The management of sleep disturbances in children with attention-deficit/hyperactivity disorder (ADHD): an update of the literature.

INTRODUCTION: Sleep disorders represent an important comorbidity in individuals with ADHD. While the links between ADHD and sleep disturbances have been extensively investigated, research on the management of sleep disorders in individuals with ADHD is relatively limited, albeit expanding. AREAS COVERED: The authors searched PubMed, Medline, PsycInfo, Embase+Embase Classic, Web of Sciences databases, and clinicaltrials.gov up to 4 January 2024, for randomized controlled trials (RCTs) of any intervention for sleep disorders associated with ADHD. They retained 16 RCTs (eight on pharmacological and eight on non-pharmacological interventions), supporting behavioral intervention and melatonin, and nine ongoing RCTs registered on clinicaltrials.gov. EXPERT OPINION: The pool of RCTs testing interventions for sleep disorders in individuals with ADHD is expanding. However, to inform clinical guidelines, there is a need for additional research in several areas, including 1) RCTs based on a precise phenotyping of sleep disorders; 2) pragmatic RCTs recruiting neurodevelopmental populations representative of those seen in clinical services; 3) trials testing alternative interventions (e.g. suvorexant or light therapy) or ways to deliver them (e.g. online); 4) sequential and longer-term RCTs; 5) studies testing the impact of sleep interventions on outcomes other than sleep; 6) and implementation of advanced evidence synthesis and precision medicine approaches.

Autism spectrum disorder (ASD) and sexual offending: A systematic review.

The relationship between autism spectrum disorder (ASD) and sexual offending (SO) is an overlooked issue, both in clinical practice and in research. Based on a pre-specified protocol (PROSPERO: CRD42024501598), we systematically searched Pubmed and Scopus, between January 1st, 1994 and January 12th, 2024, for articles related to SO in ASD. Study quality was assessed with study design-specific tools (Study Quality Assessment Tools, NHLBI, NIH). We found 19 relevant publications (five cross-sectional studies, two case-control studies, and 12 case reports). Seven of the studies were deemed of "good" quality, the rest as "fair". Included studies addressed three key aspects: 1) psychopathological characteristics of individuals with ASD that increase the risk of committing SO; 2) intervention strategies for individuals with ASD and SO; 3) involvement of individuals with ASD and SO in the justice system. Overall, while there is an increasing interest in this topic, more rigorous study designs, including randomised controlled trials, are needed to inform clinical practice and healthcare and social policies.

Multiplexed MRM-based proteomics for identification of circulating proteins as biomarkers of cardiovascular damage progression associated with diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) increases the risk of coronary heart disease (CHD) by 2-4 fold, and is associated with endothelial dysfunction, dyslipidaemia, insulin resistance, and chronic hyperglycaemia. The aim of this investigation was to assess, by a multimarker mass spectrometry approach, the predictive role of circulating proteins as biomarkers of cardiovascular damage progression associated with diabetes mellitus. METHODS: The study considered 34 patients with both T2DM and CHD, 31 patients with T2DM and without CHD, and 30 patients without diabetes with a diagnosis of CHD. Plasma samples of subjects were analysed through a multiplexed targeted liquid chromatography mass spectrometry (LC-MS)-based assay, namely Multiple Reaction Monitoring (MRM), allowing the simultaneous detection of peptides derived from a protein of interest. Gene Ontology (GO) Analysis was employed to identify enriched GO terms in the biological process, molecular function, or cellular component categories. Non-parametric multivariate methods were used to classify samples from patients and evaluate the relevance of the analysed proteins' panel. RESULTS: A total of 81 proteins were successfully quantified in the human plasma samples. Gene Ontology analysis assessed terms related to blood microparticles, extracellular exosomes and collagen-containing extracellular matrix. Preliminary evaluation using analysis of variance (ANOVA) of the differences in the proteomic profile among patient groups identified 13 out of the 81 proteins as significantly different. Multivariate analysis, including cluster analysis and principal component analysis, identified relevant grouping of the 13 proteins. The first main cluster comprises apolipoprotein C-III, apolipoprotein C-II, apolipoprotein A-IV, retinol-binding protein 4, lysozyme C and cystatin-C; the second one includes, albeit with sub-grouping, alpha 2 macroglobulin, afamin, kininogen 1, vitronectin, vitamin K-dependent protein S, complement factor B and mannan-binding lectin serine protease 2. Receiver operating characteristic (ROC) curves obtained with the 13 selected proteins using a nominal logistic regression indicated a significant overall distinction (p < 0.001) among the three groups of subjects, with area under the ROC curve (AUC) ranging 0.91-0.97, and sensitivity and specificity ranging from 85 to 100%. CONCLUSIONS: Targeted mass spectrometry approach indicated 13 multiple circulating proteins as possible biomarkers of cardiovascular damage progression associated with T2DM, with excellent classification results in terms of sensitivity and specificity.

