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Effect of Different Doses of Aerobic Exercise Training on Total Bilirubin Levels
Abstract
Low serum bilirubin levels have been associated with increased risk for cardiovascular disease, and recent data suggest that lower body fat and reductions in weight are associated with higher bilirubin levels. However, it is unknown if exercise training can increase bilirubin levels and whether a higher dose of exercise will further increase bilirubin levels compared with a lower dose.
The primary aim of our current report was to examine whether exercise dose affects bilirubin levels in obese postmenopausal women from the Dose-Response to Exercise in Women trial. In addition, we evaluated whether changes in fitness, insulin sensitivity, and waist circumference associated with exercise training were associated with change in bilirubin levels.
Participants (n = 419) were randomized to the control group or to 4, 8, and 12 kcal·kg⁻¹·wk⁻¹ (KKW) of exercise training at an intensity of 50% of aerobic capacity. Total bilirubin levels were evaluated at baseline and at follow-up.
Exercise training significantly increased serum bilirubin levels only in the 12-KKW group (0.044 mg·dL⁻¹, P = 0.026) compared with the control group (0.004 mg·dL⁻¹). Subgroup analyses showed that there was a significant increase in bilirubin levels in participants in the 12-KKW group (0.076 mg·dL⁻¹) who were classified as insulin resistant (homeostatic model assessment for insulin resistance score > 2.6) compared with insulin-resistant control participants (0.018 mg·dL⁻¹, P = 0.028).
Our findings suggest that high doses of exercise training are necessary to significantly increase bilirubin levels in previously sedentary postmenopausal women and especially those with impaired glucose metabolism.
... These ultimately cause higher bilirubin production by BVRA and less bilirubin clearance via UGT1A1 conjugation. Although research connecting bilirubin and exercise is in its infancy, a limited number of studies have demonstrated that bilirubin may be increased with both acute and regular (longterm) endurance exercise in animal models and humans (52)(53)(54)(55). This was observed in the Dose-Response to Exercise in Women Trial (DREW Trial), where participants were placed in three groups of varying exercise volumes (4, 8, or 12 kcal.kg.week) for 12 weeks, demonstrating bilirubin only increased in the 12 kcal.kg.week group, equivalent to an average of 169 min per week (54). ...
... Although research connecting bilirubin and exercise is in its infancy, a limited number of studies have demonstrated that bilirubin may be increased with both acute and regular (longterm) endurance exercise in animal models and humans (52)(53)(54)(55). This was observed in the Dose-Response to Exercise in Women Trial (DREW Trial), where participants were placed in three groups of varying exercise volumes (4, 8, or 12 kcal.kg.week) for 12 weeks, demonstrating bilirubin only increased in the 12 kcal.kg.week group, equivalent to an average of 169 min per week (54). This dose-response relationship is supported by a separate trial where 12 weeks of The heme oxygenase-bilirubin pathway. ...
... This released heme can be broken down to biliverdin by heme oxygenase-1 (HO-1) and further catabolized by BVRA to eventually form a stable, unconjugated bilirubin (43). This view is supported by several of the findings above, where only the highest dose of exercise, which had the greatest exposure to factors associated with exercise-induced hemolysis, observed increases in the plasma bilirubin (54). This logic could also be applied to trained athletes exposed to very high levels of factors that may induce hemolysis to promote the observed elevations in bilirubin levels (35,(58)(59)(60). ...
Exercise performance is dependent on many factors, such as muscular strength and endurance, cardiovascular capacity, liver health, and metabolic flexibility. Recent studies show that plasma levels of bilirubin, which has classically been viewed as a liver dysfunction biomarker, are elevated by exercise training and that elite athletes may have significantly higher levels. Other studies have shown higher plasma bilirubin levels in athletes and active individuals compared to general, sedentary populations. The reason for these adaptions is unclear, but it could be related to bilirubin's antioxidant properties in response to a large number of reactive oxygen species (ROS) that originates from mitochondria during exercise. However, the mechanisms of these are unknown. Current research has re-defined bilirubin as a metabolic hormone that interacts with nuclear receptors to drive gene transcription, which reduces body weight. Bilirubin has been shown to reduce adiposity and improve the cardiovascular system, which might be related to the adaption of bilirubin increasing during exercise. No studies have directly tested if elevating bilirubin levels can influence athletic performance. However, based on the mechanisms proposed in the present review, this seems plausible and an area to consider for future studies. Here, we discuss the importance of bilirubin and exercise and how the combination might improve metabolic health outcomes and possibly athletic performance.
... There are a limited number of articles published on this topic in humans [71,72]. In a controlled study that examined different levels of training intensity, researchers found that the high-intensity training group (defined as 12 kilocalories per kilogram per week (KKW) energy expenditure) presented a significant increase in total serum bilirubin in comparison to the sedentary control group. ...
... In both studies, bilirubin levels seem to be elevated in response to high-volume, exhaustive forms of exercise with high energy expenditure. There are a limited number of articles published on this topic in humans [71,72]. In a controlled study that examined different levels of training intensity, researchers found that the high-intensity training group (defined as 12 kilocalories per kilogram per week (KKW) energy expenditure) presented a significant increase in total serum bilirubin in comparison to the sedentary control group. ...
... In a controlled study that examined different levels of training intensity, researchers found that the high-intensity training group (defined as 12 kilocalories per kilogram per week (KKW) energy expenditure) presented a significant increase in total serum bilirubin in comparison to the sedentary control group. Those who trained at moderate intensity levels (defined as 4 and 8 KKW) experienced no significant differences in serum bilirubin levels [71]. Priest et al. observed an increase in bilirubin in male runners after a 13-mile run along with an increase in alkaline phosphatase. ...
Exercise is commonly prescribed as a lifestyle treatment for chronic metabolic diseases as it functions as an insulin sensitizer, cardio-protectant, and essential lifestyle tool for effective weight maintenance. Exercise boosts the production of reactive oxygen species (ROS) and subsequent transient oxidative damage, which also upregulates counterbalancing endogenous antioxidants to protect from ROS-induced damage and inflammation. Exercise elevates heme oxygenase-1 (HO-1) and biliverdin reductase A (BVRA) expression as built-in protective mechanisms, which produce the most potent antioxidant, bilirubin. Together, these mitigate inflammation and adiposity. Moderately raising plasma bilirubin protects in two ways: (1) via its antioxidant capacity to reduce ROS and inflammation, and (2) its newly defined function as a hormone that activates the nuclear receptor transcription factor PPARα. It is now understood that increasing plasma bilirubin can also drive metabolic adaptions, which improve deleterious outcomes of weight gain and obesity, such as inflammation, type II diabetes, and cardiovascular diseases. The main objective of this review is to describe the function of bilirubin as an antioxidant and metabolic hormone and how the HO-1–BVRA–bilirubin–PPARα axis influences inflammation, metabolic function and interacts with exercise to improve outcomes of weight management.
... The enzyme that produces bilirubin, BVRA [6,7], is also reduced in obese humans compared to lean matched controls [8]. Studies indicate that bilirubin levels might increase with exercise [9,10] and fasting [11][12][13][14], implying a possible role for metabolic regulation. ...
... Overall, there were no noticeable differences in the hepatic visualization between the HCR and LCR rats. Bilirubin has been shown to increase with exercise capacity in humans [9,10]. To determine possible differential in hepatic function between the HCR and LCR rats, we measured plasma bilirubin levels, which is a surrogate marker of liver function. ...
... To determine possible differential in hepatic function between the HCR and LCR rats, we measured plasma bilirubin levels, which is a surrogate marker of liver function. We found that plasma bilirubin levels Bilirubin has been shown to increase with exercise capacity in humans [9,10]. To determine possible differential in hepatic function between the HCR and LCR rats, we measured plasma bilirubin levels, which is a surrogate marker of liver function. ...
Exercise in humans and animals increases plasma bilirubin levels, but the mechanism by which this occurs is unknown. In the present study, we utilized rats genetically selected for high capacity running (HCR) and low capacity running (LCR) to determine pathways in the liver that aerobic exercise modifies to control plasma bilirubin. The HCR rats, compared to the LCR, exhibited significantly higher levels of plasma bilirubin and the hepatic enzyme that produces it, biliverdin reductase-A (BVRA). The HCR also had reduced expression of the glucuronyl hepatic enzyme UGT1A1, which lowers plasma bilirubin. Recently, bilirubin has been shown to activate the peroxisome proliferator-activated receptor-α (PPARα), a ligand-induced transcription factor, and the higher bilirubin HCR rats had significantly increased PPARα-target genes Fgf21, Abcd3, and Gys2. These are known to promote liver function and glycogen storage, which we found by Periodic acid-Schiff (PAS) staining that hepatic glycogen content was higher in the HCR versus the LCR. Our results demonstrate that exercise stimulates pathways that raise plasma bilirubin through alterations in hepatic enzymes involved in bilirubin synthesis and metabolism, improving liver function, and glycogen content. These mechanisms may explain the beneficial effects of exercise on plasma bilirubin levels and health in humans.
... Next, the pH parameter is also useful to determine the stress level. This is because, under stress, the body will secrete high amounts of cortisol and catecholamines from the adrenal gland which leads to the depletion of muscle glycogen and causes a high pH value [6]. This statement is also supported by the research conducted by Dobbs et al. (1981) as a result acquired showed that the urinary pH value increased after subjects had stressful conditions [7]. ...
... However, comparing MATLAB classification to our hypothesis, the hypothesis could not be true in this experiment due to several reasons, as the stress level among the male biomedical engineering students as subjects do not have a consistent rate of breaking down of the red blood cells as some would exercise and some not according to the questionnaires that may have affected the accuracy. According to the study "Effect of different doses of aerobic exercise training on total bilirubin levels" by Swift et al. (2012), exercise training was found to significantly increase serum bilirubin levels. ...
The experiment was conducted using Analysis of Variance (ANOVA) and MATLAB. Urine measurements were taken with a CLINITEK Novus device in the Clinical Engineering Simulating lab at Universiti Teknologi Malaysia (UTM). Various samples were selected to examine and analyse the relationship between urinalysis and stress levels, as detailed in the methodology.
The findings suggested that higher specific gravity (SG) levels and increased substance production in response to stress are indicative of elevated stress levels. Similarly, high pH or urobilinogen (UBG) levels suggest increased alkaline production, another potential sign of stress.
With the use of MATLAB, it was observed that a subject's ability to cope with their environment improved as their stress scores increased. The relationship between urinalysis and stress levels has been a long-standing area of research interest. However, there is still no widely accepted methodology for measuring this relationship.
The application of MATLAB in this study also had its limitations, particularly in terms of the number of subjects required. Despite these limitations, this study contributes to the ongoing research in this field and provides a basis for future studies.
... The lower TSB levels in smokers than in non-smokers in the current study may be related to the increased oxidative stress caused by both cigarette smoking and the unhealthy lifestyle habits associated with cigarette smoking, either synergistically or in an additive manner. Aerobic exercise 34 and good sleep quality 14 are healthy lifestyle habits that lead to higher TSB levels and significantly help reduce oxidative stress. Thus, they have been advocated as preventive measures against ASCVD 35 . ...
INTRODUCTION
Cigarette smoking is a significant risk factor for atherosclerotic cardiovascular diseases (ASCVDs). Mildly elevated total serum bilirubin (TSB) levels can exert anti-atherosclerotic effects and may regulate inflammation. We explore the relationship between TSB levels, smoking, and inflammation.
METHODS
This cross-sectional study evaluated health screening participants with no history of ASCVD between 1 April 2019 and 31 March 2020. TSB was compared between non-smokers and smokers using the Kruskal-Wallis test, and the influencing factors of TSB levels were identified using multivariable logistic regression with TSB levels above the 75th percentile set as the dependent variable. Mediation analysis was performed to determine whether TSB levels mediated the association between smoking and inflammation.
RESULTS
A total of 8337 participants (mean age: 46.6 ± 13.0 years; 58.9% men) were included. TSB levels were significantly lower in smokers (n=1353) than in non-smokers (n=6984) [median (IQR): 0.72 (0.56–0.92) vs 0.76 (0.60–0.97) mg/dL, p<0.0001]. Multivariable logistic regression analysis demonstrated that smoking was an independent determinant of lower TSB levels (adjusted odds ratio, AOR=0.81; 95% CI: 0.70–0.93, p=0.003). Leukocyte counts and C-reactive protein levels significantly decreased as TSB levels increased (p<0.0001). Moreover, the relationship between the duration of smoking cessation and TSB levels showed a positive correlation. Mediation analysis indicated that cigarette smoking had significant indirect effects on higher leukocyte counts and higher CRP levels (coefficient=0.014; 95% CI: 0.008–0.021; and coefficient=0.002; 95% CI: 0.001–0.003, respectively].
CONCLUSIONS
Lower TSB levels related to a smoking habit may be associated with higher inflammation, thereby increasing the ASCVD risk. TSB may regulate inflammation and exert antioxidant effects. Furthermore, smoking cessation may lead to higher TSB levels and lower inflammation.
... Furthermore, when compared to HIE, LIE has a significant increase in SBT and returns to nearly normal after 20 minutes. Similar results were also found in the study that demonstrated aerobic exercise training significantly increased serum bilirubin levels 34 . Since heme is a precursor to bilirubin formation, increased heme metabolism may raise downstream bilirubin levels 35 . ...
