Showing papers in "Metabolism-clinical and Experimental in 2017"
TL;DR: AI in medicine, which is the focus of this review, has two main branches: virtual and physical, and the virtual branch includes informatics approaches from deep learning information management to control of health management systems, and active guidance of physicians in their treatment decisions.
Abstract: Artificial Intelligence (AI) is a general term that implies the use of a computer to model intelligent behavior with minimal human intervention. AI is generally accepted as having started with the invention of robots. The term derives from the Czech word robota, meaning biosynthetic machines used as forced labor. In this field, Leonardo Da Vinci's lasting heritage is today's burgeoning use of robotic-assisted surgery, named after him, for complex urologic and gynecologic procedures. Da Vinci's sketchbooks of robots helped set the stage for this innovation. AI, described as the science and engineering of making intelligent machines, was officially born in 1956. The term is applicable to a broad range of items in medicine such as robotics, medical diagnosis, medical statistics, and human biology-up to and including today's "omics". AI in medicine, which is the focus of this review, has two main branches: virtual and physical. The virtual branch includes informatics approaches from deep learning information management to control of health management systems, including electronic health records, and active guidance of physicians in their treatment decisions. The physical branch is best represented by robots used to assist the elderly patient or the attending surgeon. Also embodied in this branch are targeted nanorobots, a unique new drug delivery system. The societal and ethical complexities of these applications require further reflection, proof of their medical utility, economic value, and development of interdisciplinary strategies for their wider application.
645 citations
TL;DR: Evidence that circadian misalignment induced by mistimed light exposure, sleep, or food intake adversely affects metabolic health in humans is reviewed and the importance of chronobiology for preventing and treating type 2 diabetes, obesity, and hyperlipidemia is underscore.
Abstract: The circadian system orchestrates metabolism in daily 24-hour cycles. Such rhythms organize metabolism by temporally separating opposing metabolic processes and by anticipating recurring feeding-fasting cycles to increase metabolic efficiency. Although animal studies demonstrate that the circadian system plays a pervasive role in regulating metabolism, it is unclear how, and to what degree, circadian research in rodents translates into humans. Here, we review evidence that the circadian system regulates glucose, lipid, and energy metabolism in humans. Using a range of experimental protocols, studies in humans report circadian rhythms in glucose, insulin, glucose tolerance, lipid levels, energy expenditure, and appetite. Several of these rhythms peak in the biological morning or around noon, implicating earlier in the daytime is optimal for food intake. Importantly, disruptions in these rhythms impair metabolism and influence the pathogenesis of metabolic diseases. We therefore also review evidence that circadian misalignment induced by mistimed light exposure, sleep, or food intake adversely affects metabolic health in humans. These interconnections among the circadian system, metabolism, and behavior underscore the importance of chronobiology for preventing and treating type 2 diabetes, obesity, and hyperlipidemia.
289 citations
TL;DR: Physicians should consider using a PPARgamma agonist, such as pioglitazone, or statin use in those with NAFLD/NASH at high CVD or HCC risk, alone and/or preferably in combination with each other or with ezetimibe, for the primary or secondary prevention of CVD.
Abstract: Non-alcoholic fatty liver disease (NAFLD), the most common liver disease, is characterized by accumulation of fat (>5% of the liver tissue), in the absence of alcohol abuse or other chronic liver diseases. It is closely related to the epidemic of obesity, metabolic syndrome or type 2 diabetes mellitus (T2DM). NAFLD can cause liver inflammation and progress to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis or hepatocellular cancer (HCC). Nevertheless, cardiovascular disease (CVD) is the most common cause of death in NAFLD/NASH patients. Current guidelines suggest the use of pioglitazone both in patients with T2DM and in those without. The use of statins, though considered safe by the guidelines, have very limited use; only 10% in high CVD risk patients are on statins by tertiary centers in the US. There are data from several animal studies, 5 post hoc analyses of prospective long-term survival studies, and 5 rather small biopsy proven NASH studies, one at baseline and on at the end of the study. All these studies provide data for biochemical and histological improvement of NAFLD/NASH with statins and in the clinical studies large reductions in CVD events in comparison with those also on statins and normal liver. Ezetimibe was also reported to improve NAFLD. Drugs currently in clinical trials seem to have potential for slowing down the evolution of NAFLD and for reducing liver- and CVD-related morbidity and mortality, but it will take time before they are ready to be used in everyday clinical practice. The suggestion of this Expert Panel is that, pending forthcoming randomized clinical trials, physicians should consider using a PPARgamma agonist, such as pioglitazone, or, statin use in those with NAFLD/NASH at high CVD or HCC risk, alone and/or preferably in combination with each other or with ezetimibe, for the primary or secondary prevention of CVD, and the avoidance of cirrhosis, liver transplantation or HCC, bearing in mind that CVD is the main cause of death in NAFLD/NASH patients.
207 citations
TL;DR: The various functions of macrophages in lean and obese adipose tissue and how obesity alters macrophage phenotypes are reviewed to help understand the molecular mechanisms underlying these processes and their therapeutic implications for obesity, metabolic syndrome, and diabetes.
Abstract: Interactions between macrophages and adipocytes influence both metabolism and inflammation. Obesity-induced changes to macrophages and adipocytes lead to chronic inflammation and insulin resistance. This paper reviews the various functions of macrophages in lean and obese adipose tissue and how obesity alters adipose tissue macrophage phenotypes. Metabolic disease and insulin resistance shift the balance between numerous pro- and anti-inflammatory regulators of macrophages and create a feed-forward loop of increasing inflammatory macrophage activation and worsening adipocyte dysfunction. This ultimately leads to adipose tissue fibrosis and diabetes. The molecular mechanisms underlying these processes have therapeutic implications for obesity, metabolic syndrome, and diabetes.