Association of COVID-19 outcomes with diabetes in the Veneto region (north-east italy): Epidemiological insights for the endemic phase?

BACKGROUND AND AIMS: Diabetes mellitus is a prevalent chronic disease in patients who die of COVID-19. The aim of this study was to investigate the clinical and metabolic characteristics of diabetic patients with COVID-19 during the pre-vaccination phase. METHODS AND RESULTS: A retrospective cohort study was conducted from February 2020 to February 2021 to examine the clinical and metabolic profiles of unvaccinated diabetic patients affected by COVID-19. Data were collected from claim databases, hospital discharge records, and clinical records within a healthcare district located in northeastern Italy with a population of 936,000. Potential prognostic indicators including sex, age, Body Mass Index (BMI), duration and type of diabetes, metabolic control, and the use of antidiabetic, antihypertensive, lipid-lowering, and antiplatelet therapies were investigated. For hospitalized patients, additional variables were recorded, such as length of hospital stay, blood pressure at admission, comorbidities, D-dimer levels, blood glucose (BG), in-hospital insulin and corticosteroid therapies, requirement for mechanical ventilation (i.e., orotracheal or tracheostomy), admission to the Intensive Care Unit (ICU), and mortality. Diabetic patients hospitalized for COVID-19 with a poorer prognosis were characterized by advanced age, longer diabetes duration, hypertension, higher usage of sulfonylureas, and lower usage of dietotherapy alone, metformin, Glucagon-Like Peptide-1 Receptor agonists (GLP1-Ra), and Renin-Angiotensin-Aldosterone System inhibitors (RAAS-i). CONCLUSION: Considering the potential for COVID-19 to become endemic, special care should be taken in managing older diabetic patients' treatments.

Do Cortisol and Dehydroepiandrosterone Influence Motivational Factors for Non-Suicidal Self-Injury in Female Adolescents?

Non-suicidal self-injury (NSSI) is a significant public health issue that particularly affects female adolescents usually emerging during puberty, with a subsequent reduction and even remission in the phenomenon later in life. The dysregulation of the hormonal stress response, particularly cortisol and dehydroepiandrosterone sulfate (DHEA-S), whose levels increase markedly during pubertal adrenarche, has been associated with the development and maintenance of a wide range of emotional disorders. Our study aims to investigate whether different cortisol-DHEA-S response patterns could be associated with the main motivational moderators to engage NSSI as well as with urgency and motivation to stop NSSI in a sample of female adolescents. We found significant correlations between stress hormones and several factors that support and sustain NSSI, specifically: cortisol levels and distressing/upsetting urge (r = 0.39 and a p = 8.94 × 10-3) and sensation seeking (r = -0.32 and a p = 0.04), as well as cortisol/DHEA-s ratio and external emotion regulation (r = 0.40 and a p = 0.01) and desire to stop NSSI (r = 0.40 and a p = 0.01). Cortisol and DHEA-S may play a role in NSSI through the regulation of stress responses and affective states. Such results could have implications for the development of new and improved treatment and prevention plans for NSSI.