Exercise provides considerable health advantages through promoting proper body system functioning, healthy growth and development, and quality of life. The present study investigated the effect of single bout High- Intensity Exercise (HIE) compared to Low-Intensity Exercise (LIE) on liver function markers in athletes. This cross-sectional study was carried out in the Department of Physical Education, Banaras Hindu University, Varanasi (UP). A total of 20 healthy male athletes with age range from 22 to 26 years were randomly selected and underwent 5 minutes of HIE and LIE separated by one week. Blood samples for selected liver function markers were taken pre-exercise, immediately, 10 and 20 minutes post-HIE and LIE, respectively. A repeated measures ANOVA with greenhouse-geisser correction found a significant difference between high and low intensity exercises for SGOT (F=5.881; p<0.05) and SBT (F=7.154; p<0.05) values, while statistically insignificant in the case of SGPT (F=1.572; p>0.05). In high intensity exercise there was statistically significant difference for SGOT (F=7.564; p<0.05) value between different time points. Post hoc analysis with a bonferroni correction showed that SGOT value was significantly increased immediately after the HIE, reducing 10 minutes after the exercise and closely returned to baseline level after 20 minutes of exercise, whereas LIE showed no significant changes. Exercise intensity is important as it triggers liver pathology by asymptomatic modifying liver function markers. These findings can be used to develop and administer exercise training plans for athletes.
... Notably, uric acid plays a crucial role in vascular regulation by increasing oxidative stress and promoting nitric oxide clearance, thereby inducing vasodilation [104]. An increase in bilirubin levels may contribute to a reduction in cardiovascular risk [105]. In summary, the growing body of evidence supports the beneficial impact of physical activity on both urinary proteins and non-protein biomolecules. ...
This review covers the diagnostic potential of urinary biomarkers, shedding light on their linkage to cancer progression. Urinary biomarkers offer non-invasive avenues for detecting cancers, potentially bypassing the invasiveness of biopsies. The investigation focuses primarily on breast and prostate cancers due to their prevalence among women and men, respectively. The intricate interplay of urinary proteins is explored, revealing a landscape where proteins exhibit context-dependent behaviors. The review highlights the potential impact of physical activity on urinary proteins, suggesting its influence on tumorigenic behaviors. Exercise-conditioned urine may emerge as a potential diagnostic biomarker source. Furthermore, treatment effects, notably after lumpectomy and prostatectomy, induce shifts in the urinary proteome, indicating therapeutic impacts rather than activating oncogenic signaling. The review suggests further investigations into the double-sided, context-dependent nature of urinary proteins, the potential role of post-translational modifications (PTM), and the integration of non-protein markers like mRNA and metabolites. It also discusses a linkage of urinary proteomes with secretomes from induced tumor-suppressing cells (iTSCs). Despite challenges like cancer heterogeneity and sample variability due to age, diet, and comorbidities, harnessing urinary proteins and proteoforms may hold promise for advancing our understanding of cancer progressions, as well as the diagnostic and therapeutic role of urinary proteins.
... Bilirubin, the end product of heme degradation, exerts antioxidant effects due to the redox cycle in which it is oxidized to biliverdin by ROS and then recycled by biliverdinreductase. Strenuous exercise has been found to induce an increase in bilirubin [42], but, in our study, we found no differences in the tested rowers at the beginning or at the end of the study after exercise. The bilirubin levels were lower in the group of rowers during the study, and all values were within the reference range. ...
A randomized, double-blind, placebo-controlled study was conducted to investigate the influence of supplementation with a superoxide dismutase (SOD)-rich plant extract on markers of oxidative stress, zonulin levels and the performance of elite athletes. Participants were 30 international-level rowers, divided into an experimental group (n = 15) and a control group (n = 15). The rowers performed a maximal effort incremental test on a rowing ergometer at the beginning and at the end of the study. Markers of oxidative stress (total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI), superoxide dismutase (SOD), glutathione peroxidase (GPx), advanced oxidation protein products (AOPPs), malondialdehyde (MDA), sulfhydryl (SH) groups, bilirubin, uric acid, albumin and zonulin) were determined in serum. A lower TOS (p = 0.010) and OSI (p = 0.004), a lower MDA (p = 0.001) and a higher level of SH groups (p = 0.031) were observed in the experimental group after supplementation. Physical performance was evaluated through metabolic efficiency, taking lactate levels and power output on the ergometer into account. After 6 weeks of supplementation, the relative increase in metabolic efficiency at a 4 mmol/L lactate concentration and maximal effort was significantly higher in the experimental group (p = 0.004 and p = 0.015, respectively). These results suggest that supplementation with a SOD-rich extract promotes lower oxidative stress, better antioxidant protection and, consequently, the better work performance of athletes.
... Obese children and adolescents have higher levels of fat than the normal population, especially in the abdomen. As a result, obese children and adolescents have high serum levels of homocysteine compared to normal weight populations [51], leading to reduced vascular endothelial function, which in turn predisposes to many cardiovascular and cerebrovascular diseases [52]. PA can reduce fat in obese children and adolescents in several ways. ...
Purpose
This study [PROSPERO CRD42023416272] systematically analysed the effects of a physical activity intervention on cardiorespiratory fitness in obese children and adolescents and elucidated the factors that influenced those effects.
Methods
A systematic review of the literature on physical activity interventions for improving cardiopulmonary fitness in obese children and adolescents from January 1, 2011, to March 1, 2023, was conducted. The search was performed on the Web of Science and PubMed databases, and the selected literature was first screened and then assessed for quality. Finally, a systematic review was conducted.
Results
Out of the initially identified 1424 search records, 28 studies were eventually included in the systematic review. These studies encompassed a total of 2724 participants aged 5 to 18 years, with the publication dates of the literature primarily ranging from 2011 to 2023. Physical activity was found to effectively improve the following parameters in obese children and adolescents: weight [mean difference (MD), -2.03 (95% confidence interval, -2.59 to -1.47), p < 0.00001], maximal oxygen consumption [MD, -1.95 (95% CI, -1.06 to -2.84), p < 0.0001], heart rate [MD, -2.77 (95% CI, -4.88 to -0.67), p = 0.010], systolic blood pressure [MD, -8.11 (95% CI, -11.41 to -4.81), p < 0.00001], and diastolic blood pressure [MD, -4.18 (95% CI, -5.32 to -3.03), p < 0.00001]. High-intensity exercise was found to yield greater improvements than low- to moderate-intensity exercise in maximal oxygen consumption [MD, 1.43 (95% CI, 0.04 to 2.82), p = 0.04] and diastolic blood pressure [MD, -6.94 (95% CI, -10.61 to -3.26), p = 0.0002] in obese children and adolescents.
Conclusion
Physical activity can effectively improve the body weight, maximal oxygen consumption, heart rate, systolic blood pressure, and diastolic blood pressure of obese children and adolescents. The type of physical activity directly influences the participation interest of obese children and adolescents, with moderate- to high-intensity physical activity showing the most significant impact on intervention outcomes. High-frequency, long-term interventions yield better results than short-term interventions.
... In general, there are few studies regarding bilirubin, and only a limited number of them have demonstrated that bilirubin can be increased with both acute and regular (long-term) resistance exercise [52]. In one study, in which participants were placed in three groups with different exercise volumes for 12 weeks, it was observed that high doses of exercise training are necessary to significantly increase bilirubin levels in previously sedentary postmenopausal women [53]. Exercise that achieves or exceeds the recommended 150 min of moderate to vigorous physical activity per week appears necessary to observe beneficial physiological increases in plasma bilirubin [54]. ...
This study aimed to depict the oxidative status variation in judokas during aerobic-dominant mixed effort (AeDME) and anaerobic-dominant mixed effort (AnDME). It is to be expected that the sporting commitment of Judo is a stimulus of oxidative stress leading to the recruitment of antioxidant responses. Blood samples were collected from 17 athletes at rest, immediately after a training session (AeDME) and after a 5-min bout (AnDME). AeDME and AnDME caused significant increases in malondialdehyde (MDA) (p < 0.01 and p < 0.001 respectively) and glutathione (GSH) (p = 0.018 and p < 0.001 respectively). Blood thiol concentrations decreased following AeDME and AnDME (p < 0.001) whilst catalase decreased significantly after AnDME (p = 0.026) only. Uric acid increased significantly after AnDME than after AeDME (p = 0.047) while, conversely, total bilirubin was higher after AnDME than after AeDME (p = 0.02). We may ultimately summarize that AeDME and AnDME caused oxidative stress, higher in AnDME, and some antioxidant response slightly higher in AnDME compared to AeDME. In sports, monitoring of oxidative stress status is recommended as part of the training regimen.
... They also found that the prevalence of Gilbert's syndrome and hyperbilirubinemia in athletes was significant [33]. These observations suggest that moderately increasing plasma bilirubin predisposes a better physical performance, which is also supported by the finding that regular physical activity elevates serum bilirubin concentrations [34,35] (and was also reviewed in [36,37]). Rats that had a loss-of-function mutation in their Ugt1a1 gene exhibited hyperbilirubinemia and were protected against hypertension and end-stage organ damage [38][39][40][41][42]. New findings have shown that bilirubin is a hormone that directly binds to the fat-burning nuclear receptor PPARα [13,15,17]. ...
Bilirubin levels in obese humans and rodents have been shown to be lower than in their lean counterparts. Some studies have proposed that the glucuronyl UGT1A1 enzyme that clears bilirubin from the blood increases in the liver with obesity. UGT1A1 clearance of bilirubin allows more conjugated bilirubin to enter the intestine, where it is catabolized into urobilin, which can be then absorbed via the hepatic portal vein. We hypothesized that when bilirubin levels are decreased, the urobilin increases in the plasma of obese humans, as compared to lean humans. To test this, we measured plasma levels of bilirubin and urobilin, body mass index (BMI), adiposity, blood glucose and insulin, and HOMA IR in a small cohort of obese and lean men and women. We found that bilirubin levels negatively correlated with BMI and adiposity in obese men and women, as compared to their lean counterparts. Contrarily, urobilin levels were positively associated with adiposity and BMI. Only obese women were found to be insulin resistant based on significantly higher HOMA IR, as compared to lean women. The urobilin levels were positively associated with HOMA IR in both groups, but women had a stronger linear correlation. These studies indicate that plasma urobilin levels are associated with obesity and its comorbidities, such as insulin resistance.
... With respect to liver parameters, our results showed that total γGt and bilirubin levels were affected by exercise in all sessions. Our results are similar to those of Swift et al. [35] and Loprinzi & Abbott [36] who reported that physical activity was associated with bilirubin increase in insulin-resistant adults, but not in insulin-sensitive adults. However, our results differ from those of Tanaka et al. [37] who reported no relationship between physical activity and bilirubin. ...
Background and objectives: The purpose of this study was to evaluate the effect of Opuntia ficus-indica juice (OFIJ) on performance and biochemical and physiological responses to a 6 min walking test (6MWT) in diabetic patients. Materials and Methods: Twenty diabetic patients performed a 6MWT at 07:00 h. During each test session, they were asked to drink 70 mL/day of natural OFIJ or placebo (PLA) for 4 days. Results: the results showed that cardiovascular parameters increased significantly after the 6MWT under both conditions. While, cortisol, HbA1c, cholesterol total (CT), triglycerides (TG), as well as low-density lipoprotein (LDL) were not modified between without and with supplementation. Likewise, no significant variation in performance was observed for PLA and OFIJ (p > 0.05). The cardiovascular parameters (heart rate max (HRmax), diastolic blood pressure (DBP), and systolic blood pressure (SBP)), lipid profile (CT, TG, LDL, and high-density lipoprotein HDL), hormonal parameters (insulin and glucagon), HbA1c and lactate ([La]) did not present any significant modification either between PLA or OFIJ (p > 0.05). Muscle-damage markers (creatine kinase (CK) and lactate dehydrogenase (LDH)], cortisol, and liver parameters (i.e., oxidative stress marker, γGT, and total bilirubin) as well as glucose (GLC) were affected by supplementation (p < 0.05) before and after the 6MWT, but this change was significant only for OFIJ (p < 0.05). Conclusion: OFIJ had an antioxidant capacity, improved performance of the 6MWT, and reduced muscle-damage markers and glucose level in type 2 diabetic patients.
... Therefore, total bilirubin elevation was prevented somewhat in the control-DGR group, while at the end of endurance training significantly increased. These findings are in agreement with Swift and coauthors (2012) [61], Hinds and coauthors (2020) [62], and Witek and coauthors (2016) [63]. One of the possible mechanisms for the change in total bilirubin might be attributed to hepatic biliverdin reductase-A (BVRA) expression and suppression of UGT1A1 as noted by Hinds and coauthors (2020) [62], which will be measured in future studies. ...