204 citations
TL;DR: A systematic review of studies that assessed serum concentrations of lipopolysaccharide (LPS) and/or lipopolysacharide-binding protein (LBP) in diabetic patients compared with healthy people found there was a great variability in the estimates of metabolic endotoxemia among the studies.
Abstract: In this systematic review we analyzed studies that assessed serum concentrations of lipopolysaccharide (LPS) and/or lipopolysacharide-binding protein (LBP) in diabetic patients compared with healthy people. Articles were selected using PubMed and Scopus. Search terms used were endotoxemia, endotoxins, LPS, LBP, diabetes mellitus (DM), type 1 (T1DM), type 2 (T2DM), insulin resistance, humans, epidemiologic studies, population-based, survey, representative, cross-sectional, case-control studies, observational, and clinical trials. Two authors independently extracted articles using predefined data fields, including study quality indicators. There was a great variability in the estimates of metabolic endotoxemia among the studies. Most of the studies observed higher LPS or LBP concentrations in diabetic subjects than in healthy controls. T1DM and T2DM subjects presented higher mean fasting LPS of 235.7% and 66.4% compared with non-diabetic subjects, respectively. Advanced complications (e.g. macroalbuminuria) and disease onset exacerbate endotoxemia. Antidiabetic medications decrease fasting LPS concentrations. Among these medications, rosiglitazone and insulin present higher and lower effects, respectively, compared with other treatments. T1DM and T2DM seem to increase metabolic endotoxemia. However, some confounders such as diet, age, medication, smoking and obesity influence both diabetes and endotoxemia manifestation. A better understanding of the interaction of these factors is still needed.
199 citations
TL;DR: Irisin reduces ischemia-induced neuronal injury via activation of the Akt and ERK1/2 signaling pathways and contributes to the neuroprotective effect of physical exercise against cerebral ischemIA, suggesting that irisin may be a factor linking metabolism and cardio-cerebrovascular diseases.
Abstract: Background Irisin is a novel exercise-induced myokine involved in the regulation of adipose browning and thermogenesis. In this study, we investigated the potential role of irisin in cerebral ischemia and determined whether irisin is involved in the neuroprotective effect of physical exercise in mice. Materials and methods The middle cerebral artery occlusion (MCAO) model was used to produce cerebral ischemia in mice. First, the plasma irisin levels and changes in expression of the irisin precursor protein FNDC5 in skeletal muscle were determined post ischemic stroke. Second, the association between plasma irisin levels and the neurological deficit score, brain infarct volume, or plasma concentrations of tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1β in mice with MCAO were evaluated. Third, the therapeutic effect of irisin on ischemic brain injury was evaluated in vivo and in vitro. Recombinant irisin was injected directly into the tail vein 30min after the MCAO operation, and then the effects of irisin treatment on brain infarct volume, neurological deficit, neuroinflammation, microglia activation, monocyte infiltration, oxidative stress and intracellular signaling pathway activation (Akt and ERK1/2) were measured. Irisin was also administered in cultured PC12 neuronal cells with oxygen and glucose deprivation (OGD). Finally, to assess the potential involvement of irisin in the neuroprotection of physical exercise, mice were exercised for 2weeks and an irisin neutralizing antibody was injected into these mice to block irisin 1h before the MCAO operation. Results The plasma irisin concentration and intramuscular FNDC5 protein expression decreased after ischemic stroke. Plasma irisin levels were negatively associated with brain infarct volume, the neurological deficit score, plasma TNF-α and plasma IL-6 concentrations. In OGD neuronal cells, irisin protected against cell injury. In mice with MCAO, irisin treatment reduced the brain infarct volume, neurological deficits, brain edema and the decline in body weight. Irisin treatment inhibited activation of Iba-1+ microglia, infiltration of MPO-1+ monocytes and expression of both TNF-α and IL-6 mRNA. Irisin significantly suppressed the levels of nitrotyrosine, superoxide anion and 4-hydroxynonenal (4-HNE) in peri-infarct brain tissues. Irisin treatment increased Akt and ERK1/2 phosphorylation, while blockade of Akt and ERK1/2 by specific inhibitors reduced the neuroprotective effects of irisin. Finally, the exercised mice injected with irisin neutralizing antibody displayed more severe neuronal injury than the exercised mice injected with control IgG. Conclusion Irisin reduces ischemia-induced neuronal injury via activation of the Akt and ERK1/2 signaling pathways and contributes to the neuroprotective effect of physical exercise against cerebral ischemia, suggesting that irisin may be a factor linking metabolism and cardio-cerebrovascular diseases.
190 citations
TL;DR: Exercise alone or combined with dietary intervention improves serum levels of liver enzymes and liver fat or histology, and exercise exerts beneficial effects on intrahepatic triglycerides even in the absence of weight loss.
Abstract: Background/Objectives Although lifestyle modifications remain the cornerstone therapy for non-alcoholic fatty liver disease (NAFLD), the optimal lifestyle intervention is still controversial. The aim of this meta-analysis was to evaluate the effect of exercise and/or dietary interventions, type or intensity of exercise and type of diet, on liver function outcomes (liver enzymes, intrahepatic fat and liver histology), as well as on anthropometric and glucose metabolism parameters in NAFLD patients. Subjects/Methods Literature search was performed in Scopus and US National Library of Medicine databases to identify all randomized controlled clinical trials (RCTs) in adult patients with NAFLD, diagnosed through imaging techniques or liver biopsy, published in English between January 2005 and August 2016. Studies' quality was evaluated using the Cochrane Risk of Bias Tool. Heterogeneity was tested using the Cochran's Q test and measured inconsistency by I 2 . Effect size was calculated as the standardized mean difference (SMD). The meta-analysis was performed in accordance with PRISMA guidelines. Results Twenty RCTs with 1073 NAFLD patients were included. Compared to standard care, exercise improved serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (all P Conclusions Exercise alone or combined with dietary intervention improves serum levels of liver enzymes and liver fat or histology. Exercise exerts beneficial effects on intrahepatic triglycerides even in the absence of weight loss.
