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Graphical abstract Abstract Diabetes is a chronic metabolic disease characterized by hyperglycemia and several associated biochemical abnormalities. Diabetes leads to multiorgan complications that collectively reduce life expectancy. Hematopoietic stem cells (HSCs) are nested within bone marrow (BM) niches whence they can be mobilized to the peripheral circulation. Clinically, this is done for HSC collection and autologous or allogenic transplantation. A great amount of data from basic and clinical studies support that diabetic patients are poor HSC mobilizers owing to BM remodeling. Dysfunction of the BM shares pathophysiological features and pathways with typical chronic diabetic complications that affect other issues (e.g. the retina and the kidney). From a clinical perspective, impaired HSC mobilization translates into the failure to collect a minimum number of CD34+ cells to achieve a safe engraftment after transplantation. Furthermore, blunted mobilization is associated with reduced steady-state levels of circulating HSCs, which have been consistently described in diabetic patients and associated with increased risk of adverse outcomes, including cardiovascular events and death. In this review, we discuss the most clinically relevant pharmacological options to overcome impaired HSC mobilization in diabetes. These therapeutic strategies may result in an improved outcome of diabetic patients undergoing HSC transplantation and restore circulating HSC levels, thereby protecting from adverse cardiovascular outcomes. [ABSTRACT FROM AUTHOR]

Background: Randomized controlled trials (RCTs) in the field of diabetes have limitations inherent to the fact that design, setting, and patient characteristics may be poorly transferrable to clinical practice. Thus, evidence from studies using routinely accumulated clinical data are increasingly valued.Aims: We herein describe rationale and design of the DARWIN-T2D (DApagliflozin Real World evIdeNce in Type 2 Diabetes), a multicenter retrospective nationwide study conducted at 50 specialist outpatient clinics in Italy and promoted by the Italian Diabetes Society.Data Synthesis: The primary objective of the study is to describe the baseline clinical characteristics (particularly HbA1c) of patients initiated on dapagliflozin from marketing authorization approval to the end of 2016. Secondary and exploratory objectives will evaluate the changes in glycaemic and extraglycaemic efficacy parameters after initiation of dapagliflozin or after initiation of comparator glucose lowering medications (DPP-4 inhibitors, gliclazide extended release, and long-acting GLP-1 receptor agonists). An automated software will extract relevant data from the same electronic chart system at all centres, thereby minimizing data treatment and human intervention.Conclusion: The study is expected to collect an enormous dataset of information on dapagliflozin- and comparator-using patients. After study completion, the Italian Diabetes Society will launch an open crowdsourcing call on the DARWIN-T2D database, challenging diabetes researchers to apply their ideas and approaches to address new unmet needs and knowledge gaps in diabetes. We believe this will move DARWIN-T2D to the next generation of real world studies. [ABSTRACT FROM AUTHOR]

Andrologists, cardiologists and diabetologists (and general practitioners) have the great opportunity to collaborate and find shared clinical workup for the benefit of a large number of men. Several evidence established a link between erectile dysfunction ( ED), cardiovascular disease ( CVD), diabetes, and metabolic syndrome. Not only these conditions share many risk factors and pathophysiological mechanisms but also an emerging paradigm indicates that ED is, in fact, an independent marker of cardiovascular disease risk, CV events and CV mortality. However, there is no consensus on the best cardiologic investigation in men with ED with no known CVD and, on the contrary, on what is the clinical and prognostic role of detecting ED during cardiovascular investigation and CVD risk assessment. Only vasculogenic ED, which represents the most common type of organic ED, indeed represents a harbinger of CVD, especially for younger patients, and might be diagnosed by dynamic penile color doppler ultrasonography, which represents a real cardiovascular imaging technique that give evidence on the presence of systemic endothelial dysfunction and atherosclerosis. Furthermore, assessment of glucose and lipid metabolism is warranted as first step workup in all ED patients, and diabetologists should ask their patients for erectile function, address ED patients to andrologists, and consider vasculogenic ED in the context of the cardiovascular and metabolic workup and in the context of diabetic complications. Sexual symptoms (and testosterone levels) should sound as harbinger for cardiovascular and metabolic investigation and cardiologists and diabetologists have the opportunity to have a symptom (erectile dysfunction) and a vascular test (penile color doppler) that help them in better management of patients, their comorbidities and complications. [ABSTRACT FROM AUTHOR]

Background and Aims: Degludec is an ultralong-acting insulin analogue with a flat and reproducible pharmacodynamic profile. As some patients with type 1 diabetes (T1D) fail to achieve 24-h coverage with glargine or detemir despite twice-daily injections, we studied the effect of switching T1D patients from twice-daily glargine or detemir to degludec.Methods and Results: In this prospective observational study, T1D patients on twice-daily glargine or detemir were enrolled. At baseline and 12 weeks after switching to degludec, we recorded HbA1c, insulin dose, 30-day blood glucose self monitoring (SMBG) or 14-day continuous glucose monitoring (CGM), treatment satisfaction (DTSQ), fear of hypoglycemia (FHS). We included 29 patients (mean age 34 ± 11 years; diabetes duration 18 ± 10 years). After switching to degludec, HbA1c decreased from 7.9 ± 0.6% (63 ± 6 mmol/mol) to 7.7 ± 0.6% (61 ± 6 mmol/mol; p = 0.028). SMBG showed significant reductions in the percent and number of blood glucose values <70 mg/dl and in the low blood glucose index (LBGI) during nighttime. CGM showed a significant reduction of time spent in hypoglycemia, an increase in daytime spent in target 70-180 mg/dl, and a reduction in glucose variability. Total insulin dose declined by 17% (p < 0.001), with 24% reduction in basal and 10% reduction in prandial insulin. DTSQ and FHS significantly improved.Conclusion: Switching from twice-daily glargine or detemir to once daily degludec improved HbA1c, glucose profile, hypoglycemia risk and treatment satisfaction, while insulin doses decreased. ClinicalTrials.govNCT02360254. [ABSTRACT FROM AUTHOR]

