided into diabetic and allicin groups. After sacrifice, frozen aortic root sections were immunohistochemically stained for nuclear factor erythroid 2-related factor 2 (Nrf2) and inflammation cytokine-tumor necrosis factor α (TNF-α), and the remaining aortic tissues were analyzed by Western blot for the expression of proinflammation genes. In vitro, Nrf2 and inflammatory relative protein expression levels in Human Umbilical Vein Endothelial Cells (HUVECs) were examined. HUVECs proliferation and apoptosis were measured. TNF-α expression was increased in diabetic group compared to that in control group; this effect was alleviated in allicin-treated mice. Inflammation relative protein expression of Vascular Cell Adhesion Molecule 1(VCAM-1), Matrix metalloproteinase 2 (MMP-2), Inducible Nitric Oxide Synthase (iNOS), and monocyte chemotactic protein 1 (MCP-1) was higher in the diabetic group than in the control group; however, allicin treatment inhibited these diabetes-induced increase. In vitro, allicin treatment reversed the hyperglycemia-induced reduction in proliferation, and decreased the apoptosis induced by high glucose. Inflammation relative protein expression was consistent with that in vivo. Additionally, the expression of nuclear factor kappa-B (NF-κB)and Nrf2 was increased in both DM mice and HUVECs; allicin treatment induced a significant reduction in NF-κB level and improvement in Nrf2 level. Allicin alleviates inflammation caused by diabetic macroangiopathy, and the mechanism may occur via increasing Nrf2 and decreasing NF-κB.

Salidroside ameliorates endothelial inflammation and oxidative stress by regulating the AMPK/NF-κB/NLRP3 signaling pathway in AGEs-induced HUVECs.

Endothelial dysfunction plays important roles in vascular dysfunction under diabetic conditions. The generation of advanced glycation end products (AGEs), which can induce inflammation and oxidative stress, is pivotal in endothelial dysfunction. Salidroside, a major active compound in Rhodiola rosea, exerts protective effects against vascular diseases. To study the effects and mechanism of salidroside in diabetes-induced vascular endothelial dysfunction, an in vitro model was established with AGEs-induced human umbilical vein endothelial cells (HUVECs). Then, cell viability, cell apoptosis, pro-inflammatory cytokines and oxidative biomarkers were tested to determine the effects of salidroside at 10, 50 and 100 µM doses on AGEs induced HUVECs. Additionally, RNA-Seq and bioinformatics analyses were used to search for the underlying mechanism of salidroside. The results showed that salidroside promoted cell viability and significantly alleviated cell apoptosis in AGEs-induced HUVECs. Furthermore, salidroside remarkably decreased the levels of the pro-inflammatory cytokines TNF-α, IL-1ß and IL-6 and impeded the expression of VCAM-1 and ICAM-1 induced by AGEs. Additionally, salidroside promoted superoxide dismutase (SOD) activity and increased catalase (CAT) and glutathione peroxidase (GSH-Px) levels while inhibiting the intracellular generation of reactive oxygen species (ROS) and malondialdehyde (MDA) in AGEs-induced HUVECs. Importantly, salidroside alleviated endothelial inflammation and oxidative stress by activating AMPK phosphorylation and inhibiting NF-ĸB p65 and NLRP3 inflammasome activation. Therefore, we used compound C, an accepted AMPK inhibitor, to further demonstrate the mechanism. Interestingly, the phenomenon produced by salidroside was abolished. Our findings suggest that salidroside ameliorates AGEs-induced endothelial inflammation and oxidative stress, partially via the AMPK/NF-κB/NLRP3 signaling pathway.

Relationship between Lipid Indices, Type IV Collagen Turnover and the Development of Microvascular Complications in Diabetic Patients with Arterial Hypertension.