188 citations
TL;DR: Data so far based on markers of subclinical atherosclerosis as well as retrospective and prospective cohort studies indicate a possible increased CVD risk, mainly for coronary heart disease.
Abstract: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women during their reproductive ages, associated with a plethora of cardiometabolic consequences, with obesity, insulin resistance and hyperandrogenemia playing a major role in the degree of such manifestations. These consequences include increased risk of glucose intolerance and diabetes mellitus (both type 2 and gestational), atherogenic dyslipidemia, systemic inflammation, non-alcoholic fatty liver disease, hypertension and coagulation disorders. Whether this cluster of metabolic abnormalities is also translated in increased cardiovascular disease (CVD) morbidity and mortality in later life, remains to be established. Data so far based on markers of subclinical atherosclerosis as well as retrospective and prospective cohort studies indicate a possible increased CVD risk, mainly for coronary heart disease. Future studies are needed to further elucidate this issue.
184 citations
TL;DR: Overall, human studies indicate that obesity and IR are associated with increased NLRP3 expression in AT, and available studies strongly points for an association betweenNLRP3 inflammasome and obesity/IR.
Abstract: NLRP3 inflammasome activation seems to be a culprit behind the chronic inflammation characteristic of obesity and insulin resistance (IR). Nutrient excess generates danger-associated molecules that activate NLRP3 inflammasome-caspase 1, leading to maturation of IL-1β and IL-18, which are proinflammatory cytokines released by immune cells infiltrating the adipose tissue (AT) from obese subjects. Although several studies have reported an association of the NLRP3 inflammasome with obesity and/or IR; contradictory results were also reported by other studies. Therefore, we conducted a systematic review to summarize results of studies that evaluated the association of the NLRP3 with obesity and IR. Nineteen studies were included in the review. These studies focused on NLRP3 expression/polymorphism analyses in AT. Overall, human studies indicate that obesity and IR are associated with increased NLRP3 expression in AT. Studies in obese mice corroborate this association. Moreover, high fat diet (HFD) increases Nlrp3 expression in murine AT while calorie-restricted diet decreases its expression. Hence, Nlrp3 blockade in mice protects against HFD-induced obesity and IR. NLRP3 rs10754558 polymorphism is associated with risk for T2DM in Chinese Han populations. In conclusion, available studies strongly points for an association between NLRP3 inflammasome and obesity/IR.
182 citations
TL;DR: FSH and LH are the essential hormonal regulators of testicular functions, acting through their receptors in Sertoli and Leydig cells, respectively, and GnRH is the main hypothalamic regulator of the release of gonadotropins.
Abstract: Reproduction is controlled by the hypothalamic-pituitary-gonadal (HPG) axis. Gonadotropin-releasing hormone (GnRH) neurons play a central role in this axis through production of GnRH, which binds to a membrane receptor on pituitary gonadotrophs and stimulates the biosynthesis and secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Multiple factors affect GnRH neuron migration, GnRH gene expression, GnRH pulse generator, GnRH secretion, GnRH receptor expression, and gonadotropin synthesis and release. Among them anosmin is involved in the guidance of the GnRH neuron migration, and a loss-of-function mutation in its gene leads to a failure of their migration from the olfactory placode to the hypothalamus, with consequent anosmic hypogonadotropic hypogonadism (Kallmann syndrome). There are also cases of hypogonadotropic hypogonadim with normal sense of smell, due to mutations of other genes. Another protein, kisspeptin plays a crucial role in the regulation of GnRH pulse generator and the pubertal development. GnRH is the main hypothalamic regulator of the release of gonadotropins. Finally, FSH and LH are the essential hormonal regulators of testicular functions, acting through their receptors in Sertoli and Leydig cells, respectively. The main features of the male HPG axis will be described in this review.
166 citations
TL;DR: It is indicated that NAFPD is a frequent clinical entity, associated with significantly increased risk of metabolic syndrome and its components, and the normal pancreatic fat percentage threshold of 6.2% may be recommended for use in future prospective studies.
Abstract: Objective Growing evidence suggests that individuals with excessive fat in the pancreas are at an increased risk of chronic metabolic disorders. The aim was to systematically review studies on non-alcoholic fatty pancreas disease (NAFPD) with a view to determine its prevalence, associations with metabolic co-morbidities, and to suggest normal pancreatic fat percentage threshold. Methods Three electronic databases (MEDLINE, Scopus, and Embase) were queried. Studies in humans were eligible for inclusion if they provided data on NAFPD and/or pancreatic fat percentage. Where possible, data were pooled using random-effects meta-analysis and the effect of covariates analysed using meta-regression. Results Pooling data on pancreatic fat percentage from nine studies (1209 healthy individuals who underwent magnetic resonance imaging), yielded the weighted mean and weighted standard deviation of 4.48% and 0.87%, respectively. Pooling data on NAFPD from eleven studies (12,675 individuals), yielded the pooled prevalence of 33% (95% confidence interval, 24% - 41%). Meta-regression analysis showed that the prevalence of NAFPD was independent of age and sex. The presence of NAFPD was associated with a significantly increased risk of arterial hypertension (risk ratio 1.67; 95% confidence interval, 1.32–2.10; p Conclusion The findings indicate that NAFPD is a frequent clinical entity, associated with significantly increased risk of metabolic syndrome and its components. The normal pancreatic fat cut-off point of 6.2% may be recommended for use in future prospective studies.
