Leptin is a principal adipose-derived hormone mostly implicated in the regulation of energy balance through the activation of anorexigenic neuronal pathways. Comprehensive studies have established ...that the maintenance of certain concentrations of circulating leptin is essential to avoid an imbalance in nutrient intake. Indeed, genetic modifications of the leptin/leptin receptor axis and the obesogenic environment may induce changes in leptin levels or action in a manner that accelerates metabolic dysfunctions, resulting in a hyperphagic status and adipose tissue expansion. As a result, a vicious cycle begins wherein hyperleptinaemia and leptin resistance occur, in turn leading to increased food intake and fat enlargement, which is followed by leptin overproduction. In addition, in the context of obesity, a defective thermoregulatory response is associated with impaired leptin signalling overall within the ventromedial nucleus of the hypothalamus. These recent findings highlight the role of leptin in the regulation of adaptive thermogenesis, thus suggesting leptin to be potentially considered as a new thermolipokine. This review provides new insight into the link between obesity, hyperleptinaemia, leptin resistance and leptin deficiency, focusing on the ability to restore leptin sensitiveness by way of enhanced thermogenic responses and highlighting novel anti-obesity therapeutic strategies.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Current views show that an impaired balance partly explains the fat accumulation leading to obesity. Fetal malnutrition and early exposure to endocrine-disrupting compounds also contribute to obesity ...and impaired insulin secretion and/or sensitivity. The liver plays a major role in systemic glucose homeostasis through hepatokines secreted by hepatocytes. Hepatokines influence metabolism through autocrine, paracrine, and endocrine signaling and mediate the crosstalk between the liver, non-hepatic target tissues, and the brain. The liver also synthetizes bile acids (BAs) from cholesterol and secretes them into the bile. After food consumption, BAs mediate the digestion and absorption of fat-soluble vitamins and lipids in the duodenum. In recent studies, BAs act not simply as fat emulsifiers but represent endocrine molecules regulating key metabolic pathways. The liver is also the main site of the production of ketone bodies (KBs). In prolonged fasting, the brain utilizes KBs as an alternative to CHO. In the last few years, the ketogenic diet (KD) became a promising dietary intervention. Studies on subjects undergoing KD show that KBs are important mediators of inflammation and oxidative stress. The present review will focus on the role played by hepatokines, BAs, and KBs in obesity, and diabetes prevention and management and analyze the positive effects of BAs, KD, and hepatokine receptor analogs, which might justify their use as new therapeutic approaches for metabolic and aging-related diseases.
In the last years, demand and availability of computational capabilities experienced radical changes. Desktops and laptops increased their processing resources, exceeding users’ demand for large part ...of the day. On the other hand, computational methods are more and more frequently adopted by scientific communities, which often experience difficulties in obtaining access to the required resources. Consequently, data centers for outsourcing use, relying on the cloud computing paradigm, are proliferating. Notwithstanding the effort to build energy-efficient data centers, their energy footprint is still considerable, since cooling a large number of machines situated in the same room or container requires a significant amount of power. The volunteer cloud, exploiting the users’ willingness to share a quote of their underused machine resources, can constitute an effective solution to have the required computational resources when needed. In this paper, we foster the adoption of the volunteer cloud computing as a green (i.e., energy efficient) solution even able to outperform existing data centers in specific tasks. To manage the complexity of such a large scale heterogeneous system, we propose a distributed optimization policy to task scheduling with the aim of reducing the overall energy consumption executing a given workload. To this end, we consider an integer programming problem relying on the Alternating Direction Method of Multipliers (ADMM) for its solution. Our approach is compared with a centralized one and other non-green targeting solutions. Results show that the distributed solution found by the ADMM constitutes a good suboptimal solution, worth to be applied in a real environment.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Diabetes and cancer are worldwide chronic diseases with a major impact on the quality and expectancy of life. Metabolic abnormalities observed during the onset and progression of diabetes may have a ...critical role on the initiation and progression of carcinogenesis. To date, there are no conclusive data on the mechanisms underlying the relationship between diabetes and any type of human cancer. However, recent evidence suggests that both hyperglycemia and hyperinsulinemia in diabetes could elicit cell damage responses, such as glucotoxicity, lipotoxicity and oxidative stress, which participate in the cell transformation process raising the risk of cancer development. In addition, clinical trials have revealed that several anti-diabetes therapies may potentially affect the risk of cancer though largely undefined mechanisms. In this review, we highlight epidemiological and pathophysiological aspects of diabetes, which may influence cancer initiation and progression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Obstructive sleep apnea (OSA) represents a frequent complication among patients with obesity and has been associated with neuroendocrine changes, including hypogonadism.
We conducted a systematic ...review and meta-analysis to evaluate the effects of continuous positive airway pressure (CPAP) on testosterone and gonadotropins in male patients with OSA.
The review was registered on PROSPERO (CRD42018103164). PubMed, Scopus, CENTRAL, and Clinicaltrials.gov were searched until June 2018. Studies reporting the effect of CPAP on total testosterone, free testosterone, sexual hormone binding globulin (SHBG), follicle stimulating hormone (FSH), luteinizing hormone (LH), and prolactin were included. A subgroup analysis on hypogonadal vs. eugonadal status at baseline was performed.
Out of 129 retrieved papers, 10 prospective cohort and 2 randomized controlled studies were included in the review. Three hundred eighty-eight patients were included. CPAP use was not associated with a significant change in total testosterone levels mean difference 1.08, 95% confidence interval (CI) -0.48 to 2.64 or other outcomes. The subgroup analysis confirmed the overall results.