BACKGROUND AND AIMS: An important factor in the development of vascular wall lesions is the degradation of the major protein of connective tissue - type IV collagen. Type IV collagen peptides (CIVDP) derived from this degradation are present in the circulation and are a stimulus for production of anti-collagen type IV antibodies (ACIVAbs) IgM, IgG and IgA. The aim of this study was to find a possible association between ACIVAbs, lipid indices and the development of microvascular complications. MATERIALS AND METHODS: Sera of 93 patients (mean age 61.4±11.3 yrs, diabetes duration 9.88±3.12 yrs; hypertension duration 9.28±4.98) with type 2 diabetes mellitus (T2DM) and arterial hypertension (AH) were investigated. ACIVAbs was determined using ELISA and then compared to serum ACIVAbs in 42 age- and sex-matched controls. Diabetics were divided into two groups according to presence (group 1, n=67) or absence (group 2, n=26) of microangiopathy. Lipid profile and lipid indices (log TG/HDL, LDL/HDL, TC/HDL and TG/HDL) were examined too. RESULTS: Patients with T2DM and AH showed statistically significant higher levels of serum ACIVAbs IgG than healthy controls [0.298 (0.237÷0.381) vs 0.210 (0.149÷0.262), KW=14.01, p<0.0001]. Group 1 had statistically significant higher levels of ACIVAbs IgG than patients without microangiopathy [0.323 (0.243÷0.391) vs 0.241 (0.207÷0.291), KW=7.66, p=0.006] and healthy controls [0.210 (0.149÷0.262), KW=17.52, p<0.0001). ACIVAbs IgG showed correlation with duration of diabetes (r=0.49, p=0.01), retinopathy (r=-0.20, p=0.04) and BMI (r=-0.24, p=0.05), HbA1c (r=0.21, p=0.04), SBP (r=0.16, p=0.05). ACIVAbs IgG correlated with log TG/HDL (r=0.21, p=0.01), LDL/HDL (r=0.19, p=0.02) TC/HDL (r=0.16, p=0.05) and with TG/HDL (r=0.15, p=0.05). CONCLUSION: Our study shows relationship between elevation of ACIVAbs IgG, high lipid indices and development of microvascular complications in patients with type 2 diabetes mellitus and arterial hypertension.

The Role of the Microbiota in the Diabetic Peripheral Artery Disease.

Vascular complications of diabetes mellitus represent a major public health problem. Although many steps forward have been made to define the causes and to find the best possible therapies, the problem remains crucial. In recent years, more and more evidences have defined a link between microbiota and the initiation, promotion, and evolution of atherosclerotic disease, even in the diabetic scenario. There is an urgency to develop the knowledge of modern medicine about the link between gut microbiota and its host's metabolic pathways, and it would be useful to understand and justify the interindividual diversity of clinical disease presentation of diabetic vascular complication even if an optimization of pharmacological treatment has been made or in the case of young patients where hypertension, dyslipidemia, and diabetes are not able to justify a very quick progress of atherosclerotic process. The aim of the present review is to gather all the best available evidence in this regard and to define a new role of the microbiota in this field, from biomarker to possible therapeutic target.

Agonistic autoantibodies against B2-adrenergic receptors correlating with macrovascular disease in longstanding diabetes type 2.

AIMS: Agonistic autoantibodies directed against adrenergic, endothelin, and angiotensin receptors are known as pathogenic factors in disease-causing vascular impairments such as Buergers' disease, dilatative cardiomyopathy, dementia, and preeclampsia. Diabetes mellitus also causes micro- and macrovascular damages, but pathogenesis is still not fully understood. Following indications for a pathogenic role of the mentioned antibodies from our preliminary investigations, we investigated the prevalence in a bigger cohort of patients with longstanding diabetes with or without diabetic complications. METHODS: We included 200 patients in four groups (grouping due to duration of diabetes and presence of complications) from our university polyclinic with longstanding diabetes mellitus type 2 and evaluated the prevalence of the agonistic autoantibodies using ELISA technique. RESULTS: Antibodies directed against the alpha1-(39%), the first extracellular loop of the beta2-(34,5%), and the first extracellular loop of the beta1-adrenergic receptor (29,0%) were the most often detectable. With progression of diabetes and its complications, we found a decrease in the prevalence of the antibodies. Regression analyses revealed a positive association of antibodies against the first loop of the beta2-receptor and the presence of macrovascular complications. CONCLUSIONS: This investigation found mid frequent prevalence of agonistic autoantibodies in patients with longstanding diabetes mellitus type 2. The association between an antibody against one epitope and the presence of macrovascular complications may indicates a pathogenic linkage. This finding is inconsistent with our preliminary data and needs further evaluation, maybe by follow-up.