TL;DR: This review brings together the current understanding of the pathogenesis that makes NAFLD a systemic disease and identifies several mechanisms involved in its pathogenesis and progression.
Abstract: Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease and leading cause of cirrhosis in the United States and developed countries. NAFLD is closely associated with obesity, insulin resistance and metabolic syndrome, significantly contributing to the exacerbation of the latter. Although NAFLD represents the hepatic component of metabolic syndrome, it can also be found in patients prior to their presentation with other manifestations of the syndrome. The pathogenesis of NAFLD is complex and closely intertwined with insulin resistance and obesity. Several mechanisms are undoubtedly involved in its pathogenesis and progression. In this review, we bring together the current understanding of the pathogenesis that makes NAFLD a systemic disease.
TL;DR: Promotion of butyrate (etc) production in gut microbiota might be one of the important mechanisms of BBR in regulating energy metabolism.
Abstract: Objective Berberine (BBR) clinically lowers blood lipid and glucose levels via multi-target mechanisms. One of the possible mechanisms is related to its effect on the short chain fatty acids (SCFAs) of the gut microbiota. The goal of this study is to investigate the therapeutic effect and mode of action of BBR working through SCFAs of the gut microbiota (especially, butyrate). Methods Gas chromatography (GC) was used to detect butyrate and other SCFAs chemically. The effect of BBR on butyrate production was investigated in vitro as well as in several animal systems. Microarrays were used to analyze the composition change in the intestinal bacteria community after treatment with BBR. BBR-induced change in the energy production and gene regulation of intestinal bacteria was examined in order to elucidate the underlying molecular mechanisms. Results We show that oral administration of BBR in animals promoted the gut microbiota to produce butyrate, which then enters the blood and reduces blood lipid and glucose levels. Incubating gut bacterial strains in vitro with BBR increased butyrate production. Orally treating animals directly with butyrate reduced blood lipid and glucose levels through a mechanism different from that of BBR. Intraperitoneal BBR administration did not increase butyrate but reduced blood lipid and glucose levels, suggesting that BBR has two modes of action: the direct effect of the circulated BBR and the indirect effect working through butyrate of the gut microbiota. Pre-treating animals orally with antibiotics abolished the effect of BBR on butyrate. A mechanism study showed that BBR (given orally) modified mice intestinal bacterial composition by increasing the abundance of butyrate-producing bacteria. Furthermore, BBR suppressed bacterial ATP production and NADH levels, resulting in increased butyryl-CoA and, eventually, butyrate production via upregulating phosphotransbutyrylase/butyrate kinase and butyryl-CoA:acetate-CoA transferase in bacteria. Conclusion Promotion of butyrate (etc) production in gut microbiota might be one of the important mechanisms of BBR in regulating energy metabolism.
TL;DR: A 12-week period of keto-adaptation and exercise training, enhanced body composition, fat oxidation during exercise, and specific measures of performance relevant to competitive endurance athletes are compared to a HC comparison group.
Abstract: Background Low-carbohydrate diets have recently grown in popularity among endurance athletes, yet little is known about the long-term (> 4 wk) performance implications of consuming a low-carbohydrate high fat ketogenic diet (LCKD) in well-trained athletes. Methods Twenty male endurance-trained athletes (age 33 ± 11 y, body mass 80 ± 11 kg; BMI 24.7 ± 3.1 kg/m2) who habitually consumed a carbohydrate-based diet, self-selected into a high-carbohydrate (HC) group (n = 11, %carbohydrate:protein:fat = 65:14:20), or a LCKD group (n = 9, 6:17:77). Both groups performed the same training intervention (endurance, strength and high intensity interval training (HIIT)). Prior to and following successful completion of 12-weeks of diet and training, participants had their body composition assessed, and completed a 100 km time trial (TT), six second (SS) sprint, and a critical power test (CPT). During post-intervention testing the HC group consumed 30–60 g/h carbohydrate, whereas the LCKD group consumed water, and electrolytes. Results The LCKD group experienced a significantly greater decrease in body mass (HC − 0.8 kg, LCKD − 5.9 kg; P = 0.006, effect size (ES): 0.338) and percentage body fat percentage (HC − 0.7%, LCKD − 5.2%; P = 0.008, ES: 0.346). Fasting serum beta-hydroxybutyrate (βHB) significantly increased from 0.1 at baseline to 0.5 mmol/L in the LCKD group (P = 0.011, ES: 0.403) in week 12. There was no significant change in performance of the 100 km TT between groups (HC − 1.13 min·s, LCKD − 4.07 min·s, P = 0.057, ES: 0.196). SS sprint peak power increased by 0.8 watts per kilogram bodyweight (w/kg) in the LCKD group, versus a − 0.1 w/kg reduction in the HC group (P = 0.025, ES: 0.263). CPT peak power decreased by − 0.7 w/kg in the HC group, and increased by 1.4 w/kg in the LCKD group (P = 0.047, ES: 0.212). Fat oxidation in the LCKD group was significantly greater throughout the 100 km TT. Conclusions Compared to a HC comparison group, a 12-week period of keto-adaptation and exercise training, enhanced body composition, fat oxidation during exercise, and specific measures of performance relevant to competitive endurance athletes.
TL;DR: The role of vitamin D in the maintenance of immune homeostasis seems to occur in part by interacting with the gut microbiota, and the attenuation of association of bacterial genera by inflammatory markers suggests that inflammation participate in part in the relationship between the Gut microbiota and vitamin D concentration.