The present review does not support the hypothesis of a direct interaction between OSA and testosterone. Strategies other than CPAP should therefore be considered in managing hypogonadism in patients with OSA.
This study explored the role of irisin as a new pancreatic β-cell secretagogue and survival factor and its potential role in the communication between skeletal muscle and pancreatic β-cells under ...lipotoxic conditions. Recombinant irisin stimulated insulin biosynthesis and glucose-stimulated insulin secretion (GSIS) in a PKA-dependent manner and prevented saturated fatty acid-induced apoptosis in human and rat pancreatic β-cells, as well as in human and murine pancreatic islets, via AKT/BCL2 signaling. Treatment of myotubes with 0.5 mmol/L palmitate for 4 h, but not with oleate, promoted an increase in irisin release in the culture medium. Moreover, increased serum levels of irisin were observed in mice fed with a high-fat diet. Mouse serum rich in irisin and the conditioned medium from myotubes exposed to palmitate for 4 h significantly reduced apoptosis of murine pancreatic islets and insulin-secreting INS-1E cells, respectively, and this was abrogated in the presence of an irisin-neutralizing antibody. Finally, in vivo administration of irisin improved GSIS and increased β-cell proliferation. In conclusion, irisin can promote β-cell survival and enhance GSIS and may thus participate in the communication between skeletal muscle and β-cells under conditions of excess saturated fatty acids.
The loss of beta-cell functional mass is a necessary and early condition in the development of type 2 diabetes (T2D). In T2D patients, beta-cell function is already reduced by about 50% at diagnosis ...and further declines thereafter. Beta-cell mass is also reduced in subjects with T2D, and islets from diabetic donors are smaller compared to non-diabetic donors. Thus, beta-cell regeneration and/or preservation of the functional islet integrity should be highly considered for T2D treatment and possibly cure. To date, the available anti-diabetes drugs have been developed as “symptomatic” medications since they act to primarily reduce elevated blood glucose levels. However, a truly efficient anti-diabetes medication, capable to prevent the onset and progression of T2D, should stop beta-cell loss and/or promote the restoration of fully functional beta-cell mass, independently of reducing hyperglycemia and ameliorating glucotoxicity on the pancreatic islets. This review provides a view of the experimental and clinical evidence on the ability of available anti-diabetes drugs to exert protective effects on beta-cells, with a specific focus on human pancreatic islets and clinical trials. Potential explanations for the lack of concordance between evidence of beta-cell protection in vitro and of persistent amelioration of beta-cell function in vivo are also discussed.
•“True” anti-diabetes drugs should be able to halt or restore beta-cell functional loss.•Metformin, GLP-1RA, and DPP-4i exert beneficial effects on human beta-cells in vitro.•In prediabetes/newly diagnosed T2D, beta-cell function is restorable with intensive therapies.•In overt T2D, beta-cells show reduced potential for improvement.•Beta-cell pro-survival effects in vitro are not mirrored by durable drug actions in vivo.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cardiovascular outcome trials (CVOT) showed that treatment with glucagon-like peptide-1 receptor agonists (GLP-1RA) is associated with significant cardiovascular benefits. However, CVOT are scarcely ...representative of everyday clinical practice, and real-world studies could provide clinicians with more relatable evidence. Here, literature was thoroughly searched to retrieve real-world studies investigating the cardiovascular and renal outcomes of GLP-1RA vs. other glucose-lowering drugs and carry out relevant meta-analyses thereof. Most real-world studies were conducted in populations at low cardiovascular and renal risk. Of note, real-world studies investigating cardio-renal outcomes of GLP-1RA suggested that initiation of GLP-1RA was associated with a greater benefit on composite cardiovascular outcomes, MACE (major adverse cardiovascular events), all-cause mortality, myocardial infarction, stroke, cardiovascular death, peripheral artery disease, and heart failure compared to other glucose-lowering drugs with the exception of sodium-glucose transporter-2 inhibitors (SGLT-2i). Initiation of SGLT-2i and GLP-1RA yielded similar effects on composite cardiovascular outcomes, MACE, stroke, and myocardial infarction. Conversely, GLP-1RA were less effective on heart failure prevention compared to SGLT-2i. Finally, the few real-world studies addressing renal outcomes suggested a significant benefit of GLP-1RA on estimated glomerular filtration rate (eGFR) reduction and hard renal outcomes vs. active comparators except SGLT-2i. Further real-world evidence is needed to clarify the role of GLP-1RA in cardio-renal protection among available glucose-lowering drugs.
Due to the increasing need for computational power, the market has shifted towards big centralized data centers. Understanding the nature of the dynamics of these data centers from machine and ...job/task perspective is critical to design efficient data center management policies like optimal resource/power utilization, capacity planning and optimal (reactive and proactive) maintenance scheduling. Whereas jobs/tasks dynamics have received a lot of attention, the study of the dynamics of the underlying machines supporting the jobs/tasks execution has received much less attention, even when these dynamics would substantially affect the performance of the jobs/tasks execution. Given the limited data available from large computing installations, only a few previous studies have inspected data centers and only concerning failures and their root causes. In this paper, we study the 2011 Google data center traces from the machine dynamics perspective. First, we characterize the machine events and their underlying distributions in order to have a better understanding of the entire machine lifecycle. Second, we propose a data-driven model to enable the estimate of the expected number of available machines at any instant of time. The model is parameterized and validated using the empirical data collected by Google during a one month period.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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