The ankle-brachial index for assessing the prevalence of peripheral artery disease and cardiovascular risk in patients with type 2 diabetes mellitus.

BACKGROUND AND AIMS: Type 2 diabetes mellitus (T2DM) is an important risk factor for peripheral artery disease (PAD). Ankle-Brachial Index (ABI) was found associated with a higher cardiovascular (CV) risk and mortality. The main goals of this study were to establish the prevalence of PAD in a T2DM population, and assess the relationship between PAD and the CV risk calculated with the CUORE Project score (CPS) (https://www.cuore.iss.it/). The association between the ABI, the main risk factors for PAD and T2DM complications was also investigated. METHODS AND RESULTS: Two hundred patients were consecutively enrolled. The prevalence of PAD in this population was 17%. The CV risk tended to be higher (p = 0.0712) in the group with a pathological ABI than in the group with a normal ABI. Glycated hemoglobin (r = -0.1591; p = 0.0244), total cholesterol (r = -0.1958; p = 0.0054), LDL cholesterol (r = -0.1708; p = 0.0156) and systolic blood pressure (r = -0.1523; p = 0.0313) correlated significantly and inversely with the left ABI. The frequency of diabetic retinopathy was significantly higher in the group with a pathological ABI (p = 0.0316). CONCLUSIONS: The data reveal a high prevalence of PAD in patients with T2DM. The CPS confirmed that patients with a pathological ABI have tendency to a higher CV risk. The results point to the importance of an accurate CV assessment - also measuring individuals' ABI and calculating their CPS - to better pinpoint those at high risk of PAD, especially among patients with T2DM.

Infection Rates and Impact of Glucose Lowering Medications on the Clinical Course of COVID-19 in People with Type 2 Diabetes: A Retrospective Observational Study.

Purpose: Diabetes is a risk factor for COVID-19 severity, but the role played by glucose lowering medications (GLM) is still unclear. The aim of this study was to assess infection rates and outcomes of COVID-19 (hospitalization and mortality) in adults with diabetes assisted by the Local Health Unit of Padua (North-East Italy) according to the ongoing GLM. Patients and Methods: People with diabetes were identified using administrative claims, while those with SARS-CoV-2 infection were detected by cross referencing with the local COVID-19 surveillance registry. A multivariate logistic regression model was used to verify the association between GLM classes and the outcome. Results: SARS-CoV-2 infection rates were marginally but significantly higher in individuals with diabetes as compared to those without diabetes (RR 1.04, p = 0.043), though such relative 4% increase may be irrelevant from a clinical and epidemiological perspective. 1923 individuals with GLM-treated diabetes were diagnosed with COVID-19; 456 patients were hospitalized and 167 died. Those treated with insulin had a significantly higher risk of hospitalizations for COVID-19 (OR 1.48 p < 0.01) as were those treated with sulphonylureas/glinides (OR 1.34, p = 0.02). Insulin use was also significantly associated with higher mortality (OR 1.90, p < 0.01). Use of metformin was significantly associated with lower death rates (OR 0.62, p = 0.02). The association of other GLM classes with the outcome was not significant. Conclusion: Diabetes does not appear to modify the risk of SARS-CoV-2 infection in a clinically meaningful way, but strongly increases the rates of hospitalization and death. Insulin use was associated with worse outcomes, whereas metformin use was associated with lower mortality.

The Burden of Impaired Serum Albumin Antioxidant Properties and Glyco-Oxidation in Coronary Heart Disease Patients with and without Type 2 Diabetes Mellitus.