Abstract The aims of the present study were to examine the effects of D-galactose (DG) supplementation on plasma aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), creatinine, albumin, urea, bilirubin, cholesterol, and triglyceride. We also investigated the effects of Rosehip (Rosa canina L) fruit extraction and endurance exercise training on DG-induced changes in the aforementioned variables in male rats. Eighty-six male rats were randomly assigned to 8 groups 1) Control Saline 2) Training Saline 3) Control D-galactose 4) Training D-galactose 5) Control Rosehip 6) Training Rosehip 7) Control combined group and 8) Training combined group. Animals received experiments on the base of groups’ names (eight weeks and five times per week). Seventy-two hours after the last training or control session plasma was collected. The results showed that endurance training significantly increased plasma albumin while reducing ALT and creatinine. Rosehip significantly reduced plasma AST, creatinine, urea, cholesterol, and triglyceride, and increased bilirubin. A combination of training and Rosehip causes an additive effect compared to each intervention alone on AST. The use of DG increased ALT, AST, ALP, creatinine, urea, bilirubin, cholesterol, and triglyceride, while decreasing albumin. The use of Rosehip in combination with DG was able to minimize DG-induced abnormal elevation on some variables. In conclusion, using a high dose of D-galactose solution or high galactose content foods could make a precondition background for the non-alcoholic fatty liver which could be attenuated by crud Rosehip extraction. Thus, it seems that the Rosehip can be considered a hepatoprotective herb.
... ++ Includes 1 individual with genotype (TA) 5 accompanied by substantial improvements in glucose and lipid metabolism [41]. These findings coincide with observations by Swift et al. [42], who documented significant increases in serum bilirubin concentration in previously sedentary postmenopausal women after being placed on an exercise regimen. ...
Objectives
Bilirubin is a potent endogenous antioxidant and immunomodulating substance, which is also implicated in both cell signalling and various metabolic pathways. Mild elevation of systemic bilirubin concentrations provides substantial protection against many diseases of civilization. Rare published reports have suggested that serum bilirubin might also be relevant to sports performance. The purpose of the current study was to evaluate serum bilirubin concentrations and the prevalence of Gilbert syndrome (GS) in elite athletes.
Methods
The study was carried out in 536 consecutive healthy elite athletes and in 2594 individuals of the Czech post-MONICA study representing the general Czech population. Serum bilirubin concentrations, the prevalence of benign hyperbilirubinemia > 17 µmol/L (1 mg/dL, a phenotypic sign of GS), and a variant of the UGT1A1 gene promoter responsible for GS manifestation in Caucasians (rs81753472) were evaluated in study subjects.
Results
Compared to the general Czech population, significantly higher serum bilirubin concentrations were found in elite athletes (9.6 vs. 11.6 µmol/L, p < 0.001), both in men (11.3 vs. 12.6 µmol/L, p < 0.001) and women (8.3 vs. 10.5 µmol/L, p < 0.001). Furthermore, the prevalence of GS was also significantly higher in elite athletes (9.6 vs. 22%, p < 0.001) together with the tendency to higher frequencies of the genotypes (TA) 7/7 and (TA) 6/7 UGT1A1 .
Conclusion
Elite athletes have significantly higher concentrations of serum bilirubin, the most potent endogenous antioxidant substance known. Simultaneously, the prevalence of GS syndrome is also much higher in elite athletes, suggesting that a mild elevation of serum bilirubin might predispose to better sports performance.
... The intensity of the exercise is important in increasing the serum bilirubin levels. An intervention study on previously sedentary postmenopausal women showed that only a high dose of exercise training of at least 12 kilocalories per kilogram per week of exercise training at an intensity of 50% of aerobic capacity resulted in a modest elevation of serum bilirubin levels, whereas lower training loads had no effect [117]. Accordingly, asymptomatic overweight and obese middle-aged individuals who had better measured aerobic body capabilities had higher serum bilirubin levels [6]. ...
Obesity is a chronic condition involving low-grade inflammation and increased oxidative stress; thus, obese and overweight people have lower values of serum bilirubin. Essentially, bilirubin is a potent endogenous antioxidant molecule with anti-inflammatory, immunomodulatory, antithrombotic, and endocrine properties. This review paper presents the interplay between obesity-related pathological processes and bilirubin, with a focus on adipose tissue and adipokines. We discuss potential strategies to mildly increase serum bilirubin levels in obese patients as an adjunctive therapeutic approach.
... Hence, our assumption that RIPC would attenuate exercise-induced increase in bilirubin levels was confirmed. Importantly, low resting bilirubin levels have been associated with increased cardiovascular risk, and exercise training increases resting bilirubin levels (Swift et al., 2012;Kang et al., 2013). However, it is important to make the distinction between training and acute exercise. ...
Clinical studies continue to provide evidence of organ protection by remote ischemic preconditioning (RIPC). However, there is lack of insight into impact of RIPC on exercise-induce changes in human organs’ function. We here aimed to elucidate the effects of 10-day RIPC training on marathon-induced changes in the levels of serum markers of oxidative stress, and liver and heart damage. The study involved 18 male amateur runners taking part in a marathon. RIPC training was performed in the course of four cycles, by inflating and deflating a blood pressure cuff at 5-min intervals (RIPC group, n=10); the control group underwent sham training (n=8). The effects of RIPC on levels of oxidative stress, and liver and heart damage markers were investigated at rest after 10 consecutive days of training and after the marathon run. The 10-day RIPC training decreased the serum resting levels of C-reactive protein (CRP), alanine transaminase (ALT), γ-glutamyl transpeptidase (GGT), and malondialdehyde (MDA). After the marathon run, creatinine kinase MB (CK-MB), lactate dehydrogenase (LDH), cardiac troponin level (cTn), aspartate aminotransferase (AST), alkaline phosphatase (ALP), ALT, total bilirubin (BIL-T), and MDA levels were increased and arterial ketone body ratio (AKBR) levels were decreased in all participants. The changes were significantly diminished in the RIPC group compared with the control group. The GGT activity remained constant in the RIPC group but significantly increased in the control group after the marathon run. In conclusion, the study provides evidence for a protective effect of RIPC against liver and heart damage induced by strenuous exercise, such as the marathon.
... High amounts of exercise training in previously sedentary patient populations significantly increased bilirubin levels (182). Exercise-induced changes in bilirubin seem to function as a mechanism by which plasma antioxidant capacity may be increased to combat reactive oxygen and reactive nitrogen species generated during the course of strenuous aerobic exercise (183). ...
Recent research on bilirubin, a historically well-known waste product of heme catabolism, suggests an entirely new function as a metabolic hormone that drives gene transcription by nuclear receptors. Studies are now revealing that low plasma bilirubin levels, defined as 'hypobilirubinemia,' are a possible new pathology analogous to the other end of the spectrum of extreme hyperbilirubinemia seen in patients with jaundice and liver dysfunction. Hypobilirubinemia is most commonly presented in patients with metabolic dysfunction, which may lead to cardiovascular complications and possibly stroke. We address the clinical significance of low bilirubin levels. A better understanding of bilirubin's hormonal function may explain why hypobilirubinemia might be deleterious. We present mechanisms by which bilirubin may be protective at mildly elevated levels and research directions that could generate treatment possibilities for hypobilirubinemic patients, such as targeting of pathways that regulate its production or turnover or the newly designed bilirubin nanoparticles. Our review here calls for a shift in the perspective of an old molecule that could benefit millions of patients with hypobilirubinemia.
... The serum-TBIL concentration also depends upon the dose of exercise, as its concentration increases with increasing the duration and intensity of physical-efforts. Swift et al. (2012) studied the influence of different-volumes of training/exercise on TBIL level and found that a greater physical workout increases the TBIL level. Other studies reported that the bilirubin has the potential to work as an antioxidant and anti-inflammatory agent (Schwertner & Vítek, 2008). ...
Abstract Nutri-bars were prepared (110 g) using dates (64 g), dried apricots (16 g), cheddar cheese (8 g), whey protein isolate (12 g) and roasted-chickpea flour (10 g). Bars were prepared for Pakistani-athletes based on their calories and protein requirement (35003925 kcals/day, 1.4-1.8 g/kg body weight). Efficacy trials were performed (1, 15 and 30 days) to evaluate the effect of nutri-bars on blood serum profile, stamina building and body-composition. Results showed that hepatic-indexes such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) were decreased (p > 0.05) during experimental-period. At day 30, ALT (6.8%), AST (1%) and ALP (0.4%) indicates the inhibitory effect of nutri-bar on the pathological serum-profile of athletes while significant increase (p > 0.05) was observed in total-protein (0.52%). Liver injury-indexes lactate dehydrogenase, Creatine kinase, total-cholesterol and total-glycerides showed a significant increase (p > 0.05) while low-density-lipoprotein and high-density-lipoprotein were decreased (p > 0.05). Effect of nutri-bar on body composition showed increase (p > 0.05) in body weight (kg) and body-mass index (BMI (kg/m2). In the twelve-minutes running test, distance covered by athletes (p < 0.05) increased after 30 days as compared to day 1. The study revealed the significant (p < 0.05) effect of nutri-bar in developing the stamina building of Pakistani-athletes while the effect on the blood-serum profile was non-significant.
... Although no systematic studies have been conducted to answer this question, bilirubin concentrations do increase after exercise (73), in line with increased skeletal muscle expression of HO-1 (74), suggesting that increased bilirubin production might represent a stress-induced response, perhaps to counteract excessive free radical production/inflammation. Exercise is commonly, but not always, associated with increased bilirubin concentrations and appears dependent on the mode, duration, and intensity of exercise. Evidence linking the impact of long-term exercise training on bilirubin concentrations has recently been published in sedentary postmenopausal women, demonstrating that a 12 kcal (but not 4 or 8)·kg Ϫ1 ·wk Ϫ1 aerobic exercise (cycling/treadmill) training program for 6 mo (50% of aerobic capacity) increases bilirubin concentrations (95). In young healthy men and women, intensity of acute exercise training also impacts total bilirubin with completion of a 2,000-m swim not associated with altered bilirubin concentrations up to 24 h after completion. ...
Bilirubin, a potentially toxic catabolite of heme and indicator of hepato-biliary insufficiency, exhibits potent cardiac and vascular protective properties. Individuals with Gilbert's syndrome (GS) may experience hyperbilirubinemia in response to stressors including reduced hepatic bilirubin excretion/increased red blood cell breakdown, with individuals usually informed by their clinician that their condition is of little consequence. However, GS appears to protect from all-cause mortality, with progressively elevated total bilirubin associated with protection from ischemic heart and chronic obstructive pulmonary diseases. Bilirubin may protect against these diseases and associated mortality by reducing circulating cholesterol, oxidative lipid/protein modifications and blood pressure. In addition, bilirubin inhibits platelet activation and protects the heart from ischemia-reperfusion (I-R) injury. These effects attenuate multiple stages of the atherosclerotic process, in addition to protecting the heart during resultant ischemic stress, likely underpinning the profound reduction in cardiovascular mortality in hyperbilirubinemic GS. This review outlines our current knowledge of and uses for bilirubin in clinical medicine, and summarises recent progress in revealing the physiological importance of this poorly understood molecule. We believe that this review will be of significant interest to clinicians, medical researchers and individuals who have GS.
... Higher ALP activity observed after exercise could be due to increased bone mass in physically active subjects. There was an observed slight increase in bilirubin levels after exercise this is in concord with a study done by Damon et al.,2013 on the effect of different doses of aerobic exercise training on total bilirubin levels. The finding of this investigation is that exercise training GSJ© 2017 www.globalscientificjournal.com resulted in a modest but significant elevation in serum bilirubin levels. ...
This study investigated the effect short-term aerobic exercise on liver function of students of the College of Health Sciences, Okofia, Nnewi, Nigeria. A total of 41students aged 18-28years comprising of 22 males and 19 females who volunteered to participate in the study for one week were recruited. Their blood pressure readings and body mass index (BMI) were obtained, 5mls each of baseline (day zero) and post exercise(day 8) samples were collected into lithium heparin containers for estimation of biochemical parameters (ALP, AST, ALT, Bilirubin, Albumin and Total protein) respectively using standard methods. The results showed that the mean plasma activities of ALP, AST and plasma levels of Total bilirubin and Albumin in subjects were significantly higher after exercise when compared to their activities before exercise (P=0.046; 0.017; 0.047; 0.012) respectively. There was no significant difference in the mean plasma level of total protein and ALT activity in subject before and after exercise. SBP was strongly association with exercise in this study (p=0.087). it is important to impose exercise restrictions for at least one week before clinical trials or tests especially liver function tests. Exercise should be considered as a cause of asymptomatic elevations of liver function tests in daily clinical practice to reduce the risk of erroneous attribution of changes in liver function to pathological conditions or drug effects.
... Higher ALP activity observed after exercise could be due to increased bone mass in physically active subjects. There was an observed slight increase in bilirubin levels after exercise this is in concord with a study done by Damon et al.,2013 on the effect of different doses of aerobic exercise training on total bilirubin levels. The finding of this investigation is that exercise training GSJ© 2017 www.globalscientificjournal.com resulted in a modest but significant elevation in serum bilirubin levels. ...