Toll-Like Receptor 4 and Heat-Shock Protein 70: Is it a New Target Pathway for Diabetic Vasculopathies?

Diabetes is one of the most concerning diseases in modern times. Despite considerable advances in therapeutic management, the prevalence of diabetes and its contribution to death and disability continue to be a major health problem. Diabetic vasculopathies are the leading cause of mortality and morbidity in diabetic patients. Its pathophysiology includes oxidative stress, advanced glycation end products, and a low-grade inflammatory state. Lately, actions of the innate immune system via Toll-like receptors (TLRs) have been suggested as a new insight in this field. TLRs are pattern recognition receptors activated by highly conserved structural motifs of exogenous or endogenous ligands. Heat-shock proteins (HSPs), normally known for their ability to protect cells during stressful conditions, when released from injured cells bind to TLR4 and trigger the release of pro-inflammatory cytokines in a MyD88-dependent pathway. This pathway had been investigated in pancreatic beta cells and skeletal muscle, but it has not yet been explored in the vascular system and deserves investigation. In this work, the interplay between TLR4 and HSP70 in the vasculature during diabetes is reviewed and discussed. The current literature and preliminary results from our laboratory led us to hypothesize that hyperglycemia-associated HSP70 plays an important role in the pathophysiology of diabetic vasculopathies via the TLR4 pathway and might be a new target for therapeutic intervention.

Dendritic cell activation is blunted in patients with coronary artery disease and diabetes mellitus.

BACKGROUND: It has been shown that functional status of dendritic cells (DCs) in diabetic patients with unstable angina pectoris (UAP) are more mature and activated than diabetic patients without coronary artery disease (CAD) and none diabetic patients with UAP. Accordingly we aimed to assess the activation of DCs in patients with CAD with/and without Diabetes Mellitus (DM) and compare to those in subjects with normal coronary arteries (NCA). MATERIALS AND METHODS: Twenty three patients with severe CAD who were scheduled to coronary artery by-pass grafting surgery and 6 patients with angiographycally NCAs were included in the study. Activation of peripheral blood DCs have been analyzed by flow cytometric measures of CD86 activation. RESULTS: In patients with CAD and without DM, DC activation significantly increased after stimulation of oxidesized LDL (135 ±â€¯121 vs 248 ±â€¯197 p = 0.024). However this activation didn't significantly increased in patients with CAD and DM (100 ±â€¯20 vs 120 ±â€¯97, p = 0,54). Patients with NCAs and without DM showed marked activation of CD86 after stimulation with ox-LDL. CONCLUSION: We have documented that DC activation, upon stimulation of ox-LDL has blunted in patients with CAD compared to patients with NCAs. Moreover this defective activation is more pronounced in those with diabetic patients with CAD.

Metabolic and genetic response to probiotics supplementation in patients with diabetic nephropathy: a randomized, double-blind, placebo-controlled trial.