Human serum albumin (HSA) has an important antioxidant activity due to the presence of the reduced cysteine at position 34, which represents the most abundant free thiol in the plasma. In oxidative-based diseases, HSA undergoes S-thiolation (THIO-HSA) with changes in the antioxidant function of albumin that could contribute to the progression of the disease. The aim of this study was to verify, for the first time, the different burdens of THIO-HSA, glycated HSA (GLY-HSA), and advanced glycation end products (AGE) accumulation both in type 2 diabetes mellitus (T2DM) patients and in non-diabetic patients, with or without coronary heart disease (CHD). In this study, we assessed the presence of modified forms of HSA, THIO-HSA, and GLY-HSA by means of mass spectrometry in 33 patients with both T2DM and CHD, in 31 patients with T2DM and without CHD, in 30 patients without diabetes with a history of CHD, and 27 subjects without diabetes and CHD. All the patients' anthropometric and clinical data were recorded including age, sex, duration of diabetes, body mass index (BMI), blood pressure, and history of CHD defined with anamnestic data. Metabolic parameters, such as fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), lipids, pentosidine, AGE, receptor for advanced glycation end-products (RAGE) and its soluble form (sRAGE), were measured. AGE and pentosidine are significantly higher in T2DM patients with and without CHD with respect to non-diabetic patients with CHD and control subjects. RAGE levels are significantly higher in T2DM patients with respect to non-diabetic patients, and among T2DM patients, the group with CHD showed significantly higher RAGE levels than those without CHD (217 ± 171 pg/mL and 140 ± 61 pg/mL, respectively). Albumin isoforms discriminate between non-diabetic patients with CHD and T2DM patients with and without CHD and control subjects, with GLY-HSA levels higher in T2DM with and without CHD, and THIO-HSA higher in CHD patients without T2DM. Finally, we demonstrated that the oxidized forms of HSA can increase the expression of the inflammatory cytokine Tumor Necrosis Factor-alpha (TNFα) in monocytic cells. In patients with CHD, GLY-HSA and THIO-HSA have a different prevalent distribution, the first one prevailing in patients with T2DM and the second one in patients without T2DM. These findings suggest that albumin quality and homeostasis balance between glyco-oxidation and thiolation might have an impact on the antioxidant defense system in cardiovascular diseases.

Body Emotional Investment and Emotion Dysregulation in a Sample of Adolescents with Gender Dysphoria Seeking Sex Reassignment.

Adolescents with gender dysphoria (GD) often have internalizing symptoms, but the relationship with affective bodily investment and emotion dysregulation is actually under-investigated. The aims of this study are: (1) the comparison of Self-Administrated Psychiatric Scales for Children and Adolescents' (SAFA), Body Investment Scale's (BIS), and Difficulties in Emotion Regulation Scale's (DERS) scores between GD adolescents (n = 30) and cisgenders (n = 30), (2) finding correlations between body investment and emotion regulation in the GD sample, (3) evaluating the link between these dimensions and internalizing symptomatology of GD adolescents. In addition to the significant impairment in emotion regulation and a negative body investment in the GD sample, Spearman's correlation analyses showed a relationship between worse body protection and impaired emotion regulation, and binary logistic regressions of these dimensions on each SAFA domain evidenced that they may have a role in the increased probability of pathological scores for depression. Our results focused on the role played by emotion regulation and emotional investment in the body in the exacerbating and maintenance of internalizing symptoms, in particular depression, and self-harming behaviors in GD adolescents.

Glucose and Lipid Profiles Predict Anthropometric Changes in Drug-Naïve Adolescents Starting Treatment with Risperidone or Sertraline: A Pilot Study.

Psychiatric disorders are associated with cardiometabolic diseases, partly due to adverse drug effects with individual risk variabilities. Risperidone and sertraline are widely used for youths. Although they may be exposed to anthropometric changes, few data about this population exist. We evaluated the correlation between several blood parameters and body changes in a very small group of drug-naïve adolescents who had started risperidone or sertraline. We examined weight, waist circumference (WC), WC/height ratio and body mass index (BMI) at baseline (T0) and after at least three months of therapy (T1), and blood glucose and lipid profiles at T0. Here, we show significant increases in several anthropometric parameters in both groups, a negative correlation between HDL and ΔWC in the risperidone group and positive correlations between insulin and ΔBMI and between HOMA-IR and ΔBMI in the sertraline group. Despite the sample size, these results are important because it is difficult to study adolescents who are long-term-compliant with psychotropic drugs. This pilot study supports the importance of future large-scale investigations to understand the metabolic risk profiles of psychotropic drugs, their individual vulnerabilities and their underlying mechanisms. Simultaneous guideline-based psychiatric and metabolic interventions should be part of daily practice.