Abstract
This study investigated the effect short-term aerobic exercise on liver function of students of the College of Health Sciences, Okofia, Nnewi, Nigeria. A total of 41students aged 18-28years comprising of 22 males and 19 females who volunteered to participate in the study for one week were recruited. Their blood pressure readings and body mass index (BMI) were obtained, 5mls each of baseline (day zero) and post exercise(day 8) samples were collected into lithium heparin containers for estimation of biochemical parameters (ALP, AST, ALT, Bilirubin, Albumin and Total protein) respectively using standard methods. The results showed that the mean plasma activities of ALP, AST and plasma levels of Total bilirubin and Albumin in subjects were significantly higher after exercise when compared to their activities before exercise (P=0.046; 0.017; 0.047; 0.012) respectively. There was no significant difference in the mean plasma level of total protein and ALT activity in subject before and after exercise. SBP was strongly association with exercise in this study (p=0.087). it is important to impose exercise restrictions for at least one week before clinical trials or tests especially liver function tests. Exercise should be considered as a cause of asymptomatic elevations of liver function tests in daily clinical practice to reduce the risk of erroneous attribution of changes in liver function to pathological conditions or drug effects.
Key Words: Aerobic Exercise, Alkaline phosphatase, Aspartate aminotransferase, Alanine aminotransferase, Direct Bilirubin, Total Bilirubin, Total Protein, Albumin.
... It is known, however, that aerobic exercise training leads to an increase in total serum bilirubin in humans (e.g. Swift et al., 2012); perhaps, the increased motion activity of the BPC-protected rats compared with those exposed without such protection had some relation to this seeming contradiction. The most surprising thing that we have never seen before is a noticeable decrease in the body mass gain in the groups administered the BPC either with or without Me-NPs. ...
Stable suspensions of metal oxide nanoparticles (Me-NPs) obtained by laser ablation of 99.99% pure copper, zinc or lead under a layer of deionized water were used separately, in three binary combinations and a triple combination in two independent experiments on rats. In one of the experiments the rats were instilled with Me-NPs intratracheally (i.t.) (for performing a broncho-alveolar lavage in 24h to estimate the cytological and biochemical indices of the response of the lower airways), while in the other, Me-NPs were repeatedly injected intraperitoneally (i.p.) 18 times during 6 weeks (for estimating the accumulation of corresponding metals in the blood and their excretion with urine and feces and for assessing subchronic intoxication by a large number of functional and morphological indices). Mathematical description of the results from both experiments with the help of the Response Surface Methodology has shown that, as well as in the case of any other binary toxic combinations previously investigated by us, the response of the organism to a simultaneous exposure to any two of the Me-NPs under study is characterized by complex interactions between all possible types of combined toxicity (additivity, subadditivity or superadditivity of unidirectional action and different variants of opposite effects) depending on which effect it is estimated for as well as on the levels of the effect and dose. With any third Me-NP species acting in the background, the type of combined toxicity displayed by the other two may change significantly (as in the earlier described case of a triple combination of soluble metal salts). It is shown that various harmful effects produced by CuO-NP+ZnO-NP+PbO-NP combination may be substantially attenuated by giving rats per os a complex of innocuous bioactive substances theoretically expected to provide a protective integral and/or metal-specific effect during one month before i.t. instillation or during the entire period of i.p. injections.
... Exercise induced oxidative stress may contribute to exercise-induced hemolysis in sedentary humans [19] . Swift et al. found that only the highest dose of exercise training significantly increases bilirubin concentration in overweight and obese postmenopausal women [20] . Elevated serum bilirubin levels are associated with decreased risk for cardiovascular diseases [21] , reduced risk of stroke [22] and peripheral arterial disease [23] . ...
... Since bilirubin can be produced through its pre-cursor heme [28], another plausible mechanism of bilirubin elevation is the stimulation of heme catabolism through an exercise-induced hemolysis and subsequent increased heme bio-availability, promoting the increased bilirubin concentrations. There is a major lack of studies concerning the effects of aerobic exercise on the bilirubin levels; however, we can find the support in a study by Swift and coworkers [29], who concluded the possible beneficial effect on the decrease of cardiovascular risk through an increase in bilirubin concentrations. ...
Herein, we present a study focused on the determination of the influence of long-distance (53 km) bicycle riding on levels of chosen biochemical urinary and serum prostate cancer (PCa) biomarkers total prostate-specific antigen (tPSA), free PSA (fPSA) and sarcosine. Fourteen healthy participants with no evidence of prostate diseases, in the age range from 49-57 years with a median of 52 years, underwent physical exercise (mean race time of 150 ± 20 min, elevation increase of 472 m) and pre- and post-ride blood/urine sampling. It was found that bicycle riding resulted in elevated serum uric acid (p = 0.001, median 271.76 vs. 308.44 µmol/L pre- and post-ride, respectively), lactate (p = 0.01, median 2.98 vs. 4.8 mmol/L) and C-reactive protein (p = 0.01, 0.0-0.01 mg/L). It is noteworthy that our work supports the studies demonstrating an increased PSA after mechanical manipulation of the prostate. The subjects exhibited either significantly higher post-ride tPSA (p = 0.002, median 0.69 vs. 1.1 ng/mL pre- and post-ride, respectively) and fPSA (p = 0.028, median 0.25 vs. 0.35 ng/mL). Contrary to that, sarcosine levels were not significantly affected by physical exercise (p = 0.20, median 1.64 vs. 1.92 µmol/mL for serum sarcosine, and p = 0.15, median 0.02 µmol/mmol of creatinine vs. 0.01 µmol/mmol of creatinine for urinary sarcosine). Taken together, our pilot study provides the first evidence that the potential biomarker of PCa-sarcosine does not have a drawback by means of a bicycle riding-induced false positivity, as was shown in the case of PSA.
Regular aerobic exercise has a significant impact on glucose metabolism and lipid profiles, contributing to overall health improvement. However, evidence for optimal exercise duration to achieve these effects is limited. This study aims to explore the effects of 4 and 8 weeks of moderate-intensity aerobic exercise on glucose metabolism, lipid profiles, and associated metabolic changes in young female students with insulin resistance and varying body mass, seeking to determine the optimal duration for physiological adaptations. Twenty-eight physically semi-active female students were randomly assigned to 4-week (G4, n = 13, age = 23.31 ± 5.19, BMI = 24.78 ± 5.87) and 8-week (G8, n = 15, age = 21.8 ± 2.56, BMI = 24.95 ± 4.81) training groups. The aerobic intervention maintained an intensity of 40–70% of maximum heart rate (HRmax). 6-min-walk test (6MWT), handgrip strength tests, insulin, HOMA-IR, lipid profiles, and metabolic profiles were assessed pre- and post-intervention. Following the intervention, G8, but not G4, exhibited a significant decrease in HOMA-IR (-14.59%, p = 0.047). The improvement in HOMA-IR was accompanied by notable improvements in 6-MWT (+ 38.18%, p < 0.001) and handgrip strength (+ 11.62, p = 0.027 and + 17.59%, p = 0.013), and increased levels of bilirubin degradation products, ribose, and glutarate. The elevated levels of bilirubin degradation products, known for their antioxidant properties, suggested a potential antioxidative response triggered by prolonged aerobic exercise. Additionally, an increase in ribose and glutarate indicated improved metabolic flexibility and enhanced utilization of alternative energy substrates. The 8-week aerobic exercise regimen demonstrated enhanced insulin sensitivity, upper body strength, and cardiovascular performance in young females compared to a 4-week regimen by triggering specific metabolic adaptations. These findings emphasize the complex relationship between exercise duration, metabolic adaptations, and overall well-being in young women, providing valuable insights for optimizing exercise prescriptions in promoting metabolic health.
Aim: The aim was to evaluate the biochemical and hormonal parameters of athletes using reference ranges. Methods: The study sample consisted of 25 male athletes with an average age of 28.50±4.25 (years) who played active professional football in the 2022-2023 season. Basal blood samples were collected 48 hours after the game at rest in the biochemical testing laboratory. The frequency distribution was calculated to determine the distribution of the athletes' biochemical parameters within and outside the normal range. The normal values for each parameter and the high or low deviations from these values were analysed. Results: According to the results of the study, ALT and AST levels were 28.38±9.86 U/L and 36.69±14.08 U/L, respectively, bilirubin level was 1.12±0.39 mg/dL, iron level was 114.58±34.63 µg/dL, ferritin level was 110.95±110.94 ng/mL, glucose level was 73.62±6.76 mg/dL and the average HDL cholesterol level was 62.47±12.32 mg/dL, the total cholesterol level 178.58±23.97 mg/dL, the LDL cholesterol level 109.49±19.10 mg/dL, the vitamin B12 level 575.15±251.55 pg/mL, the transferrin level 2.36±0.27 g/L and the thyroglobulin level 103.94±473.45 µg/L. Conclusion: It was found that ALT, AST, ferritin, bilurubin, iron, glucose, HDL cholesterol, vitamin B12, transferrin and thyroglobulin levels were within the reference range and normal range in a large proportion of athletes, but LDL cholesterol levels were too high in 50% of athletes and total cholesterol levels were too high in 11.5% of athletes.
Background
After menopause, reductions in ovarian hormones increase the risk of cardiovascular disease. Aerobic exercise training has been shown to reduce cardiovascular risk in older adults, but its effectiveness in postmenopausal females is less definitive.
Objectives
The objectives of this study were to examine the: (1) effects of aerobic training, and (2) association between aerobic training intensity and cardiometabolic health outcomes in postmenopausal females.
Design
Systematic review and meta-analysis of randomized controlled trials.
Data Sources and Methods
Six electronic databases were searched from inception to July 21, 2023 for aerobic training interventions reporting cardiometabolic outcomes in postmenopausal females. Data were synthesized qualitatively and random-effects meta-analyses and subgroup analyses (light, moderate, and vigorous intensity) were performed. Grading of Recommendations, Assessment, Development and Evaluation was used to assess the certainty of evidence.
Results
Fifty-nine studies (n = 4,225; 45–78 years old) were identified, 53 (n = 3,821) were included in the quantitative analyses. Aerobic training interventions varied in frequency (3–21×/week), intensity, type, time (8–60 min/session), and duration (3–52 weeks). Aerobic training improved systolic blood pressure (mean difference (MD) = −4.41 mmHg, 95% confidence interval (95%CI) [−7.29, −1.52], p = 0.01), resting heart rate (MD = −3.08 bpm, 95%CI [−5.11, −1.05], p < 0.01), body mass index (BMI, MD = −0.65 kg/m², 95%CI [−0.99, −0.31], p < 0.01), waist circumference (MD = −2.03 cm, 95%CI [−2.65, −1.41], p < 0.01), body fat (MD = −2.57 kg, 95%CI [−3.65, −1.49], p < 0.01), low-density lipoprotein cholesterol (MD = −10.46 mg/dL, 95%CI [−16.31, −4.61], p < 0.01), high-density lipoprotein cholesterol (MD = 3.28 mg/dL, 95%CI [0.20, 6.36], p = 0.04) and cardiorespiratory fitness (standardized MD = 1.38, 95%CI [1.13, 1.64], p < 0.01). There was a very low certainty of evidence for all outcomes. In subgroup analyses, light- and vigorous intensities were beneficial for BMI with no effect for moderate-intensity exercise (p < 0.01). Light intensity showed a beneficial effect (p = 0.02) for glucose levels (p < 0.01) and triglycerides; there was no effect with moderate or vigorous intensities.
Conclusion
Aerobic training may improve cardiometabolic health outcomes in postmenopausal females. There may be differential effects of exercise intensity on BMI, blood triglycerides, and blood glucose; however, this warrants further investigation.
Registration
PROSPERO—CRD42022313350
Bile acids (BAs) and bilirubin, primarily known for their role in lipid metabolism and as heme catabolite, respectively, have been found to have diverse effects on various physiological processes, including oxidative stress and inflammation. Indeed, accumulating evidence showed that the interplay between BAs and bilirubin in these processes involves intricate regulatory mechanisms mediated by specific receptors and signaling pathways under certain conditions and in specific contexts. Oxidative stress plays a significant role in the development and progression of cardiovascular diseases (CVDs) due to its role in inflammation, endothelial dysfunction, hypertension, and other risk factors. In the cardiovascular (CV) system, recent studies have suggested that BAs and bilirubin have some opposite effects related to oxidative and inflammatory mechanisms, but this area of research is still under investigation. This review aims to introduce BAs and bilirubin from a biochemical and physiological point of view, emphasizing their potential protective or detrimental effects on CVDs. Moreover, clinical studies that have assessed the association between BAs/bilirubin and CVD were examined in depth to better interpret the possible link between them.
Background:
In this study, by analyzing the correlation between various components of health-related physical fitness (HPF) and liver function indicators, the indicators of physical fitness that were highly correlated with liver function and could be monitored at home were screened to prevent more serious liver disease in the future, and to provide experimental basis for prescribing personalized exercise.
Methods:
A total of 330 faculties (female = 198) of a university were recruited. The indicators of HPF and liver function were measured. Spearman correlation analysis, multivariate linear regression, and cross-lagged panel model was used to data statistics.