This study was carried out to evaluate the effects of probiotics administration on the metabolic and genetic profiles in patients with diabetic nephropathy (DN). This was a randomized, placebo-controlled clinical trial with homeostasis model of assessment-estimated insulin resistance (HOMA-IR) as the primary and other metabolic profiles, and biomarkers of inflammation and oxidative stress as the secondary outcomes. This randomized, double-blind, placebo-controlled clinical trial was performed on 60 patients with DN. The patients were randomly assigned into two groups to receive either 8 × 109 CFU day-1 probiotic supplements or placebo (n = 30 in each group) for 12 weeks. Fasting blood was collected at the baseline and end of intervention to measure glycemic control, lipid profiles, biomarkers of inflammation and oxidative stress. Multiple linear regression models were used to assess the treatment effects on the outcomes adjusting for confounding variables. Probiotics supplementation, compared with the placebo, resulted in a significant reduction in fasting plasma glucose (P = 0.01), serum insulin concentrations (P = 0.01) and HOMA-IR (P = 0.007), and a significant increase in the quantitative insulin sensitivity check index (P = 0.04). Additionally, compared with the placebo, probiotic intake resulted in a significant reduction in triglycerides (P = 0.001) and total-/HDL-cholesterol ratio (P < 0.001), and a significant increase in HDL-cholesterol levels (P < 0.001). Supplementation with probiotics, compared with the placebo, was associated with a significant reduction in high-sensitivity C-reactive protein (P = 0.001), malondialdehyde (P < 0.001) and advanced glycation end products (P < 0.001), and a significant elevation in plasma total glutathione (P < 0.001). Overall, our study indicated that probiotics supplementation had beneficial effects on glycemic control and markers of cardio-metabolic risk.

l-Citrulline Supplementation: Impact on Cardiometabolic Health.

Diminished bioavailability of nitric oxide (NO), the gaseous signaling molecule involved in the regulation of numerous vital biological functions, contributes to the development and progression of multiple age- and lifestyle-related diseases. While l-arginine is the precursor for the synthesis of NO by endothelial-nitric oxide synthase (eNOS), oral l-arginine supplementation is largely ineffective at increasing NO synthesis and/or bioavailability for a variety of reasons. l-citrulline, found in high concentrations in watermelon, is a neutral alpha-amino acid formed by enzymes in the mitochondria that also serves as a substrate for recycling l-arginine. Unlike l-arginine, l-citrulline is not quantitatively extracted from the gastrointestinal tract (i.e., enterocytes) or liver and its supplementation is therefore more effective at increasing l-arginine levels and NO synthesis. Supplementation with l-citrulline has shown promise as a blood pressure lowering intervention (both resting and stress-induced) in adults with pre-/hypertension, with pre-clinical (animal) evidence for atherogenic-endothelial protection. Preliminary evidence is also available for l-citrulline-induced benefits to muscle and metabolic health (via vascular and non-vascular pathways) in susceptible/older populations. In this review, we examine the impact of supplementing this important urea cycle intermediate on cardiovascular and metabolic health outcomes and identify future directions for investigating its therapeutic impact on cardiometabolic health.

Diabetes Shared Care Program (DSCP) and risk of infection mortality: a nationwide cohort study using administrative claims data in Taiwan.

OBJECTIVE: The Diabetes Shared Care Program (DSCP) is an integrated care model in Taiwan that has been proven to improve the care quality of patients with diabetes. We aimed to evaluate the efficacy of DSCP in decreasing the hospital mortality of infectious diseases. METHODS: From 1 662 929 patients with type 2 diabetes newly diagnosed between 1999 and 2013, we retrieved a total of 919 patients who participated in the DSCP with the first hospitalisation for an infectious disease as the study cohort and 9190 propensity score-matched patients with type 2 diabetes who did not participate as the comparison.The efficacy of DSCP was evaluated via the following comparisons between the DSCP and non-DSCP cohorts: hospital mortality, 1-year medical cost prior to and during the hospitalisation, and complications, such as receiving mechanical ventilation and intensive care unit admission. The ratio (OR) for hospital mortality of the DSCP participants was calculated by logistical regression. Further stratification analyses were conducted to examine which group of patients with type 2 diabetes benefited the most from the DSCP during hospitalisation for infectious diseases. RESULTS: The DSCP cohort had a lower hospital mortality rate than the non-DSCP participants (2.18% vs 4.82%, p<0.001). The total medical cost during the hospitalisation was lower in the DSCP cohort than in the non-DSCP cohort (NT$72 454±30 429 vs NT$86 385±29 350) (p=0.006). In the logistical regression model, the DSCP participants exhibited a significantly decreased adjusted OR for hospital mortality (adjusted OR=0.42, 95% CI 0.26 to 0.66, p=0.0002). The efficacy of the DSCP was much more prominent in male patients with type 2 diabetes and in patients with lower incomes. CONCLUSION: Participation in the DSCP was associated with a lower risk of hospital mortality for infectious diseases.