Non-Suicidal Self-Injury: An Observational Study in a Sample of Adolescents and Young Adults.

Non-Suicidal Self-Injury (NSSI) is the self-inflicted destruction of body tissues without suicidal intent with a prevalence of 1.5% to 6.7% in the youth population. At present, it is not clear which emotional and behavioral components are specifically associated with it. Therefore, we studied NSSI in a clinical sample of youth using the Ottawa Self-injury Inventory and the Barratt Impulsiveness Scale 11. The Mann-Whitney test was used to compare the numerical responses provided to the tests. We found 54 patients with NSSI, with a mean age of 17 years. Scores were analyzed in the total sample and in four subgroups. In the total sample, Internal Emotion and External Emotion Regulation, Craving, Non-Planning and Total Impulsivity were significantly associated with NSSI. There were statistically significant differences in Craving between patients with multiple NSSI episodes, suicide attempts and multiple injury modes and patients of other corresponding subgroups, in Internal Emotion Regulation, Sensation Seeking and Motor Impulsivity between NSSI patients with suicide attempts and no suicide attempts, and in Cognitive Impulsivity between NSSI patients with multiple injury modes and one injury mode. It is necessary to carefully evaluate the components underlying NSSI in order to activate personalized treatment options.

The interaction between cannabis use and a CB1-related polygenic co-expression index modulates dorsolateral prefrontal activity during working memory processing.

Convergent findings indicate that cannabis use and variation in the cannabinoid CB1 receptor coding gene (CNR1) modulate prefrontal function during working memory (WM). Other results also suggest that cannabis modifies the physiological relationship between genetically induced expression of CNR1 and prefrontal WM processing. However, it is possible that cannabis exerts its modifying effect on prefrontal physiology by interacting with complex molecular ensembles co-regulated with CB1. Since co-regulated genes are likely co-expressed, we investigated how genetically predicted co-expression of a molecular network including CNR1 interacts with cannabis use in modulating WM processing in humans. Using post-mortem human prefrontal data, we first computed a polygenic score (CNR1-PCI), combining the effects of single nucleotide polymorphisms (SNPs) on co-expression of a cohesive gene set including CNR1, and positively correlated with such co-expression. Then, in an in vivo study, we computed CNR1-PCI in 88 cannabis users and 147 non-users and investigated its interaction with cannabis use on brain activity during WM. Results revealed an interaction between cannabis use and CNR1-PCI in the dorsolateral prefrontal cortex (DLPFC), with a positive relationship between CNR1-PCI and DLPFC activity in cannabis users and a negative relationship in non-users. Furthermore, DLPFC activity in cannabis users was positively correlated with the frequency of cannabis use. Taken together, our results suggest that co-expression of a CNR1-related network predicts WM-related prefrontal activation as a function of cannabis use. Furthermore, they offer novel insights into the biological mechanisms associated with the use of cannabis.

Antibodies to post-translationally modified mitochondrial peptide PDC-E2(167-184) in type 1 diabetes.