Results:
In males, body fat (BF) was positively correlated with alanine aminotransferase (ALT); vital capacity and the vital capacity index were positively correlated with albumin; and vertical jump was positively correlated with globulin and negatively correlated with the albumin-globulin ratio (P < 0.05). However, there was no significant correlation among all indicators controlled confounding factors. In females, BF was negatively correlated with direct bilirubin; VO2max was positively correlated with indirect bilirubin; and vertical jump was positively correlated with the albumin-globulin ratio and significantly negatively correlated with globulin (P < 0.05). Controlled confounding factors, body fat percentage was positively correlated with globulin (β = 0.174) and negatively correlated with direct bilirubin (β = -0.431), and VO2max was positively correlated with indirect bilirubin (β = 0.238, P < 0.05). Cross-lagged panel analysis showed that BF percentage can negatively predict direct bilirubin levels with great significance (β = -0.055, P < 0.05).
Conclusions:
HPF may play a crucial role in liver function screening, particularly for female faculty members. For males, BF, vertical jump, vital capacity and vital capacity index could be associated with liver function but are susceptible to complex factors such as age, smoking, diabetes, and hypertension. In females, BF percentage is an important predictor of abnormal liver function in addition to VO2max and vertical jump, which are not affected by complex factors.
The optimal functioning of the liver is essential for athletic performance. It is necessary to maintain the liver’s enzymes at an optimal level so that liver cells can be protected from inflammation or damage. This study investigated the effects of a 12-week aerobic exercise program on the liver function of adult athletes. A pretest–posttest experimental design was used. A total of thirty healthy male athletes (football players) aged 21 to 24 years were recruited for this study and randomly and equally divided into the experimental group (EG) and control group (CG). The CG did not participate in any special activities. The EG performed an aerobic training program consisting of several exercises for 12 weeks. Evaluation of all participants in both groups was carried out before and after the intervention by measuring the blood levels of Alkaline phosphate, AST/SGOT, ALT/SGPT, Bilirubin Total/indirect/direct, Albumin, Globulin, and Total protein using the standard methods by collecting blood samples. There was a significant decrease (p < 0.05) in Bilirubin and globulin levels in the EG after 12 weeks of aerobic training sessions. However, there was no significant difference in alkaline phosphate, AST/SGOT, ALT/SGPT Total protein, and Albumin (p > 0.05) between both groups post-treatment. The 12 weeks of aerobic training used in the study can potentially improve the liver function of adult athletes.
Habitual fish consumption and a healthy lifestyle are associated with lower atherosclerotic cardiovascular disease (ASCVD) risk. Mildly elevated bilirubin, an end-product of hemoglobin metabolism, may be associated with anti-inflammatory effects, suppressing ASCVD risk. No data exist on the relationship between fish consumption, total serum bilirubin (TSB), and inflammation in clinical settings. We conducted a cross-sectional study between April 2019 and March 2020 in a cohort of 8,292 participants (average age, 46.7 ± 12.9 years and 58.9% men) with no history of ASCVD and TSB concentrations < 2.0 mg/dL. Multiple stepwise regression analysis showed hemoglobin concentrations were a solid positive determinant of TSB concentrations (β = 0.302, p < 0.0001). Fish consumption (β = 0.025, p = 0.019) and aerobic exercise (β = 0.021, p = 0.043) were statistically weak but significant positive determinants of TSB concentrations. Cigarette smoking negatively affected TSB concentrations (β = -0.104, p < 0.0001). Moreover, with increasing fish consumption, the proportion of participants with a habit of cigarette smoking decreased, and that of participants who engaged in aerobic exercises increased (p < 0.0001 for both). Furthermore, as TSB concentrations increased, the leukocyte counts and C-reactive protein concentrations decreased (p < 0.0001 for both). In conclusion, despite the lesser relevance given to TSB concentrations than hemoglobin concentrations, higher fish consumption and healthier lifestyle behaviors related to fish consumption habits may be additively or synergistically associated with higher TSB concentrations and anti-inflammatory activity, leading to attenuated ASCVD risk. Further investigations are needed to clarify the causal relationships between these factors.
Bilirubin has several physiological functions, both beneficial and harmful. In addition to reactive oxygen species-scavenging activities, bilirubin has potent immunosuppressive effects associated with long-term pathophysiological sequelae. It has been recently recognized as a hormone with endocrine actions and interconnected effects on various cellular signaling pathways. Current studies show that bilirubin also decreases adiposity and prevents metabolic and cardiovascular diseases. All in all, the physiological importance of bilirubin is only now coming to light, and strategies for increasing plasma bilirubin levels to combat chronic diseases are starting to be considered. This review discusses the beneficial effects of increasing plasma bilirubin, incorporates emerging areas of bilirubin biology, and provides key concepts to advance the field.
It has been shown that small doses of oral D-glyceric acid (DGA) activate mitochondrial metabolism and reduce inflammation among 50–60-year-old healthy volunteers. The present results with the same small doses reveal that after a 4-day DGA regimen, a dose of DGA activated the HO-1 pathway acutely, while enhanced inflammatory status after the 4-day DGA regimen seemed to be able to downregulate the HO-1 pathway in non-acute measurement. Blood bilirubin was strongly upregulated towards the end of the altogether 21-day study period with positive associations towards improved inflammation and reduced blood triglycerides. After the 4-day DGA regimen, hepatic inflow of blood bilirubin with albumin as the carrier was clearly upregulated in the lower-aerobic-capacity persons. At the same time also, blood triglycerides were down, pointing possibly to the activation of liver fatty acid oxidation. The combination of activated aerobic energy metabolism with transient HO-1 pathway activation and the upregulation of blood bilirubin may reduce the risks of chronic diseases, especially in aging. Furthermore, there exist certain diseases with unsatisfactorily-met medical needs, such as fatty and cholestatic liver diseases, and Parkinson’s disease, that can be possibly ameliorated with the whole-body mechanism of the action of the DGA regimen.
Background:
Obesity is correlated with many biomarkers but the extent to which these correlate with underlying body composition is poorly understood.
Objective:
Our objectives were: 1) describe/compare distinct contributions of fat/lean mass to BMI-metabolite correlations and 2) identify novel metabolite biomarkers of fat/lean mass.
Design:
The Alberta Physical Activity and Breast Cancer Prevention Trial was a two-center randomized trial of healthy, inactive, postmenopausal women (n = 304). BMI (kg/m2) was calculated using weight and height, while dual X-ray absorptiometry estimated fat/lean mass. Ultra-performance liquid chromatography and mass spectrometry measured relative concentrations of serum metabolite levels. We estimated partial Pearson correlations between 1052 metabolites and BMI, adjusting for age, smoking, and site. Fat mass index (FMI: kg/m2) and lean mass index (LMI; kg/m2) correlations were estimated similarly, with mutual adjustment to evaluate independent effects.
Results:
Using a Bonferroni-corrected alpha-level < 4.75 × 10-5, we observed 53 BMI-correlated metabolites (|r|:0.24-0.42). Of those, 21 were robustly correlated with FMI (|r|>0.20), 25 modestly (0.10≤|r|≤0.20), and seven virtually null (|r|<0.10). Ten of 53 were more strongly correlated with LMI than with FMI. Examining non-BMI-correlated metabolites, six robustly correlated with FMI (|r|:0.24-0.31) and two with LMI (r:0.25-0.26). For these, correlations for fat and lean mass were in opposing directions as compared to BMI-correlated metabolites where correlations were mostly in the same direction.
Conclusions:
Our results demonstrate how a thorough evaluation of the components of fat and lean mass, along with BMI provides a more accurate assessment of the associations between body composition and metabolites than BMI alone. Such an assessment makes evident that some metabolites correlated with BMI predominantly reflect lean mass rather than fat, and some metabolites related to body composition are not correlated with BMI. Correctly characterizing these relationships is important for accurate understanding of how and why obesity is associated with disease.
Bilirubin has antioxidant and anti‐inflammatory properties in vitro and in animal studies and protects against inflammatory, cardiovascular, and other diseases in observational studies; therefore, bilirubin has potential as a therapeutic agent. However, observational studies could be confounded by many factors. We used a genetic (n=61,281) and clinical (n=234,670) approach to define the association between bilirubin and 19 conditions with a putative protective signal in observational studies. We also tested if individuals with genetically higher bilirubin levels underwent more diagnostic tests. We used a common variant in UGT1A1 (rs6742078) associated with an 26% increase in bilirubin levels in the genetic studies. Carriers of the variant had higher bilirubin levels (P= 2.2x10‐16) but there was no significant association with any of the 19 conditions. In a phenome‐wide association study (pheWAS) to seek undiscovered genetic associations, the only significant finding was increased risk of “jaundice ‐ not of newborn”. Carriers of the variant allele were more likely to undergo an abdominal ultrasound (OR=1.04 [1.00, 1.08], P=0.03). In contrast, clinically measured bilirubin levels were significantly associated with 15 of the 19 conditions (P< 0.003) and with 431 clinical diagnoses in the pheWAS (P<1x10‐5 adjusted for sex, age, and follow‐up). With additional adjustment for smoking and body mass index, 7 of 19 conditions and 260 pheWAS diagnoses remained significantly associated with bilirubin levels. In conclusion, bilirubin does not protect against inflammatory or other diseases using a genetic approach; the many putative beneficial associations reported clinically are likely due to confounding.
Significance:
As the central metabolic organ, the liver is exposed to a variety of potentially cytotoxic, pro-inflammatory, pro-fibrotic, and carcinogenic stimuli. To protect the organism from these deleterious effects, the liver has evolved a number of defense systems, which include antioxidant substrates and enzymes, anti-inflammatory tools, enzymatic biotransformation systems, and metabolic pathways. Recent advances: One of the pivotal systems that evolved during phylogenesis was the heme catabolic pathway. Comprising the important enzymes heme oxygenase and biliverdin reductase, this complex pathway has a number of key functions including enzymatic activities, but also cell signaling, and DNA transcription. It further generates two important bile pigments, biliverdin and bilirubin, as well as the gaseous molecule carbon monoxide. These heme degradation products have potent antioxidant, immunosuppressive, and cytoprotective effects. Recent data suggest that the pathway participates in the regulation of metabolic and hormonal processes implicated in the pathogenesis of hepatic and other diseases.
Critical issues:
This review discusses the impact of the heme catabolic pathway on major liver diseases, with particular focus on the involvement of cellular targeting and signaling in the pathogenesis of these conditions.
Future directions:
To utilize the biological consequences of the heme catabolic pathway, several unique therapeutic strategies have been developed. Research indicates that pharmaceutical, nutraceutical and lifestyle modifications positively affect the pathway, delivering potentially long-term clinical benefits. However, further well-designed studies are needed to confirm the clinical benefits of these approaches.
Bilirubin is among the most potent of the endogenous antioxidants. Data developed over the last three decades have convincingly demonstrated the protective effects of mildly elevated serum bilirubin concentrations; whereas lower levels of it have been associated with an increased risk of various diseases of civilization, commonly accompanied with increased oxidative stress. Even tiny, micromolar changes of serum bilirubin concentrations have been associated with substantial modulation for the risk of these diseases. However, clinical data published in the current literature are influenced by many confounding factors that have not been properly controlled for. These include the use of improper reference intervals, which are mostly used as common intervals without any partitioning for gender, ethnicity, age, or other important factors (such as smoking). The clinical chemistry methods used for bilirubin determination have not been standardized; in fact, these methods are known to be among the least reliable of any used in clinical chemistry labs. As a result, the data from epidemiological studies are not always comparable. Therefore, it is highly recommended to conduct properly-designed large epidemiological studies. Based on this data, the establishment of decision limits is highly warranted, especially for the lower concentration values of serum bilirubin.
Background:
Circulating total bilirubin is a biomarker of ischemic stroke and may serve as a potential prognostic factor. It is imperative to systemically evaluate the correlation between circulating total bilirubin and risk for stroke. This systematic review and meta-analysis investigated the relationship between total serum bilirubin and risk for stroke.
Methods:
Studies published before 30 June 2017 were searched in four databases (PubMed, EMBASE, Web of Science and Cochrane Central). Additional studies were searched by reviewing references and contacting authors. Cohort, cross-sectional and case-control studies in adults that examined the association between serum total bilirubin and stroke were included irrespective of language and date of publication. The primary outcome of this study was ischemic stroke, and the secondary outcome was stroke. Abstract and full-text were reviewed by two independent reviewers, and disagreement was resolved by consulting a third reviewer. Data were extracted by two independent reviewers using a pre-designed data collection form.
Results:
Eleven observational studies (5 prospective and 6 cross-sectional studies) involving 131,450 subjects were included for analysis. In four studies with 83,380 subjects, the relationship between circulating total bilirubin and ischemic stroke was investigated, ischemic stroke was found in 2,496 patients, and the total odds ratio (OR) of the highest bilirubin and the lowest bilirubin for the occurrence of ischemic stroke was 0.66 (95% CI: 0.58-0.74). Eleven studies with 131,450 subjects explored the correlation between bilirubin and stroke, stroke was reported in 5,060 patients, and the total OR of the highest bilirubin and the lowest bilirubin for the occurrence of stroke was 0.73 (95% CI: 0.68-0.79). A stratified analysis based on the gender showed that the total bilirubin level in males correlated with ischemic stroke or stroke, which was not noted in females.
Conclusions:
The available studies support an inverse association between circulating total bilirubin and risk for ischemic stroke and stroke in males. Prospective studies with large sample size are needed to establish the role of circulating bilirubin in the prevention of stroke.