Aims: To review the significance of a new type of neutrophil cell death (NETosis) in diabetes and cardiometabolic diseases.Data Synthesis: Diabetes and the metabolic syndrome are characterized by activation of the innate immune system. In this framework, neutrophils are front line defences against infections, but can also turn deleterious if abnormally stimulated. NETosis refers to a type of cell death whereby neutrophils release nuclear material and granule enzymes that together form the NETs (neutrophil extracellular traps). As NETs entrap bacteria, NETosis is instrumental to the clearance of microorganisms, but an exaggerated NETosis response can also lead to tissue damage in several pathological conditions. In diabetes, the finely tuned balance of NETosis required to protect the human body from microorganisms yet avoiding self-damage seems to be lost. In fact, in vitro induction of NETosis and circulating concentrations of NET-associated proteins appear to be enhanced in diabetic patients. Furthermore, NETs contribute to endothelial damage, thrombosis, and ischemia/reperfusion injury, making it a novel player in the pathobiology of cardiovascular disease. Though the cellular events taking place during NETosis have been described and directly visualized, its molecular machinery is still incompletely understood. Protein kinase C (PKC) and NADPH oxidase (NOX) are two important targets to counter NETosis in the setting of diabetes.Conclusions: NETosis appears to be part of an abnormal response to damage in diabetes that, in turn, can promote or aggravate end-organ complications. We suggest that this will be a hot topic of investigation in diabetology in the near future. [ABSTRACT FROM AUTHOR]

Background and aims Prediabetes increases cardiovascular risk and is associated with excess mortality. In preclinical models, metformin has been shown to exert anti-ageing effects. In this study, we sought to assess whether metformin modulates putative effector longevity programs in prediabetic subjects. Methods and results In a randomized, single-blind, placebo-controlled trial, 38 prediabetic subjects received metformin (1500 mg/day) or placebo for 2 months. At baseline and after treatment, we collected anthropometric and metabolic parameters. Gene and protein levels of SIRT1 , mTOR , p53 , p66Shc , SIRT1 activity, AMPK activation, telomere length, and SIRT1 promoter chromatin accessibility were determined in peripheral blood mononuclear cells (PBMCs). Plasma N-glycans, non-invasive surrogate markers of ageing, were also analysed. Compared to baseline, metformin significantly improved metabolic parameters and insulin sensitivity, increased SIRT1 gene/protein expression and SIRT1 promoter chromatin accessibility, elevated mTOR gene expression with concomitant reduction in p70S6K phosphorylation in subjects' PBMCs, and modified the plasma N-glycan profile. Compared to placebo, metformin increased SIRT1 protein expression and reduced p70S6K phosphorylation (a proxy of mTOR activity). Plasma N-glycans were also favourably modified by metformin compared to placebo. Conclusion In individuals with prediabetes, metformin ameliorated effector pathways that have been shown to regulate longevity in animal models. ClinicalTrials.gov Identifier NCT01765946 – January 2013. [ABSTRACT FROM AUTHOR]

Abstract: Background and aims: Common mechanisms for the development of micro- and macroangiopathic diabetic complications have been suggested. We aimed to cross-sectionally investigate strength and characteristics of the association between carotid atherosclerosis and microangiopathy in type 2 diabetic patients. Methods and results: Common carotid artery intima–media thickness (cIMT), carotid plaque (CP) type and degree of stenosis were evaluated by ultrasound, along with the determination of anthropometric parameters, HbA1c, lipid profile, assessment of diabetic retinopathy and nephropathy, in 662 consecutive patients with type 2 diabetes mellitus (T2DM). Patients were divided according to high/low cIMT, presence/absence of CP and of retinopathy and nephropathy. Patients with CP were older, more prevalently males, past smokers, had longer diabetes duration, significantly lower HDL cholesterol and more prevalent ischemic heart disease (all p <0.05) as compared to those with cIMT<1mm. Microangiopathies were more prevalent in patients with CP than in those without. At multivariate logistic regression, factors independently associated with the presence of CP were age, past smoke, HDL cholesterol, retinopathy and retinopathy plus nephropathy. A significant independent correlation of CP stenosis with stage of retinopathy and nephropathy was found. Finally, echolucent CPs were associated with a lower prevalence of proliferative retinopathy than CP containing calcium deposits. Conclusion: In T2DM, retinopathy, alone or in combination with nephropathy, is independently associated to CP, and severity of microangiopathy correlates with severity of carotid atherosclerosis. These observations, together with the different prevalence of proliferative retinopathy according to CP types, point to possible common pathogenic mechanisms in micro- and macrovascular complications. [Copyright &y& Elsevier]