Abstract: Background Due to immunomodulatory properties, vitamin D status has been implicated in several diseases beyond the skeletal disorders. There is evidence that its deficiency deteriorates the gut barrier favoring translocation of endotoxins into the circulation and systemic inflammation. Few studies investigated whether the relationship between vitamin D status and metabolic disorders would be mediated by the gut microbiota composition. Objective We examined the association between vitamin D intake and circulating levels of 25(OH)D with gut microbiota composition, inflammatory markers and biochemical profile in healthy individuals. Methods In this cross-sectional analysis, 150 young healthy adults were stratified into tertiles of intake and concentrations of vitamin D and their clinical and inflammatory profiles were compared. The DESeq2 was used for comparisons of microbiota composition and the log2 fold changes (log2FC) represented the comparison against the reference level. The association between 25(OH)D and fecal microbiota (16S rRNA sequencing, V4 region) was tested by multiple linear regression. Results Vitamin D intake was associated with its concentration ( r = 0.220, p = 0.008). There were no significant differences in clinical and inflammatory variables across tertiles of intake. However, lipopolysaccharides increased with the reduction of 25(OH)D ( p -trend Prevotella was more abundant (log2FC 1.67, p Haemophilus and Veillonella were less abundant (log2FC − 2.92 and − 1.46, p r = − 0.170, p = 0.039), E-selectin ( r = − 0.220, p = 0.007) and abundances of Coprococcus ( r = − 0.215, p = 0.008) and Bifdobacterium ( r = − 0.269, p = 0.001) were inversely correlated with 25(OH)D. After adjusting for age, sex, season and BMI, 25(OH)D maintained inversely associated with Coprococcus ( β = − 9.414, p = 0.045) and Bifdobacterium ( β = − 1.881, p = 0.051), but significance disappeared following the addition of inflammatory markers in the regression models. Conclusion The role of vitamin D in the maintenance of immune homeostasis seems to occur in part by interacting with the gut microbiota. The attenuation of association of bacterial genera by inflammatory markers suggests that inflammation participate in part in the relationship between the gut microbiota and vitamin D concentration. Studies with appropriate design are necessary to address hypothesis raised in the current study.
TL;DR: In the present narrative review, cross-sectional, prospective and intervention studies examining the relationship between diet and frailty development and prevention are critically evaluated.
Abstract: Frailty is a geriatric condition characterized by unintentional weight loss, low muscle strength, feeling of exhaustion, reduced physical activity capacity and slow walking speed. Theoretically, nutrition is a factor closely related to the frailty syndrome: all frailty criteria are more or less affected by poor eating habits, whereas frailty itself may have a negative effect on eating and, thus, on the nutritional status. Indeed, research data suggest an association between frailty and specific constituents of diet, namely protein and energy intake, as well as intakes of specific micronutrients. Furthermore, healthy dietary patterns, such as the Mediterranean diet, have been linked to the frailty prevention. In the present narrative review, we critically evaluate cross-sectional, prospective and intervention studies examining the relationship between diet and frailty development and prevention. Potential mechanisms linking nutrition and frailty as well as directions for future research are discussed.
TL;DR: A great deal of clinical and genetic overlap characterizes the spectrum of the IGD disorders, and genetic screening should be offered in patients with IGD, as it can provide valuable information for genetic counseling and further understanding of IGD.
Abstract: Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency (IGD) IGD is a genetically and clinically heterogeneous disorder. Mutations in many different genes are able to explain ~40% of the causes of IGD, with the rest of cases remaining genetically uncharacterized. While most mutations are inherited in X-linked, autosomal dominant, or autosomal recessive pattern, several IGD genes are shown to interact with each other in an oligogenic manner. In addition, while the genes involved in the pathogenesis of IGD act on either neurodevelopmental or neuroendocrine pathways, a subset of genes are involved in both pathways, acting as "overlap genes". Thus, some IGD genes play the role of the modifier genes or "second hits", providing an explanation for incomplete penetrance and variable expressivity associated with some IGD mutations. The clinical spectrum of IGD includes a variety of disorders including Kallmann Syndrome (KS), i.e. hypogonadotropic hypogonadism with anosmia, and its normosmic variation normosmic idiopathic hypogonadotropic hypogonadism (nIHH), which represent the most severe aspects of the disorder. Apart from these disorders, there are also "milder" and more common reproductive diseases associated with IGD, including hypothalamic amenorrhea (HA), constitutional delay of puberty (CDP) and adult-onset hypogonadotropic hypogonadism (AHH). Interestingly, neurodeveloplmental genes are associated with the KS form of IGD, due to the topographical link between the GnRH neurons and the olfactory placode. On the other hand, neuroendocrine genes are mostly linked to nIHH. However, a great deal of clinical and genetic overlap characterizes the spectrum of the IGD disorders. IGD is also characterized by a wide variety of non-reproductive features, including midline facial defects such as cleft lip and/or palate, renal agenesis, short metacarpals and other bone abnormalities, hearing loss, synkinesia, eye movement abnormalities, poor balance due to cerebellar ataxia, etc. Therefore, genetic screening should be offered in patients with IGD, as it can provide valuable information for genetic counseling and further understanding of IGD.
TL;DR: QA meta-analysis of studies assessing the risk of MetS with LTPA provides quantitative data suggesting that any amount of LTPA is better than none and that LTPA substantially exceeding the current LTPA guidelines is associated with an additional reduction in MetS risk.