Bonus Effects of Antidiabetic Drugs: Possible Beneficial Effects on Endothelial Dysfunction, Vascular Inflammation and Atherosclerosis.

Diabetes currently affects more than 400 million people worldwide. This metabolic disorder causes various micro- and macrovascular complications that accelerate atherosclerosis and yet trigger other cardiovascular diseases. The characteristic frame of hyperglycaemia, hyperinsulinaemia and hyperlipidaemia in diabetes increases several inflammatory mediators leading to endothelial dysfunction and pro-atherosclerotic processes. This MiniReview summarizes evidence that antidiabetic drugs have effects beyond lowering glycaemic levels. In experimental studies, antidiabetic drugs reduce the vascular production and release of pro-inflammatory cytokines, the recruitment, infiltration and activation of immune cells and pro-inflammatory mediators, thus decreasing vascular inflammatory responses; they also re-establish vascular redox homeostasis by reducing oxidative stress and balancing the release of vasoconstrictor and vasodilator factors, hence contributing to the improvement of endothelial function. These effects are associated with a reduction in vascular remodelling due to decreased matrix metalloproteinases expression/activity, reduced inflammatory processes and vascular wall fibrosis. In clinical studies, antidiabetic drugs also reduce the production and release of pro-inflammatory, pro-atherosclerotic and pro-oxidative mediators and improve flow-mediated dilatation, indicating beneficial effects on endothelial function. These bonus effects of antidiabetic drugs may delay and/or reduce the installation and development of the atherosclerotic disease, decrease cardiovascular risk and possibly impact mortality risk, life expectancy and quality.

Human Aldose Reductase Expression Prevents Atherosclerosis Regression in Diabetic Mice.

Guidelines to reduce cardiovascular risk in diabetes include aggressive LDL lowering, but benefits are attenuated compared with those in patients without diabetes. Consistent with this, we have reported in mice that hyperglycemia impaired atherosclerosis regression. Aldose reductase (AR) is thought to contribute to clinical complications of diabetes by directing glucose into pathways producing inflammatory metabolites. Mice have low levels of AR, thus raising them to human levels would be a more clinically relevant model to study changes in diabetes under atherosclerosis regression conditions. Donor aortae from Western diet-fed Ldlr-/- mice were transplanted into normolipidemic wild-type, Ins2Akita (Akita+/- , insulin deficient), human AR (hAR) transgenic, or Akita+/- /hAR mice. Akita+/- mice had impaired plaque regression as measured by changes in plaque size and the contents of CD68+ cells (macrophages), lipids, and collagen. Supporting synergy between hyperglycemia and hAR were the even more pronounced changes in these parameters in Akita+/- /hAR mice, which had atherosclerosis progression in spite of normolipidemia. Plaque CD68+ cells from the Akita+/- /hAR mice had increased oxidant stress and expression of inflammation-associated genes but decreased expression of anti-inflammatory genes. In summary, hAR expression amplifies impaired atherosclerosis regression in diabetic mice, likely by interfering with the expected reduction in plaque macrophage inflammation.

Mediterranean Diet, Glucose Homeostasis, and Inflammasome Genetic Variants: The CORDIOPREV Study.

SCOPE: Insulin resistance (IR) and chronic low-grade inflammation are hallmarks of type 2 diabetes mellitus (T2DM). The "NOD-like receptor pyrin domain containing-3" (NLRP3) inflammasome component of innate immunity is a metabolic stress sensor modulated by dietary and genetics factors. The aim of this study was to evaluate the effects of the consumption of two diets for 3 years, Mediterranean (Med) and low fat, on glucose homeostasis in the 1002 coronary heart disease patients of the CORDIOPREV study, according to a genetic variant of NLRP3 inflammasome. METHODS AND RESULTS: The study was conducted in the framework of the CORDIOPREV study, a randomized dietary intervention with Med and low-fat diets. Single nucleotide polymorphisms (SNPs) located at inflammasome NLRP3 gene were genotyped by OpenArray platform. Nondiabetic CT+TT carriers of the rs4612666 SNP and AG+AA carriers of the rs10733113 SNP increased insulin sensitivity index (ISI) after 3 years of dietary intervention, whereas no effect was observed in diabetic patients. Further analysis by diet showed that the improvement of the ISI in nondiabetic rs10733113 AG+AA carriers was specific to the consumption of the Med diet. CONCLUSION: Our results show that the benefits associated with a Med diet regarding glucose homeostasis in non-T2DM patients depend on genetic variation in the inflammasome.