BACKGROUND: Mitochondria play a role in type 1 diabetes (T1D) particularly in the treatment and prevention of disorder consequences. Due to their demonstrated role in diabetes pathology, mitochondrial proteins can be an interesting starting point to study candidate antigens in T1D. We investigated the role of relevant post-translational modifications (PTM) on a synthetic mitochondrial peptide as putative antigen. METHODS: The antibody response in T1D was evaluated by solid phase-ELISA using a collection of synthetic peptides bearing different PTMs. We investigated the role of lipoylation, phosphorylation, and glycosylation. The PTMs were introduced at position 173 of the mitochondrial pyruvate dehydrogenase E2 complex peptide PDC-E2(167-184) and at position 7 of a structure-based designed ß-turn peptide as an irrelevant sequence to investigate the role of the specific PDC-E2 peptide sequence. RESULTS: IgM titres in 31 T1D patients were higher than IgGs to all the synthetic PTM peptides. Results demonstrated the crucial role of lysine lipoamide, serine O-phosphorylation, and O-glycosylation into the PDC-E2(167-184) peptide sequence for IgM antibody recognition. CONCLUSIONS: Results highlight the importance of immune dysregulation in T1D, furthermore, if confirmed in a large number of patients, they will contribute to add novel diagnostic markers for the understanding the physiopathology of the disease.

Low Glucose Concentrations Induce a Similar Inflammatory Response in Monocytes from Type 2 Diabetic Patients and Healthy Subjects.

This study aims to assess the proinflammatory interleukin 1ß (IL-1ß) and anti-inflammatory IL-10 production by monocytes from 38 patients with type 2 diabetes and 31 controls in different glucose concentrations. Monocytes were incubated in low (2.5 mmol/L)-, normal (5.0 mmol/L)-, and high (20 mmol/L)-glucose conditions in the presence and absence of lipopolysaccharide (LPS). Monocytes from both patients and controls only produced a significant increase in IL-1ß in low-glucose conditions (p < 0.01), and this phenomenon was amplified in the presence of LPS, while it was not seen in normal- or high-glucose conditions, not even in the presence of LPS stimulation. There was no increase in IL-10 production by monocytes from either diabetic patients or controls using whatever glucose concentrations, except when treated with LPS in normal-glucose conditions. These findings seem to suggest that low-glucose conditions induce an inflammatory response in monocytes in all individuals, as an intrinsic capacity of this cell line. On the other hand, monocytes only retain their anti-inflammatory ability in response to known inflammatory stimuli such as LPS, under normal-glucose concentrations. In conclusion, human monocytes express an inflammatory pattern in low-glucose conditions in vitro. This response could contribute to explaining the higher cardiovascular risk induced by hypoglycemia in diabetic patients.

Correlation between baseline characteristics and clinical outcomes in a large population of diabetes patients treated with liraglutide in a real-world setting in Italy.

PURPOSE: Treatment with liraglutide in randomized controlled trials is associated with significant reductions in glycated hemoglobin (HbA1c) and weight loss in type 2 diabetes patients. The aim of this retrospective observational study was to investigate correlations of glycemic control and weight outcomes with baseline characteristics of patients starting liraglutide in outpatient clinics in Italy. METHODS: Type 2 diabetes patients were followed from baseline to 4, 8, and 12 months. Changes in glycemic parameters, weight, blood pressure, and lipids were assessed. Subanalyses were performed according to baseline characteristics. Multivariate linear and logistic regressions were used to assess correlations between glycemic efficacy, weight reduction, and liraglutide discontinuation after 12 months and baseline characteristics. FINDINGS: Four hundred and eighty-one patients were included. Mean (SD) age at baseline was 57.3 (9.2) years, diabetes duration was 9.5 (6.8) years, weight was 106.7 (20.8) kg, body mass index (BMI; calculated as kg/m(2)) was 37.1 (6.6), HbA1c was 8.7% (1.3%), fasting plasma glucose was 168.5 (45.3) mg/dL; 38.2% were treated previously with insulin and 52.2% were treated with metformin alone. After 12 months, mean (SD) changes were HbA1c -1.2% (1.4%), fasting plasma glucose -28.3 (41.1) mg/dL, weight -3.5 (5.8) kg, BMI -1.3 (2.1), waist circumference -2.6 (6.7) cm (all, P < 0.001). Drop in weight and HbA1c did not differ between baseline BMI classes ≤30 or >30. Weight loss was unchanged among diabetes duration quartiles, and HbA1c reduction was significantly greater in patients with ≤4 years of diabetes duration (P = 0.01). Non-insulin-treated patients reached HbA1c ≤7% significantly more often than treated patients (44.2% vs 21.2%; odds ratio = 2.94; P < 0.001) and had significantly greater weight loss (-4.5 [8.2] kg vs -2.6 [5.4] kg; P = 0.03). Patients on metformin reached HbA1c target more frequently than others (43.1% vs 29.7%; odds ratio = 1.80; 95% CI, 1.05-3.07). Significant positive determinants for HbA1c reduction after 12 months were baseline HbA1c, age, and prior metformin monotherapy, and weight loss at 12 months was positively correlated with baseline weight, and negatively correlated with prior insulin treatment. Overall, 5.0% of patients interrupted liraglutide before the 12th month due to lack of glycemic control; they were less frequently treated with metformin only before liraglutide (29.2% vs 50.2%; P = 0.04). IMPLICATIONS: Treatment with liraglutide in a real-world setting is associated with low therapy failure, good glycemic response, weight loss, and improvement in systolic blood pressure and lipid profile. The HbA1c drop did not differ among baseline BMI classes, indicating that efficacy is maintained in patients with lower BMI. The probability of reaching HbA1c ≤7% was significantly higher in patients previously treated with metformin alone and without any previous insulin. This could reinforce the hypothesis that better results with liraglutide could be achieved in patients after early metformin failure.