Observational epidemiological studies showed that mild hyperbilirubinemia has beneficial effects on prevention from cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS). In mammals, bilirubin plays a major role as a potent antioxidant. UGT1A1 variants coding for bilirubin UDP‐glucuronosyl transferase resulting in mild hyperbilirubinemia (as in Gilbert syndrome (GS)) may confer a strong genetic advantage. Strategies to boost bioavailability of bilirubin or to mimic GS represent an attractive approach to prevent many oxidative stress and inflammation‐mediated diseases. Even a tiny, micro molar increase in serum bilirubin concentrations substantially decreases the risk of oxidative stress‐mediated diseases. There are several possible ways to achieve this including lifestyle changes, changes in dietary patterns, regular physical activities, or use of chemical drug or of specific plant products either in the form of regular food items or nutraceuticals. Further basic and experimental research is required to fully uncover this promising therapeutic field. This article is protected by copyright. All rights reserved.
A randomized, double-blind, placebo-controlled study was conducted, in order to evaluate if Lactobacillus helveticus Lafti® L10 (Lallemand Health Solutions, Montreal, Canada) supplementation during three months could influence oxidative markers in the population of elite athletes: triathletes, cyclists and endurance athletes. Twenty-two elite athletes were randomized to either placebo (n = 12) or probiotic (n = 10) groups. The probiotic group received 2x1010 colony forming units of Lafti® L10. Before and after the supplementation serum samples were collected. Markers of oxidative stress and anti-oxidative defense: superoxide dismutase (SOD), paraoxonase (PON), advanced oxidation protein products (AOPP), malondialdehyde (MDA), total antioxidant status, total oxidant status, pro-oxidant-antioxidant balance, oxidative stress index, bilirubin, uric acid and albumin were determined in serum. Parameters of lipid status, as well as susceptibility to copper-induced oxidation of LDL particles in vitro were also determined. There was a significant interaction effect for MDA (p = 0.039), with a decrease in MDA in the probiotic group only (p = 0.049). There was a significant interaction effect for AOPP (p = 0.037), with a significant decrease in the probiotic group (p = 0.045). Interaction effect for SOD was approaching to formal significance (p = 0.108) and the post-hoc test showed a significant decrease in the probiotic group (p = 0.041) only. A significant correlation between AOPP and SOD (p = 0.012, r = -0.40) was found in the probiotic group at the end of the study. PON1 activity was decreased in both the probiotic (p = 0.032) and placebo group (p = 0.035). No significant changes in the remainder of the evaluated parameters were noted. In conclusion, probiotic strain Lafti® L10 exerts certain antioxidant potential, but further research is needed.
Background
Circulating total bilirubin is known to be inversely and independently associated with future risk of cardiovascular disease. However, the relationship of circulating total bilirubin with incident hypertension is uncertain. We aimed to assess the association of total bilirubin with future hypertension risk and supplemented this with a Mendelian randomization approach to investigate any causal relevance to the association.
Methods and Results
Plasma total bilirubin levels were measured at baseline in the PREVEND (Prevention of Renal and Vascular End‐Stage Disease) prospective study of 3989 men and women without hypertension. Hazard ratios (95% confidence intervals) of total bilirubin with incident hypertension were assessed. New‐onset hypertension was recorded in 1206 participants during a median follow‐up of 10.7 years. Baseline total bilirubin was approximately log‐linearly associated with hypertension risk. Age‐ and sex‐adjusted hazard ratio for hypertension per 1‐SD increase in loge total bilirubin was 0.86 (0.81–0.92; P<0.001), which was attenuated to 0.94 (0.88–0.99; P=0.040) after further adjustment for established risk factors and other potential confounders. The association was marginally significant on further adjustment for high‐sensitivity C‐reactive protein (0.94; 0.88–1.00; P=0.067). A genetic variant at the UGT1A1*28 locus consistently shown to be strongly associated with circulating bilirubin levels—rs6742078—was not significantly associated with blood pressure or hypertension (P>0.05 for all), arguing against a strong causal association of circulating bilirubin with blood pressure.
Conclusions
The weak and inverse association of circulating total bilirubin with future hypertension risk may be driven by biases such as unmeasured confounding and/or reverse causation. Further evaluation is warranted.
The purpose of this study was to determine a typical reference range for the population of athletes. Results of blood tests of 339 athletes (82 women and 257 men, aged 18-37 years) were retrospectively analysed. The subjects were representatives of different sports disciplines. The measurements of total bilirubin (BIT), iron (Fe), alkaline phosphatase (ALP), alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) were made using a Pentra 400 biochemical analyser (Horiba, France). Red blood cell count (RBC), reticulocyte count and haemoglobin concentration measurements were made using an Advia 120 haematology analyser (Siemens, Germany). In groups of women and men the percentage of elevated results were similar at 18%. Most results of total bilirubin in both sexes were in the range 7-14 μmol·L⁻¹ (49% of women and 42% of men). The highest results of elevated levels of BIT were in the range 21-28 μmol·L⁻¹ (12% of women and 11% of men). There was a significant correlation between serum iron and BIT concentration in female and male athletes whose serum total bilirubin concentration does not exceed the upper limit of the reference range. Elevated concentrations of total bilirubin appear to be due to changes caused by regular exercise. The obtained upper limit of the reference range for total bilirubin concentration in the group of athletes is 29.0 μmol·L⁻¹. It seems reasonable to use dedicated reference values for total bilirubin concentration in relation to the group of athletes.
Objective: Emerging evidence suggests that bilirubin levels might be associated with metabolic syndrome (MetS) and type 2 diabetes (T2D), but the nature of the association remains unclear.
Design: Systematic review and meta-analyze studies investigating the relation between total plasma bilirubin and risk of MetS and T2D.
Data Sources: Relevant studies were identified using five databases (Embase.com, Medline (Ovid), Web-of-Science, PubMed, Cochrane Central and Google Scholar) last searched on October 21st 2015. Moreover, references of these studies were checked and authors were contacted to identify additional studies.
Study selection: We included randomized controlled trials, cohorts, case-control and cross-sectional studies in adult humans that examined the association between bilirubin levels in blood with MetS and T2D irrespective of language and date of publication. Abstracts and full text selection was done by two independent reviewers, with a third reviewer available for disagreements.
Data extraction: Data were extracted by two independent reviewers using a pre-designed data collection form.
Main outcomes and measures: MetS and T2D.
Methods: Summary estimates were obtained with random effects meta-analysis.
Results: Of the 2,313 searched references, we included 16 observational (11 cross-sectional, 2 prospective, 1 both cross-sectional and prospective, 2 retrospective and 1 national survey) studies that met our inclusion criteria. Overall, data were available on 175,911 non-overlapping participants, with a total of 7,414 MetS cases and approximately 9,406 T2D cases. In the meta-analysis of 7 cross-sectional studies, pooled odds ratio (95% Confidence Interval (CI)) for MetS in a comparison of extreme thirds of serum bilirubin levels was 0.70 (95% CI 0.62, 0.78), whereas, no significant association was found for pooled relative risk estimate between two prospective studies ( 0.57, 95% CI 0.11, 2.94). The corresponding estimate was 0.77 (95% CI 0.67, 0.87) for type 2 diabetes from four cross-sectional evidence.
Conclusions: Available evidence, mainly from cross-sectional studies, supports inverse association of bilirubin levels with adverse metabolic outcomes. Large-scale prospective studies are needed to establish whether bilirubin levels may be useful in the prevention of metabolic syndrome or type 2 diabetes.
Objective:
To determine response rates for clinically significant weight loss (CWL) following different aerobic exercise training amounts and whether enhanced cardiometabolic adaptations are observed with CWL compared to modest weight loss (MWL) or neither.
Methods:
Participants (N = 330) performed 6 months of aerobic training at 4 kcal per kilogram per week (KKW), 8 KKW, or 12 KKW (50%, 100%, and 150% of recommended levels respectively). Weight loss was categorized as CWL (≥5%) or MWL (3.0% to 4.9%) or neither.
Results:
The CWL response rate was greater in the 8 KKW group (20.2%, CI: 13.0% to 27.5%) compared to 4 KKW (10.3%, CI: 4.6% to 16.0%), but not compared to the 12 KKW group (14.6%, CI: 7.6% to 21.6%). Reductions in HOMA-IR were observed in participants with CWL (-0.60, CI: -0.98 to -0.22) and with MWL (-0.48, CI: -0.87 to -0.10), but not those who achieved neither (-0.06, CI -0.22 to 0.10). No changes between groups were observed for cholesterol, fitness, or blood pressure.
Conclusions:
Low response rates for CWL were observed following training, even at levels above recommended levels. Achieving MWL with exercise may represent a reasonable initial weight loss target since the improvement in insulin resistance with MWL is similar to what is achieved with CWL.
Background: People are forced to exercise in areas with inappropriate conditions such as polluted air. Harmful effects of air pollution are intensified during physical activity and training due to increased metabolic needs. This study compared the effects of intermittent exercise in polluted and clean air on hemolysis of red blood cells in endurance runners. Methods: Using purposive convenience sampling, 10 female endurance runners with at least three years of experience of regular exercise were selected. Their mean age, height, weight, and body mass index were 18.80 ± 2.74 years, 164 ± 2.84 cm, 51.58 ± 3.37 kg, and 19.67 ± 1.28, respectively. Immediately after an interval training protocol with 85% of maximum heart rate, blood samples from left brachial vein were collected in a sitting position. The first samples were obtained on a polluted day (air quality index: 118). Second sampling was conducted 18 days later, after a rainy night (air quality index: 77). Both procedures were performed at a particular time of day. Hemolysis of red blood cells was determined by measuring bilirubin and serum haptoglobin levels through spectrophotometry and immunoturbidometric tests, respectively. Paired t-tests were used to compare the two measurements. Findings: Bilirubin levels increased significantly (22%) after exercise in polluted air compared to clean air (P = 0.001). Although haptoglobin levels decreased (23.86%) after exercise in high concentrations of pollutants, this reduction was not statistically significant compared to the levels obtained in clean air (P = 0.09). Conclusion: It seems that an interval training session in high concentrations of air pollutants will be associated with more hemolysis of red blood cells.
Introduction:
Serum bilirubin is an endogenous antioxidant biomarker and its low level is a potential risk factor for smoking related health disorders. This study investigated the association of cigarette smoke with serum total bilirubin among Koreans.
Methods:
Between 2006 and 2011, we examined 4899 Korean adults living in a rural community. After excluding 38 participants with serum bilirubin > 2 mg/dl, 75 participants who did not report their smoking status or who had liver or bile duct disorders, and 711 participants with liver enzymes exceeding the upper reference values, we performed a cross-sectional analysis on 4075 participants. Participants were classified into four groups: never smokers without secondhand smoke exposure (SHSE), never smokers with SHSE, former smokers, and active smokers. Serum total bilirubin concentration was measured using the enzyme method.
Results:
Compared to never smokers without SHSE, never smokers with SHSE (β = -0.025 mg/dl), former smokers (β = -0.049 mg/dl), and active smokers (β = -0.149 mg/dl) had significantly lower serum bilirubin even after adjusting for demographic factors, study year, alanine aminotransferase, gamma-glutamyl transferase, hemoglobin, lifestyle factors, and chronic diseases. A sex-stratified analysis indicated that for men, former smokers and active smokers were significantly associated with having lower bilirubin when compared to never smokers without SHSE. However, for women, never smokers with SHSE and active smokers were significantly associated with having lower bilirubin when compared to never smokers without SHSE.
Conclusion:
Our findings suggest that both active and passive cigarette smoking are associated with low serum bilirubin among Korean adults.
Experimental studies suggest oxidative stress could lead to the development of hypertension. Serum bilirubin is a major contributor to the antioxidant capacity in blood plasma and has been identified as an independent cardiovascular risk factor in cohort studies. However, data on the relationship between bilirubin and blood pressure are scarce and inconclusive.
We analysed data from the National Health and Nutrition Examination Surveys (NHANES) 1999-2012 (N = 31 069). Fifty multiple imputed data sets were generated and analysed to avoid selection/confounding bias due to excluding individuals/variables with missing values. A minimal sufficient adjustment set of variables (MSAS) needed to estimate the unconfounded effect of bilirubin on blood pressure and hypertension (systolic/diastolic blood pressure ≥140/90 mmHg or using antihypertensive medication) was identified using the back-door criterion and included in all regression models.
After adjustment for the MSAS variables, systolic blood pressure decreased progressively up to -2.5 mmHg (p < 0.001) and the prevalence of hypertension was up to 25% lower (P < 0.001) in those with bilirubin ≥1.0 mg/dl-the highest two deciles-compared with those with 0.1-0.4 mg/dl-the lowest decile. Sensitivity analyses showed these results were unlikely to be explained by residual confounding or selection bias.
High serum bilirubin may decrease the risk of hypertension by inactivating and inhibiting the synthesis of reactive oxygen species in vascular cells. Strategies to boost the bioavailability of circulating and tissue bilirubin or to mimic bilirubin's antioxidant properties could have a significant impact on prevention and control of hypertension as well as coronary heart disease.
© The Author 2014; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.