Abstract: Background Leisure-time physical activity (LTPA) has been suggested to reduce risk of metabolic syndrome (MetS). However, a quantitative comprehensive assessment of the dose-response association between LTPA and incident MetS has not been reported. We performed a meta-analysis of studies assessing the risk of MetS with LTPA. Method MEDLINE via PubMed and EMBase databases were searched for relevant articles published up to March 13, 2017. Random-effects models were used to estimate the summary relative risk (RR) of MetS with LTPA. Restricted cubic splines were used to model the dose-response association. Results We identified 16 articles (18 studies including 76,699 participants and 13,871 cases of MetS). We found a negative linear association between LTPA and incident MetS, with a reduction of 8% in MetS risk per 10 metabolic equivalent of task (MET) h/week increment. According to the restricted cubic splines model, risk of MetS was reduced 10% with LTPA performed according to the basic guideline-recommended level of 150min of moderate PA (MPA) per week (10METh/week) versus inactivity (RR=0.90, 95% CI 0.86-0.94). It was reduced 20% and 53% with LTPA at twice (20METh/week) and seven times (70METh/week) the basic recommended level (RR=0.80, 95% CI 0.74-0.88 and 0.47, 95% CI 0.34-0.64, respectively). Conclusion Our findings provide quantitative data suggesting that any amount of LTPA is better than none and that LTPA substantially exceeding the current LTPA guidelines is associated with an additional reduction in MetS risk.
TL;DR: US-FLI accurately identifies histological severity and is correlated with metabolic parameters in patients with various steatogenic liver diseases, and is an easy and versatile tool for the screening of steatosis and the metabolic health of these patients.
Abstract: Background and aims Fatty liver is a common feature of different types of liver diseases. The sensitivity and specificity of ultrasonography for diagnosing fatty liver are variable. A semi-quantitative ultrasound score, i.e., the ultrasonographic fatty liver indicator (US-FLI), is closely associated with metabolic/histological variables in patients with nonalcoholic fatty liver disease (NAFLD). The main aims of this study were to assess the diagnostic performance of US-FLI in detecting varying degrees of histological steatosis, and to examine the association of US-FLI with metabolic/histological parameters in 352 biopsied patients with various chronic liver diseases (173 with hepatitis C [HCV], 23 with hepatitis B [HBV], 123 with NAFLD and 33 with other etiologies). Results US-FLI accurately detected mild steatosis (minimum amount 10% on histology) with a cut-off value ≥ 2 (sensitivity 90.1%, specificity 90%), moderate steatosis (≥ 30%) with a cut-off value ≥ 3 (sensitivity 86.4%, specificity 92.5%) and severe steatosis (> 66%) with a cut-off value ≥ 5 (sensitivity 88.5%, specificity 87%). US-FLI was correlated with steatosis percentage in each liver disease group as well as with lobular inflammation, ballooning, portal fibrosis, grading and staging in patients with NAFLD or HCV. US-FLI was also correlated with waist circumference, body mass index and insulin resistance both in the whole sample and in each liver disease group. Conclusions US-FLI accurately identifies histological severity and is correlated with metabolic parameters in patients with various steatogenic liver diseases. US-FLI is an easy and versatile tool for the screening of steatosis and the metabolic health of these patients.
TL;DR: Cardiac uptakes of carbohydrate (glucose, lactate and pyruvate) were decreased, whereas those of total ketone bodies and β-hydroxybutyrate were increased in the diabetics as compared to the non-diabetics in humans.
Abstract: Background Diabetic heart is characterized by failure of insulin to increase glucose uptake and increasingly relies on free fatty acids (FFAs) as a source of fuel in animal models. However, it is not well known how cardiac energy metabolism is altered in diabetic hearts in humans. We examined cardiac fuel metabolism in the diabetics as compared to non-diabetics who underwent cardiac catheterization for heart diseases. Material and Methods The study subjects comprised 81 patients (male 55, female 26, average age 63.0 ± 10.0 years) who underwent the cardiac catheterization for heart diseases. Thirty-six patients were diagnosed as diabetics (diabetic group) and 45 as non-diabetics (non-diabetic group). Blood samplings were done in both the aortic root (Ao) and coronary sinus (CS) simultaneously and the plasma levels of FFAs, glucose, lactate, pyruvate, total ketone bodies and β-hydroxybutyrate were measured and compared between the two groups. Results The myocardial uptake of glucose, lactate and pyruvate were decreased, whereas those of total ketone bodies, β-hydroxybutyrate and acetoacetate were increased in the diabetics as compared to the non-diabetics. However, the myocardial uptakes of FFAs were not significantly increased in the diabetics as compared to the non-diabetics. Conclusions Cardiac uptakes of carbohydrate (glucose, lactate and pyruvate) were decreased, whereas those of total ketone bodies and β-hydroxybutyrate were increased in the diabetics as compared to the non-diabetics in humans. Ketone bodies therefore are utilized as an energy source partially replacing glucose in the human diabetic heart.
TL;DR: This systematic review aims to investigate the impact of vitamin K (plasma levels, dietary intake, and oral supplementation) on bone health with a particular interest in bone remodeling, mineral density and fragility fractures.
Abstract: Vitamin K is a liposoluble vitamin. The predominant dietary form, phylloquinone or vitamin K1, is found in plants and green vegetables; whereas menaquinone, or vitamin K2, is endogenously synthesized by intestinal bacteria and includes several subtypes that differ in side chain length. Aside from its established role in blood clotting, several studies now support a critical function of vitamin K in improving bone health. Vitamin K is in fact required for osteocalcin carboxylation that in turn regulates bone mineral accretion; it seems to promote the transition of osteoblasts to osteocytes and also limits the process of osteoclastogenesis. Several observational and interventional studies have examined the relationship between vitamin K and bone metabolism, but findings are conflicting and unclear. This systematic review aims to investigate the impact of vitamin K (plasma levels, dietary intake, and oral supplementation) on bone health with a particular interest in bone remodeling, mineral density and fragility fractures.
TL;DR: Intravenous bisphosphonates are the most widely used intervention, having significant favorable effects regarding areal bone mineral density and vertebral reshaping following fractures in growing children, but more research is needed to delineate the best therapeutic approach in this heterogeneous disease.