A preliminary fastview of mitochondrial protein profile from healthy and type 2 diabetic subjects.

Type 2 diabetes results from the development of insulin resistance and a concomitant impairment of insulin secretion. Mitochondrial dysfunctions are thought to be the major contributor to the development of various pathologies, including type 1 and type 2 diabetes mellitus. Mitochondrial oxidative stress has been reported in models of both type 1 and type 2 diabetes mellitus and may play a central role in mitochondrial dysfunction. In the present study, we investigated the occurrence of protein alterations, due to the presence of type 2 diabetes, in mitochondria isolated from human peripheral blood mononuclear cells (PBMCs] by matrix-assisted laser desorp- tion/ionization mass spectrometry (MALDI-MS]. PBMCs may be suitable for this investigation because they have insulin receptors that quickly respond to changes in insulin concentration, and in the presence of insulin rapidly increase their rates of glucose utiliza- tion. In the presence of insulin-resistance conditions, such as type 2 diabetes mellitus, this mechanism is altered and the glycation of cytoplasmic as well as mitochondrial proteins may plausibly appear. Therefore, PBMCs may be useful tools to verify modifications or altered expression of mitochondrial proteins. Human mitochondria were obtained from 32 subjects, 16 healthy controls and 16 type 2 diabetic patients. Two different methods for mitochondria isolation and purification were employed and compared. Some proteins have been found to be differently expressed in the two groups of subjects under investigation and can be classified into two sets: i.e. proteins related to ATP synthase [e.g. 6.8kDa mitochondrial proteolipid [MLQ]; ATP-CF6 [m/z 12,597)] and proteins related to cell proliferation and apoptosis [e.g. TIMM9 [m/z 10,378); Bcl-2-like protein 2 (m/z20,742)].

Glyco-oxidation and cardiovascular complications in type 2 diabetes: a clinical update.

Diabetes is associated with a greatly increased risk of cardiovascular disease (CVD), which cannot be explained only by known risk factors, such as smoking, hypertension, and atherogenic dyslipidemia, so other factors, such as advanced glycation end-products (AGEs) and oxidative stress, may be involved. In this frame, hyperglycemia and an increased oxidative stress (AGE formation, increased polyol and hexosamine pathway flux, and protein kinase C activation) lead to tissue damage, thus contributing to the onset of cardiovascular complications. Several studies have identified in various cell systems, such as monocytes/macrophages and endothelial cells, specific cellular receptors (RAGE) that bind AGE proteins. The binding of AGEs on RAGE induces the production of cytokines and intracellular oxidative stress, thus leading to vascular damage. Soluble RAGE levels have been identified as hypothetical markers of CVD, but, in this regard, there are sparse and conflicting data in the literature. The purpose of this review was to examine all the available information on this issue with a view to clarifying or at least highlighting the points that are still weak, especially from the point of clinical view.