Aim:
Serum bilirubin is an endogenous antioxidant with anti-inflammatory properties. Several cross-sectional studies have reported that bilirubin was negatively associated with oxidative stress-mediated diseases, including the metabolic syndrome (MetS). However, the clinical relevance of bilirubin as a risk factor for incident MetS remains controversial. For this reason, the longitudinal effects of baseline serum bilirubin concentrations on incident MetS were evaluated in Korean men.
Methods:
This 4-year retrospective longitudinal observational study involved 6205 Korean men without MetS. Subjects underwent routine health examinations in 2007 and returned for a follow-up examination in 2011. Baseline serum bilirubin concentrations were determined using the vanadate oxidation method.
Results:
During the 4-year period, 936 cases of incident MetS (15.1%) were identified. Its incidence decreased across baseline bilirubin quartile categories (P<0.001), with an odds ratio (OR) for developing MetS being significantly lower in the highest quartile group (≥ 1.40 mg/dL) compared with the lowest (≤ 0.90 mg/dL) after adjusting for all confounding variables [OR=0.70, 95% confidence interval (CI) 0.54-0.90; P for trend=0.019]. Among individual components of MetS, bilirubin was found to be negatively associated with only the risk of incident hypertriglyceridaemia. The OR (95% CI) for incident hypertriglyceridaemia in the highest vs lowest quartile was 0.75 (0.61-0.91; P for trend=0.002).
Conclusion:
Serum total bilirubin level was negatively associated with incidence of MetS in healthy Korean men over a 4-year period.
Obesity (Silver Spring). 2008 Oct.; 16(10): 2281-8
Heme oxygenase-1 (HO-1) is central to the regulation of oxidative injury. The role of increased HO-1 expression and Heme oxygenase (HO) activity in mitigating the detrimental side effect of diabetes is examined. A review of the mechanism(s) of action is in- cluded. This may lead to the development of pharmacological and genetic approaches to mitigate the clinical complications associated with the progression of diabetes and obesity. Hyperglycemia, a major cause of kidney disease, results in hy- pertension and the risk of developing diabetic neuropathy. Hyper- glycemia, defined as elevated levels of serum glucose, produces oxidative stress through the increased generation of reactive oxygen species (ROS) leading to the derangement of cell physiology in diabetes. In addition it plays a critical role in the pathogenesis of diabetic complications including cell survival in animal models of diabetes. Impairment of vascular responses due to the formation of superoxide anion radical (O2 - ) represents the major contributor to vascular injury and the clinical complications of diabetes (1). The perturbations in heme metabolism resulting in increased expression of heme oxygenase(HO)-1 and increased production of carbon monoxide (CO), iron and biliverdin/bilirubin that occur and their role in the regulation of oxidative stress and cell survival will be examined in detail and its relation to obesity and metabolic syn- drome. In Type 1 diabetes, insulin deficiency provokes high blood glucose levels and alterations in lipid metabolism. The evolution of this disease may be associated with the development of premature micro- and macrovascular complications; the pathogenesis of which may be linked to oxidative stress (2-5). Increased ROS generation may contribute to beta cell damage and vascular dysfunction through various mechanisms (5-7). In diabetic children, puberty may trigger microvascular complications that may later be the ma- jor cause of tissue damage, disability and death. Although the mechanism of glucose toxicity is unknown, recent in vitro and whole animal studies have implicated ROS, which promote the formation of cytotoxic lipid peroxides (8-11). The beta cell destruc- tion by ROS, whether induced by oxidants given exogenously or elicited by cytokines, is a process that occurs through changes in the apoptotic and antiapoptotic balance (12-16). There appears to be an intrinsic cardiovascular sensitivity to oxidative stress in diabetic rats and in nonobese diabetic (NOD) mice, a property that may extend to human patients. Type 2 diabetes mellitus is a common disorder, characterized by hyperglycemia, insulin resistance and relative impairment in insulin secretion. Over seven percent of adults in the United States are known to have diabetes and the number continues to rise every year (17). The spectacular increase in prevalence of type 2 diabetes in the past decade, in large part is linked to the trends in obesity and physical inactivity (18). Abdominal obesity, in particular, is associ- ated with resistance to the effects of insulin on peripheral glucose and fatty acid utilization. Insulin resistance plays a major role in the pathogenesis of type 2 diabetes and is often accompanied by other
Women with the metabolic syndrome (central obesity, insulin resistance, and dyslipidemia) are known to be at especially high risk for cardiovascular disease (CVD). The prevalence of the metabolic syndrome increases with menopause and may partially explain the apparent acceleration in CVD after menopause. The transition from pre- to postmenopause is associated with the emergence of many features of the metabolic syndrome, including 1) increased central (intraabdominal) body fat; 2) a shift toward a more atherogenic lipid profile, with increased low density lipoprotein and triglycerides levels, reduced high density lipoprotein, and small, dense low density lipoprotein particles; 3) and increased glucose and insulin levels. The emergence of these risk factors may be a direct result of ovarian failure or, alternatively, an indirect result of the metabolic consequences of central fat redistribution with estrogen deficiency. It is unclear whether the transition to menopause increases CVD risk in all women or only those who develop features of the metabolic syndrome. This article will review the features of the metabolic syndrome that emerge with estrogen deficiency. A better understanding of these metabolic changes with menopause will aid in the recognition and treatment of women at risk for future CVD, leading to appropriate interventions.
To examine whether genes associated with cellular defense against oxidative stress are associated with insulin sensitivity, patients with type 2 diabetes (n = 7) and age-matched (n = 5) and young (n = 9) control subjects underwent a euglycemic-hyperinsulinemic clamp for 120 min. Muscle samples were obtained before and after the clamp and analyzed for heat shock protein (HSP)72 and heme oxygenase (HO)-1 mRNA, intramuscular triglyceride content, and the maximal activities of beta-hydroxyacyl-CoA dehydrogenase (beta-HAD) and citrate synthase (CS). Basal expression of both HSP72 and HO-1 mRNA were lower (P < 0.05) by 33 and 55%, respectively, when comparing diabetic patients with age-matched and young control subjects, with no differences between the latter groups. Both basal HSP72 (r = 0.75, P < 0.001) and HO-1 (r = 0.50, P < 0.05) mRNA expression correlated with the glucose infusion rate during the clamp. Significant correlations were also observed between HSP72 mRNA and both beta-HAD (r = 0.61, P < 0.01) and CS (r = 0.65, P < 0.01). HSP72 mRNA was induced (P < 0.05) by the clamp in all groups. Although HO-1 mRNA was unaffected by the clamp in both the young and age-matched control subjects, it was increased (P < 0.05) approximately 70-fold in the diabetic patients after the clamp. These data demonstrate that genes involved in providing cellular protection against oxidative stress are defective in patients with type 2 diabetes and correlate with insulin-stimulated glucose disposal and markers of muscle oxidative capacity. The data provide new evidence that the pathogenesis of type 2 diabetes involves perturbations to the antioxidant defense mechanism within skeletal muscle.
To identify a reliable yet simple indirect method for detection of insulin resistance (IR).
A total of 65 subjects (44 men and 21 women aged 30-60 years) were selected by a simple random sampling method. Inclusion criteria were voluntary participation from staff and hospital personnel, absence of abnormal glucose tolerance, and normal results of lipid profile and basic blood chemistry. A blood sample was taken after a 12-h overnight fast to determine plasma lipid, glucose, and insulin levels. An intravenous glucose tolerance test with administration of insulin after 20 min and extraction of multiple blood samples for glucose and insulin measurements and calculation of the minimal model approximation of the metabolism of glucose (MMAMG) S(i) value were performed. Three indirect indexes used to predict insulin sensitivity or IR were calculated, and metabolic syndrome was diagnosed using the Adult Treatment Panel III (ATP III) criteria. All results were correlated with those of the MMAMG.
The 75th percentile value as the cutoff point to define IR corresponded with a fasting plasma glucose level of 12 mU/l, a homeostasis model assessment of 2.6, a 25th percentile for S(i) value of 21, and QUICKI (quantitative insulin sensitivity check index) and McAuley indexes of 0.33 and 5.8, respectively. The S(i) index correlated (P < 0.001) with all the indirect indexes and parameters of the metabolic syndrome.
When compared with the S(i) index, the most sensitive and specific indirect method was the score proposed by McAuley et al. (specificity 0.91, sensitivity 0.75, 9.2 probability ratio of a positive test), followed by the existence of metabolic syndrome (specificity 0.91, sensitivity 0.66, 7.8 probability ratio of a positive test).
Intravascular hemolysis is one of the most emphasized mechanisms for destruction of erythrocytes during and after physical activity. Exercise-induced oxidative stress has been proposed among the different factors for explaining exercise-induced hemolysis. The validity of oxidative stress following exhaustive cycling exercise on erythrocyte damage was investigated in sedentary and trained subjects before and after antioxidant vitamin treatment (A, C, and E) for 2 mo. Exercise induced a significant increase in thiobarbituric acid-reactive substance and protein carbonyl content levels in sedentary subjects and resulted in an increase of osmotic fragility and decrease in deformability of erythrocytes, accompanied by signs for intravascular hemolysis (increase in plasma hemoglobin concentration and decrease in haptoglobulin levels). Administration of antioxidant vitamins for 2 mo prevented exercise-induced oxidative stress (thiobarbituric acid-reactive substance, protein carbonyl content) and deleterious effects of exhaustive exercise on erythrocytes in sedentary subjects. Trained subjects' erythrocyte responses to exercise were different from those of sedentary subjects before antioxidant vitamin treatment. Osmotic fragility and deformability of erythrocytes, plasma hemoglobin concentration, and haptoglobulin levels were not changed after exercise, although the increased oxidative stress was observed in trained subjects. After antioxidant vitamin treatment, functional and structural parameters of erythrocytes were not altered in the trained group, but exercise-induced oxidative stress was prevented. Increased percentage of young erythrocyte populations was determined in trained subjects by density separation of erythrocytes. These findings suggest that the exercise-induced oxidative stress may contribute to exercise-induced hemolysis in sedentary humans.
Physical inactivity in postmenopausal women contributes to a rise in atherogenic risk factors associated with the metabolic syndrome. Although regular physical activity positively contributes to health, inactivity progressively increases with age. The Dose Response to Exercise in Women aged 45-75 yr (DREW) study is designed to investigate the effect of different amounts of exercise training on cardiorespiratory fitness and risk factors for cardiovascular disease (CVD) in postmenopausal women at moderately increased risk of CVD.
DREW will recruit 450 sedentary, healthy, postmenopausal women with a body mass index of 25-40 kg.m-2, resting systolic blood pressure (BP) of 120-159 mm Hg, and a resting diastolic BP of < or = 99 mm Hg. Laboratory and self-report measures completed at baseline and 6 months include maximal oxygen consumption (.VO2max), resting BP, anthropometry, dietary habits, physical activity history, medication use, menstrual history, personal and family medical history, and fasting HDL cholesterol, LDL cholesterol, triglycerides, and glucose. Eligible participants are randomly assigned to a nonexercise group or one of three exercise groups. Participants exercise 3 to 4x wk-1 at a heart rate equivalent to 50% of .VO2max expending 4, 8, or 12 kcal.kg-1.wk-1, depending on group assignment. This study will allow quantification of possible dose-response relations (50%, 100%, and 150% of the consensus physical activity recommendation) between exercise training and study outcomes.
DREW can make important contributions to our understanding of the effects of physical activity in postmenopausal women and help refine public health and clinical recommendations for this group.
Low levels of cardiorespiratory fitness are associated with high risk of mortality, and improvements in fitness are associated with reduced mortality risk. However, a poor understanding of the physical activity-fitness dose response relation remains.
To examine the effect of 50%, 100%, and 150% of the NIH Consensus Development Panel recommended physical activity dose on fitness in women.
Randomized controlled trial of 464 sedentary, postmenopausal overweight or obese women whose body mass index ranged from 25.0 to 43.0 and whose systolic blood pressure ranged from 120.0 to 159.9 mm Hg. Enrollment took place between April 2001 and June 2005 in the Dallas, Tex, area.
Participants were randomly assigned to 1 of 4 groups: 102 to the nonexercise control group and 155 to the 4-kcal/kg, 104 to the 8-kcal/kg, and 103 to the 12-kcal/kg per week energy-expenditure groups for the 6-month intervention period. Target training intensity was the heart rate associated with 50% of each woman's peak Vo2.
The primary outcome was aerobic fitness assessed on a cycle ergometer and quantified as peak absolute oxygen consumption (Vo2abs, L/min).
The mean (SD) baseline Vo2abs values were 1.30 (0.25) L/min. The mean (SD) minutes of exercising per week were 72.2 (12.3) for the 4-kcal/kg, 135.8 (19.5) for the 8-kcal/kg, and 191.7 (33.7) for the 12-kcal/kg per week exercise groups. After adjustment for age, race/ethnicity, weight, and peak heart rate, the exercise groups increased their Vo2abs compared with the control group by 4.2% in the 4-kcal/kg, 6.0% in the 8-kcal/kg, and 8.2% in the 12-kcal/kg per week groups (P<.001 for each vs control; P for trend <.001). There was no treatment x subgroup interaction for age, body mass index, weight, baseline Vo2abs, race/ethnicity, or baseline hormone therapy use. There were no significant changes in systolic or diastolic blood pressure values from baseline to 6 months in any of the exercise groups vs the control group.