Abstract: Osteogenesis imperfecta (OI) is the most common inherited form of bone fragility and includes a heterogenous group of genetic disorders which most commonly result from defects associated with type 1 collagen. 85%-90% of cases are inherited in an autosomal dominant manner and are caused by mutations in the COL1A1 and COL1A2 genes, leading to quantitative or qualitative defects in type 1 collagen. In the last decade, defects in several other proteins involved in the normal processing of type 1 collagen have been described. Recent advances in genetics have called for reconsideration of the classification of OI, however, most recent classifications align with the classic clinical classification by Sillence. The hallmark of the disease is bone fragility but other tissues are also affected. Intravenous bisphosphonates (BPs) are the most widely used intervention, having significant favorable effects regarding areal bone mineral density (BMD) and vertebral reshaping following fractures in growing children. BPs have a modest effect in long bone fracture incidence, their effects in adults with OI concerns only BMD, while there are reports of subtrochanteric fractures resembling atypical femoral fractures. Other therapies showing promising results include denosumab, teriparatide, sclerostin inhibition, combination therapy with antiresorptive and anabolic drugs and TGF-β inhibition. Gene targeting approaches are under evaluation. More research is needed to delineate the best therapeutic approach in this heterogeneous disease.
TL;DR: The mechanistic basis of these adaptive changes, as a background for the development of pregnancy related disorders, with a discourse on the pathophysiology relating hypovitaminosis D and clinical outcomes is focused on.
Abstract: This critical time frame of intrauterine life development is considered of major importance on the metabolic imprinting of overall health of the offspring, in later life. This requires a delicate immune balance that nurtures the allogeneic fetus, while maintaining reactivity against pathogens. Dysregulation of these tightly controlled biophenomena at a systemic and placental level, have been considered as a potential mechanism mediating pathogenesis of preeclampsia and spontaneous birth. In this context, vitamin D has been considered as a significant regulator of both innate and adaptive immunity by regulating cell proliferation, differentiation and apoptosis. Vitamin D metabolism during pregnancy manifests striking differences as compared to the non-pregnant state. Calcitriol is increasing >2-3 fold in the first weeks of pregnancy whereas maternal 25-hydroxyvitamin D crosses the placental barrier and represents the main pool of vitamin D in the fetus. Moreover, during pregnancy, vitamin D receptor and regulatory metabolic enzymes are expressed in the placenta and decidua, indicating a potential critical point in the immunomodulation at the maternal-fetal interface. Considering these effects, maternal hypovitaminosis D during pregnancy has been associated with pregnancy related disorders. This review focuses on the mechanistic basis of these adaptive changes, as a background for the development of pregnancy related disorders, with a discourse on the pathophysiology relating hypovitaminosis D and clinical outcomes.
TL;DR: This review highlights recent developments in consumer and clinical devices for sleep, emphasizing the need for validation at multiple levels, with the ultimate goal of using personalized data and advanced algorithms to provide actionable information that will improve sleep health.
Abstract: The field of sleep is in many ways ideally positioned to take full advantage of advancements in technology and analytics that is fueling the mobile health movement. Combining hardware and software advances with increasingly available big datasets that contain scored data obtained under gold standard sleep laboratory conditions completes the trifecta of this perfect storm. This review highlights recent developments in consumer and clinical devices for sleep, emphasizing the need for validation at multiple levels, with the ultimate goal of using personalized data and advanced algorithms to provide actionable information that will improve sleep health.
TL;DR: The clinical manifestations and appropriate diagnostic approach of the disease are discussed, with all possible therapeutic measures that can be taken, also including the potential beneficial effect of probiotics.
Abstract: Non-alcoholic fatty liver disease (NAFLD) is a significant global health burden in children, adolescents and adults with substantial rise in prevalence over the last decades. Accumulating data from manifold studies support the idea of NAFLD as a hepatic manifestation of metabolic syndrome, being rather a systemic metabolic disease than a liver confined pathology. Emerging data support that the gut microbiome represents a significant environmental factor contributing to NAFLD development and progression. Apart from other regimens, probiotics may have a positive role in the management of NAFLD through a plethora of possible mechanisms. The current review focuses on the NAFLD multifactorial pathogenesis, including mainly the role of intestinal microbiome and all relevant issues are raised. Furthermore, the clinical manifestations and appropriate diagnostic approach of the disease are discussed, with all possible therapeutic measures that can be taken, also including the potential beneficial effect of probiotics.
TL;DR: Vitamin D supplementation could be effective at improving glycemic control in vitamin D deficient or non-obese type 2 diabetes patients.
Abstract: Introduction Low vitamin D status has been found to be associated with impaired glycemic control in patients who suffer from type 2 diabetes; however, whether vitamin D supplementation is associated with improved glycemic status remains controversial The aim of this study was to summarize evidence from randomized controlled trials (RCTs) to assess the efficacy of vitamin D supplementation in reducing glycosylated haemoglobinA1c (HbA1c) and fasting blood glucose (FBG) levels Materials/Methods We searched PubMed, Web of Science and the Cochrane Library for reports published up to March 2017 We selected parallel RCTs investigating the effect of vitamin D or vitamin D analogues on HbA1c or FBG levels in type 2 diabetes patients Cohen's d was calculated to represent the standardized mean difference (SMD) for each study, and the SMDs with 95%confidence intervals (CIs) were pooled using a random effects model Results Twenty-four studies were included that evaluated HbA1c levels and 18 studies were included that evaluated FBG levels Meta-analyses showed that vitamin D supplementation was associated with reduced HbA1c levels (standardized mean difference (SMD) − 025 [− 045 to − 005]) but had no influence on FBG levels (SMD − 014 [− 031 to 003]) However, the subgroup analyses suggested that vitamin D supplementation was associated with reduced HbA1c levels (SMD − 039 [− 067 to − 010]) and FBG (SMD − 027 [− 046 to − 007]) among patients with 25-hydroxyvitamin D (25(OH) D) deficiency at baseline Significantly reduced HbA1c levels were also observed in association with vitamin D supplementation in the subgroup including type 2 diabetes patients with a body mass index (BMI) Conclusions Vitamin D supplementation could be effective at improving glycemic control in vitamin D deficient or non-obese type 2 diabetes patients
TL;DR: BCAA can alleviate hepatic steatosis and liver injury associated with NASH by suppressing FAS gene expression and protein levels.
