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Twenty years have passed since Brownlee and colleagues proposed a single unifying mechanism for diabetic complications, introducing a turning point in this field of research. For the first time, reactive oxygen species (ROS) were identified as the causal link between hyperglycemia and four seemingly independent pathways that are involved in the pathogenesis of diabetes-associated vascular disease. Before and after this milestone in diabetes research, hundreds of articles describe a role for ROS, but the failure of clinical trials to demonstrate antioxidant benefits and some recent experimental studies showing that ROS are dispensable for the pathogenesis of diabetic complications call for time to reflect. This twenty-year journey focuses on the most relevant literature regarding the main sources of ROS generation in diabetes and their role in the pathogenesis of cell dysfunction and diabetic complications. To identify future research directions, this review discusses the evidence in favor and against oxidative stress as an initial event in the cellular biochemical abnormalities induced by hyperglycemia. It also explores possible alternative mechanisms, including carbonyl stress and the Warburg effect, linking glucose and lipid excess, mitochondrial dysfunction, and the activation of alternative pathways of glucose metabolism leading to vascular cell injury and inflammation.

Aims: To investigate the relationship between changes in physical fitness and cardiovascular risk factors and scores in patients with type 2 diabetes receiving either a behavioural counselling intervention to increase moderate‐to‐vigorous‐intensity physical activity (MVPA) and decrease sedentary‐time (SED‐time) or standard care. Materials and Methods: This is a pre‐specified ancillary analysis of the Italian Diabetes and Exercise Study_2, a 3‐year randomized clinical trial in which 300 physically inactive and sedentary patients were randomized 1:1 to receive either a one‐month theoretical and practical counselling each year or standard care. Mean changes from baseline throughout the 3‐year period in MVPA, SED‐time, cardiorespiratory fitness (VO2max), muscle strength, flexibility, cardiovascular risk factors and scores were calculated for study completers (n = 267) and considered irrespective of study arm. Results: Haemoglobin (Hb) A1c and coronary heart disease (CHD) risk scores decreased with quartiles of VO2max and lower body muscle strength changes. Multivariable linear regression analysis showed that increases in VO2max independently predicted decreases in HbA1c, blood glucose, diastolic blood pressure (BP), CHD and total stroke 10‐year risk and increases in HDL cholesterol, whereas increases in lower body muscle strength independently predicted decreases in body mass index (BMI), waist circumference, triglycerides, systolic BP, CHD and fatal stroke 10‐year risk. These associations remained after including changes in BMI, waist circumference, fat mass and fat‐free mass, or MVPA and SED‐time as covariates. Conclusions: Improvement in physical fitness predicts favourable changes in cardiometabolic risk profile, independent of changes not only in (central) adiposity or body composition but also in MVPA and SED‐time. Trial Registration: ClinicalTrials.gov; NCT01600937; URL https://clinicaltrials.gov/ct2/show/NCT01600937. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) ranks seventh as a cause of death worldwide. Chronic complications, including cardiovascular, renal, and eye disease, as well as DM-associated non-alcoholic fatty liver disease (NAFLD) account for most of the morbidity and premature mortality in DM. Despite continuous improvements in the management of late complications of DM, significant gaps remain. Therefore, searching for additional strategies to prevent these serious DM-related conditions is of the utmost importance. DM is characterized by a state of low-grade chronic inflammation, which is critical in the progression of complications. Recent clinical trials indicate that targeting the prototypic pro-inflammatory cytokine interleukin-1β (IL-1 β) improves the outcomes of cardiovascular disease, which is the first cause of death in DM patients. Together with IL-18, IL-1β is processed and secreted by the inflammasomes, a class of multiprotein complexes that coordinate inflammatory responses. Several DM-related metabolic factors, including reactive oxygen species, glyco/lipoxidation end products, and cholesterol crystals, have been involved in the pathogenesis of diabetic kidney disease, and diabetic retinopathy, and in the promoting effect of DM on the onset and progression of atherosclerosis and NAFLD. These metabolic factors are also well-established danger signals capable of regulating inflammasome activity. In addition to presenting the current state of knowledge, this review discusses how the mechanistic understanding of inflammasome regulation by metabolic danger signals may hopefully lead to novel therapeutic strategies targeting inflammation for a more effective treatment of diabetic complications.

This article discusses a study that aimed to evaluate the presence of undiagnosed pelvic diseases in patients who underwent in vitro fertilization (IVF) and experienced recurrent implantation failure (RIF). The study used high-quality transvaginal sonography (TVS) performed by experts to assess the patients. The results showed that only 17% of patients had a normal pelvic scan after RIF, with a significant difference observed between the already known abnormal TVS group before IVF and the new diagnosis after RIF. The study suggests that expert TVS should be performed before the first embryo transfer and not just after RIF, as it could potentially lead to new diagnoses and improve the outcomes of IVF. [Extracted from the article]

Objective. Quantitative ultrasound (QUS) provides an estimate of bone mineral density (BMD) and also evaluates bone quality, which has been related to increased fracture risk in people with diabetes. This study aimed at assessing the correlates of calcaneal QUS parameters in diabetic subjects encompassing various degrees of micro and macrovascular complications and a wide-range of peripheral nerve function. Methods. Four hundred consecutive diabetic patients were examined by QUS to obtain values of broadband ultrasound attenuation (BUA), the speed of sound (SOS), quantitative ultrasound index (QUI), and BMD. Results. Among surrogate measures of complications, sensory and motor nerve amplitude and heart rate response to cough test and standing correlated with QUS parameters at univariate analysis, together with age, body mass index (BMI), waist circumference, lipid profile, and renal function. Multivariate analysis revealed that BUA, SOS, QUI, and BMD were independently associated with age, male gender, hemoglobin A1c, BMI (or fat, but not fat-free mass), and somatic and autonomic nerve function parameters. Conclusions. These data indicate that peripheral nerve dysfunction is associated with worse QUS parameters, possibly contributing to increased fracture risk in diabetes. The positive relation of QUS measures with adiposity needs further investigation. This trial is registered with ClinicalTrials.gov (NCT01600924).

The lack of BTK in X-linked agammaglobulinemia (XLA) patients does not affect monocytes and polymorphonuclear cells (PMN) phenotype and functions. In this study, we show that XLA patients had an increased frequency of the intermediate monocytes subset and that BTK-deficient monocytes and PMN had a normal expression of receptors involved in the activation and cellular responses. We demonstrate that BTK is not required for migration, phagocytosis and the production of reactive oxygen species (ROS) following engagement of FC gamma receptors (FcγR). XLA monocytes and PMN showed an efficient calcium (Ca2+)-independent activation of oxidative burst, suggesting that oxidative burst is less dependent by Ca2+ mobilization. The phagocytosis was functional and it remained unaltered also after Ca2+ chelation, confirming the independence of phagocytosis on Ca2+ mobilization. Intravenous immunoglobulin (IVIg) infusion exerted an anti-inflammatory effect by reducing the frequency of pro-inflammatory monocytes. In monocytes, the IVIg reduce the oxidative burst and phagocytosis even if these functions remained efficient.