Cardiovascular biomarkers in clinical studies of type 2 diabetes.

When planning cardiovascular (CV) studies in type 2 diabetes (T2D), selection of CV biomarkers is a complex issue. Because the pathophysiology of CV disease (CVD) in T2D is multifactorial, ideally, the selected CV biomarkers should cover all aspects of the known pathophysiology of the disease. This will allow the researcher to distinguish between effects on different aspects of the pathophysiology. To this end, we discuss a host of biomarkers grouped according to their role in the pathogenesis of CVD, namely: (1) cardiac damage biomarkers; (2) inflammatory biomarkers; and (3) novel biomarkers (oxidative stress and endothelial dysfunction biomarkers). Within each category we present the best currently validated biomarkers, with special focus on the population of interest (people with T2D). For each individual biomarker, we discuss the physiological role, validation in the general population and in people with T2D, analytical methodology, modifying factors, effects of glucose-lowering drugs, and interpretation. This approach will provide clinical researchers with the information necessary for planning, conducting and interpreting results from clinical trials. Furthermore, a systematic approach to selection of CV biomarkers in T2D research will improve the quality of future research.

Is there a role for exosomes in foetoplacental endothelial dysfunction in gestational diabetes mellitus?

Gestational diabetes mellitus (GDM) is a disease of pregnancy associated with endothelial dysfunction in the foetoplacental vasculature. Foetoplacental endothelial dysfunction is characterized by changes in the l-arginine-adenosine signalling pathway and inflammation. The mechanisms involved in these alterations are suggested to be hyperglycaemia, hyperinsulinemia, and oxidative stress. These conditions increase the release of exosomes, nanovesicles that are generated from diverse cell types, including endothelial cells. Since exosomes can modulate vascular function, they may play an important role in foetoplacental endothelial dysfunction seen in GDM pregnancies. In this review, we summarized current knowledge on the potential role of exosomes in foetoplacental endothelial dysfunction seen in this disease of pregnancy.

Serum amyloid A enrichment impairs the anti-inflammatory ability of HDL from diabetic nephropathy patients.

AIMS: Impaired anti-inflammatory ability of high-density lipoprotein (HDL) has been demonstrated in patients with type-2 diabetes mellitus (T2DM). However, whether HDL from patients with diabetic nephropathy (DN) suffers additional damage remains unknown. This study compared the anti-inflammatory capacities of HDL from healthy controls, T2DM patients with normal renal function, and T2DM patients with DN. MATERIALS AND METHODS: HDL was isolated from healthy controls (n=33) and T2DM patients with normal renal function (n=21), chronic kidney disease (CKD) (n=27), and end-stage renal disease (ESRD) (n=27). Human peripheral blood mononuclear cells (PBMCs) from healthy volunteers were pretreated with HDL (100µg/mL) for 1h, then incubated with lipopolysaccharide (LPS) (50ng/mL) for 24h. The anti-inflammatory ability of HDL was measured as the secretion of TNF-α in LPS-activated monocytes. RESULTS: The anti-inflammatory ability of HDL was gradually impaired as kidney function declined. Serum amyloid A (SAA) concentration in HDLDN significantly increased and was positively correlated with the impaired anti-inflammatory ability of HDL (Pearson r=0.315, P=0.006). Furthermore, HDL supplemented with SAA significantly increased TNF-α release from PBMCs compared with that from control HDL. CONCLUSIONS: These findings identified an impaired anti-inflammatory capacity of HDL from DN patients, which might be attributable to SAA enrichment.