Abstract: Background For successful treatment for nonalcoholic steatohepatitis (NASH), it may be important to treat the individual causative factors. At present, however, there is no established treatment for this disease. Branched-chain amino acids (BCAAs) have been used to treat patients with decompensated cirrhosis. Aim In order to elucidate the mechanisms responsible for the effects of BCAAs on hepatic steatosis and disease progression, we investigated the effects of BCAA supplementation in mice fed a choline-deficient high-fat diet (CDHF), which induces NASH. Methods Male mice were divided into four groups that received (1) choline-sufficient high fat (HF) diet (HF-control), (2) HF plus 2% BCAA in drinking water (HF-BCAA), (3) CDHF diet (CDHF-control), or (4) CDHF-BCAA for 8 weeks. We monitored liver injury, hepatic steatosis and cholesterol, gene expression related to lipid metabolism, and hepatic fat accumulation. Results Serum alanine aminotransferase (ALT) levels and hepatic triglyceride (TG) were significantly elevated in CDHF-control relative to HF-control. Liver histopathology revealed severe steatosis, inflammation, and pericellular fibrosis in CDHF-control, confirming the NASH findings. Serum ALT levels and hepatic TG and lipid droplet areas were significantly lower in CDHF-BCAA than in CDHF-control. Gene expression and protein level of fatty acid synthase (FAS), which catalyzes the final step in fatty acid biosynthesis, was significantly decreased in CDHF-BCAA than in CDHF-control (P Conclusions BCAA can alleviate hepatic steatosis and liver injury associated with NASH by suppressing FAS gene expression and protein levels.
TL;DR: Though controversial, an intimate connection betweenSCFAs and kidney injury has been revealed, suggesting that SCFAs may act as new therapeutic targets of kidney injury.
Abstract: It has been found that several circulating metabolites derived from gut microbiota fermentation associate with a systemic immuno-inflammatory response and kidney injury, which has been coined the gut-kidney axis. Recent evidence has suggested that short-chain fatty acids (SCFAs), which are primarily originated from fermentation of dietary fiber in the gut, play an important role in regulation of immunity, blood pressure, glucose and lipid metabolism, and seem to be the link between microbiota and host homeostasis. In addition to their important role as fuel for colonic epithelial cells, SCFAs also modulate different cell signal transduction processes via G-protein coupled receptors, and act as epigenetic regulators by the inhibition of histone deacetylase and as potential mediators involved in the autophagy pathway. Though controversial, an intimate connection between SCFAs and kidney injury has been revealed, suggesting that SCFAs may act as new therapeutic targets of kidney injury. This review is intended to provide an overview of the impact of SCFAs and the potential link to kidney injury induced by gut-derived inflammatory response.
TL;DR: It is concluded that obesity is associated with decreased central dopaminergic and serotonergic signaling and that future research, especially in long-term follow-up and interventional settings, is needed to advance the understanding of the neuronal pathophysiology of obesity in humans.
Abstract: Obesity results from an imbalance between energy intake and expenditure, and many studies have aimed to determine why obese individuals continue to (over)consume food under conditions of caloric excess. The two major "neurotransmitter hypotheses" of obesity state that increased food intake is partially driven by decreased dopamine-mediated reward and decreased serotonin-mediated homeostatic feedback in response to food intake. Using molecular neuroimaging studies to visualize and quantify aspects of the central dopamine and serotonin systems in vivo, recent PET and SPECT studies have also implicated alterations in these systems in human obesity. The interpretation of these data, however, is more complex than it may appear. Here, we discuss important characteristics and limitations of current radiotracer methods and use this framework to comprehensively review the available human data on central dopamine and serotonin in obesity. On the basis of the available evidence, we conclude that obesity is associated with decreased central dopaminergic and serotonergic signaling and that future research, especially in long-term follow-up and interventional settings, is needed to advance our understanding of the neuronal pathophysiology of obesity in humans.
TL;DR: Preliminary evidence supports an intimate relationship between bone and fat in the marrow and the relationship of cellular as well as whole body metabolism on the ultimate fate of bone marrow stromal cells.
Abstract: The bone marrow niche is composed of cells from hematopoietic and mesenchymal origin. Both require energy to power differentiation and these processes are intimately connected to systemic metabolic homeostasis. Glycolysis is the preferred substrate for mesenchymal stromal cells in the niche, although fatty acid oxidation and glutaminolysis are important during stage specific differentiation. Autophagy and lipophagy, in part triggered by adenosine monophosphate-activated protein kinase (AMPK), may also play an important but temporal specific role in osteoblast differentiation. Enhanced marrow adiposity is caused by clinical factors that are genetically, environmentally, and hormonally mediated. These determinants mediate a switch from the osteogenic to the adipogenic lineage. Preliminary evidence supports an important role for fuel utilization in those cell fate decisions. Although both the origin and function of the marrow adipocyte remain to be determined, and in some genetic mouse models high marrow adiposity may co-exist with greater bone mass, in humans changes in marrow adiposity are closely linked to adverse changes in skeletal metabolism. This supports an intimate relationship between bone and fat in the marrow. Future studies will likely shed more light on the relationship of cellular as well as whole body metabolism on the ultimate fate of bone marrow stromal cells.