Role of endogenous secretory RAGE (esRAGE) in defending against plaque formation induced by oxidative stress in type 2 diabetic patients.

OBJECTIVES: This study was conducted to examine the relationship between endogenous secretory receptors for advanced glycation end products (esRAGE) and oxidative stress in type 2 diabetic patients (T2DM) with/without advanced macro-angiopathy. METHODS: Sixty-one T2DM were assessed for glycemic control, lipid profile, AGEs, carboxymethyl-lysine (CML), soluble receptor for advanced glycation end products (sRAGE), esRAGE and vitamin E levels, and underwent echo-color-Doppler of the abdominal aorta and aorto-iliac tree, carotid and lower limb arteries to check for evidence of plaques. RESULTS: AGEs and CML levels were significantly higher in T2DM with plaques than in those without (P = 0.0156 and P = 0.007, respectively) despite a comparable metabolic control and history of disease. EsRAGE and vitamin E levels were lower in T2DM with than in those without plaques (P < 0.0001), while no differences were observed as regards sRAGE levels. Considering all T2DM, univariate regression analysis showed a positive correlation between esRAGE and vitamin E (r = 0.456, P < 0.001), and a negative correlation between esRAGE and AGEs (r = -0.284, P < 0.05). After dividing patients by the presence/absence of plaques, esRAGE only correlated directly with vitamin E (r = 0.563, P < 0.01) and CML (r = 0.479, P < 0.05) in patients without plaques. CONCLUSIONS: This is the first study to establish a relationship between esRAGE and oxidative stress and/or antioxidant power, suggesting that esRAGE upregulation might be part of the cell's antioxidative defenses against plaque forming as a result of oxidative stress in the T2DM phenotype (cases with a more efficient esRAGE production being better protected).

Subclinical diastolic dysfunction in type 2 diabetic patients with and without carotid atherosclerosis: relationship with glyco-oxidation, lipid-oxidation and antioxidant status.

OBJECTIVES: The aim of this study was to evaluate subclinical diastolic dysfunction in type 2 diabetic patients and its relationship with glyco-oxidation, lipo-oxidation and antioxidant capacity in the presence or absence of carotid plaques. BACKGROUND: Subclinical diastolic dysfunction is the early stage of diabetic cardiomyopathy, the pathogenic mechanisms of which are still little known. In particular, few data are available on the role of glyco-oxidation, lipo-oxidation and antioxidant status, factors known to be involved in the atherosclerotic process. METHODS: We assessed myocardial systolic and diastolic functions in 57 consecutive asymptomatic type 2 diabetic patients (24 patients with no carotid plaques; 33 with plaques) and 27 healthy volunteers using transthoracic echocardiography. Glyco-oxidation and lipo-oxidation parameters and antioxidant status were also evaluated in fasting venous blood samples. RESULTS: Systolic function was similar between diabetic patients and controls, while most of the diastolic parameters (A, e', E/A, E/e') differed significantly between diabetics and controls, being worse in the former. Among the diastolic parameters, only the peak late diastolic velocity A differed significantly between the two groups of diabetic patients with no carotid plaques and with plaques (0.72 ± 0.16 m/s vs 0.84 ± 0.25 m/s, p<0.05). The diastolic parameters A and E/e' related to glycemic control, glyco-oxidation and antioxidant capacity, and to LDL size and density. CONCLUSIONS: Glyco-oxidation and antioxidant status, combined with the presence of small, dense LDL correlate with subclinical diastolic dysfunction in type 2 diabetic patients. Atherosclerotic lesions are associated with an altered atrial function.