In this study, previously sedentary, overweight or obese postmenopausal women experienced a graded dose-response change in fitness across levels of exercise training.
clinicaltrials.gov Identifier: NCT00011193.
Heme oxygenase-1 (HO-1) is central to the regulation of oxidative injury. The role of increased HO-1 expression and Heme oxygenase (HO) activity in mitigating the detrimental side effect of diabetes is examined. A review of the mechanism(s) of action is included. This may lead to the development of pharmacological and genetic approaches to mitigate the clinical complications associated with the progression of diabetes and obesity.
We hypothesized that the induction of heme oxygenase (HO)-1 and increased HO activity, which induces arterial antioxidative enzymes and vasoprotection in a mouse and a rat model of diabetes, would ameliorate insulin resistance, obesity, and diabetes in the ob mouse model of type 2 diabetes.
Lean and ob mice were intraperitoneally administered the HO-1 inducer cobalt protoporphyrin (3 mg/kg CoPP) with and without the HO inhibitor stannous mesoporphyrin (2 mg/100 g SnMP) once a week for 6 weeks. Body weight, blood glucose, and serum cytokines and adiponectin were measured. Aorta, adipose tissue, bone marrow, and mesenchymal stem cells (MSCs) were isolated and assessed for HO expression and adipogenesis.
HO activity was reduced in ob mice compared with age-matched lean mice. Administration of CoPP caused a sustained increase in HO-1 protein, prevented weight gain, decreased visceral and subcutaneous fat content (P < 0.03 and 0.01, respectively, compared with vehicle animals), increased serum adiponectin, and decreased plasma tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and IL-1beta levels (P < 0.05). HO-1 induction improved insulin sensitivity and glucose tolerance and decreased insulin levels. Upregulation of HO-1 decreased adipogenesis in bone marrow in vivo and in cultured MSCs and increased adiponectin levels in the culture media. Inhibition of HO activity decreased adiponectin and increased secretion of TNF-alpha, IL-6, and IL-1beta levels in ob mice.
This study provides strong evidence for the existence of an HO-1-adiponectin regulatory axis that can be manipulated to ameliorate the deleterious effects of obesity and the metabolic syndrome associated with cardiovascular disease and diabetes.
This review examines in vitro and in vivo studies, indicating that bilirubin inhibits lipid oxidation and oxygen radical formation. Experimental and epidemiological evidence is presented that suggests that bilirubin may serve as a physiological antioxidant providing protection against cardiovascular disease. Special attention is focused on large prospective studies that noted a strong, inverse relationship between serum bilirubin concentrations and cardiovascular morbidity and mortality even after adjustment for traditional risk factors. Overall, the evidence from these studies suggests that bilirubin, via its antioxidant potential, has antiatherogenic properties, and that serum bilirubin concentrations in the upper portion of the reference interval for the general population may provide some protection against cardiovascular disease, whereas concentrations in the lower portion of the reference interval indicate increased cardiovascular risk.
Coronary heart disease (CHD) is the leading cause of morbidity and mortality in women in the United States. Although CHD is less common in premenopausal women than in men, this difference begins to disappear after the onset of menopause, presumably related to reduced levels of female sex hormones.
An association between both a postmenopausal increase in blood pressure and CHD that coincide with loss of ovarian function suggests that estrogen and/or progesterone may be protective against hypertension and CHD. Diabetes removes the normal sex difference in the prevalence of CHD. Increased mortality in women with CHD and diabetes compared with women without diabetes has been observed in epidemiological studies.
Diabetes appears to obviate the protective effects of female sex hormones. Possible reasons for this catastrophic effect of diabetes in women are discussed.
The objective of this study was to determine if there is an association between serum hepatic markers and the metabolic syndrome in postmenopausal women.
This study involved 1229 postmenopausal women aged 44-85 years, who visited the Center for Health Promotion for a health check-up. We excluded subjects from the analysis if they had a daily alcohol consumption of more than 1.5 drinks (alcohol consumption ≥20 g/day) or had chronic viral hepatitis. We also excluded subjects who had abnormal hepatic function, as defined by serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >100 IU/L, serum γ-glutamyltransferase (GGT) >100 IU/L, or serum total bilirubin concentrations >2 mg/dL.
Serum ALT and GGT concentrations increased in proportion to the number of elements of the metabolic syndrome (p<0.01). However, total bilirubin concentrations decreased (p=0.01). After adjusting for age, body mass index, and the presence of fatty liver in the patients with metabolic syndrome, the odds ratios (95% confidence interval) were 1.38 (0.89-2.15) for log (ALT), 1.69 (1.30-2.20) for log (GGT), and 0.53 (0.33-0.86) for log (total bilirubin).
We found that an increase in GGT and a decrease in total bilirubin was associated with metabolic syndrome in postmenopausal women. Hepatic enzymes could be proposed as simple clinical metabolic markers that identify the metabolic syndrome.
Studies on the effects of bilirubin on cardiovascular disease have typically focused only on total serum bilirubin composed with direct bilirubin plus indirect bilirubin. In this study, we examined which type of fasting bilirubin is more associated with the metabolic syndrome (MS).
Five thousand six hundred and fifty-four individuals who visited the Center for Health Promotion for a periodic medical health check-up were screened for inclusion in the study. We excluded subjects who had a chronic viral liver disease, an alcoholic liver disease, or an abnormal liver function defined as a serum aspartate aminotransferase or alanine aminotransferase >100IU/l, a gamma glutamyltransferase >100IU/l, or a fasting total bilirubin level >3mg/dl.
In men, only fasting direct bilirubin levels decreased with an increase in the number of MS components (p=0.001). However, all three types of fasting bilirubin decreased when the subjects had more components of MS (p<0.001) in women. Both in men and women fasting direct bilirubin levels were related with the MS (p for trend=0.003 in men and <0.001 in women) after the adjustments for age, body mass index, smoking, alcohol drinking, exercise habits, and presence of fatty liver. The odds ratio (95% confidence interval) of MS for each fasting direct bilirubin quartile was 0.88 (0.59-1.29), 0.63 (0.42-0.95), 0.61 (0.38-0.97) in men, and 0.66 (0.50-0.87), 0.52 (0.35-0.78), 0.27 (0.12-0.59) in women, respectively. However, fasting total and indirect bilirubin levels were related with the MS in women, but not in men.
Our findings suggest that MS is more related to the fasting direct bilirubin in Korean adults than the other types of fasting bilirubin.
This review examines in vitro and in vivo studies, indicating that bilirubin inhibits lipid oxidation and oxygen radical formation. Experimental and epidemiological evidence is presented that suggests that bilirubin may serve as a physiological antioxidant providing protection against cardiovascular disease. Special attention is focused on large prospective studies that noted a strong, inverse relationship between serum bilirubin concentrations and cardiovascular morbidity and mortality even after adjustment for traditional risk factors. Overall, the evidence from these studies suggests that bilirubin, via its antioxidant potential, has antiatherogenic properties, and that serum bilirubin concentrations in the upper portion of the reference interval for the general population may provide some protection against cardiovascular disease, whereas concentrations in the lower portion of the reference interval indicate increased cardiovascular risk.
Several studies have suggested a potential effect of serum bilirubin as an antioxidant and cytoprotectant factor. For the results presented here, we evaluated the correlation between serum bilirubin and diabetes mellitus (DM) or chronic kidney disease originated from DM (DMCKD) in a Korean population. We used a cross-sectional, population-based design to examine 93,909 subjects (aged 18-96 years, 53.0% male). The trend of P values in the odds ratios for being DM and DMCKD was calculated using patients separated into five groups based on individual serum bilirubin concentrations. The prevalence of DM and DMCKD was 6.7% and 0.8%, respectively. Higher serum bilirubin levels were significantly associated with decreased prevalence of DM in both men (P trend < 0.001) and women (P trend = 0.014). The risk of DMCKD also decreased as bilirubin levels increased in women (P trend = 0.011), but not in men (P trend = 0.467). Serum bilirubin level was inversely related to insulin resistance using the homeostasis model assessment (HOMA-IR), serum insulin, and C-reactive protein (CRP) levels in multiple linear regression analyses. The regression coefficients (B) of log-HOMA-IR, log-insulin, and log-CRP were as follows: -0.09, -0.13, and -0.60 in men; -0.07, -0.09, and -0.50 in women, respectively. All the regressions were statistically significant (P < 0.001). These results indicate that serum bilirubin might have some protective function against DM and DMCKD, although the association between high serum bilirubin and decreased prevalence of DMCKD is observed only in women.
Subnormal levels of plasma bilirubin levels are associated with premature coronary artery disease and cardiovascular morbidity. Plasma gamma-glutamyltransferase (GGT) activity is linked to bilirubin level in hepatic disease and elevated GGT is equally associated with hepatic steatosis, a frequent feature of metabolic syndrome (MS). In order to assess the potential relationship between GGT activity and bilirubin levels in subjects exhibiting features of the metabolic syndrome, we determined circulating bilirubin levels and GGT activity in a cohort of dyslipidemic patients.
This cross-sectional study involved patients (n=1433) displaying atherogenic dyslipidemia in primary prevention referred to our Prevention Center. Among these patients, 25% presented with MS as defined by recent NCEP ATP III criteria. Circulating levels of transaminases, as well as GGT activity, were elevated in MS patients; by contrast, bilirubin concentrations were significantly lower in such patients as compared to those lacking this syndrome (p<10-4 for all comparisons). Comparisons of patient groups on the basis of the number of MS criteria which were concomitantly present revealed a progressive decrease in mean bilirubin levels; this reduction paralleled a progressive increase in mean GGT activity as a function of the number of MS components in the overall population (p value for trend<10-4).
Elevation in systemic GGT activity, which is characterized by extended generation of ROS, together with potentially deficient bilirubin-mediated antioxidative capacity of plasma, may therefore constitute key components of the systemic oxidative stress typical of metabolic syndrome.
Accumulating clinical evidence indicates that impaired glucose tolerance is a common phenomenon in essential hypertension. Although recent evidence underscores the role of heme-oxygenase (HO) in diabetes, its effects on insulin sensitivity and glucose metabolism in spontaneously hypertensive rat (SHR), a model of essential hypertension with characteristics of metabolic syndrome including insulin resistance/impaired glucose metabolism remains largely unclear. Here we report the effects of the HO inducer, hemin, and the HO blocker, chromium-mesoporphyrin on insulin sensitivity and glucose metabolism in SHRs. Adult SHRs were severely hypertensive but normoglycemic. Hemin therapy lowered blood pressure, increased plasma insulin, decreased glycemia, and enhanced insulin sensitivity by improving glucose tolerance (ip glucose tolerance test) and insulin tolerance (ip insulin tolerance test) but reduced insulin resistance (homeostasis model assessment index). These effects were accompanied by increased gastrocnemius muscle HO-1, HO activity, cGMP, cAMP alongside antioxidants including bilirubin, ferritin, superoxide dismutase, catalase, and the total antioxidant capacity, whereas oxidative/inflammatory mediators like 8-isoprostane, nuclear-factor-kappaB, activating-protein-1, activating-protein-2, c-Jun-NH2-terminal-kinase, and heme were abated. Furthermore, hemin reduced proteinuria/albuminuria and enhanced the depressed levels of adiponectin, AMP-activated protein-kinase, and glucose transporter-4 in SHRs, suggesting that although SHRs are normoglycemic, insulin signaling and renal function may be impaired. Contrarily, the HO inhibitor chromium-mesoporphyrin exacerbated oxidative stress, aggravated insulin resistance, glucose tolerance, insulin tolerance and nephropathy. Hemin also enhanced HO signaling in Wistar Kyoto and Sprague Dawley rats and increased insulin sensitivity albeit less intensely than in SHRs, suggesting greater selectivity of HO in SHRs with dysfunctional insulin signaling. These results suggest that perturbations of insulin signaling may be a forerunner to hyperglycemia in essential hypertension. By concomitantly potentiating insulin-sensitizing agents, suppressing insulin/glucose intolerance, and abating oxidative stress, HO inducers may prevent metabolic and cardiovascular complications in essential hypertension.
Low levels of bilirubin are associated with an increased risk of cardiovascular adverse events. Weight reduction is known to reduce several cardiovascular risk factors, but effects on bilirubin levels have not been reported. We studied the response of weight loss therapy with sibutramine and lifestyle change on levels of total bilirubin in an overweight or obese, cardiovascular high-risk population. Data from the first 4 weeks of the lead-in period of the Sibutramine Cardiovascular Outcome study were analyzed. A total of 10 198 patients provided body weight measurements before and after 4 weeks of sibutramine treatment (10 mg daily), of whom 1059 (10.4%) gained weight, 1467 (13.7%) lost greater than 0% to 1%, 2492 (23.2%) lost greater than 1% to 2%, 2280 (21.2%) lost greater than 2% to 3%, 1498 (13.9%) lost greater than 3% to 4%, and 1402 (13.1%) lost greater than 4% of their initial weight, respectively. At screening, bilirubin concentrations were similar between weight loss groups (around 11 micromol/L, P = .7) and increased linearly as a function of weight loss. The effect was significantly more pronounced in men compared with women (P for interaction = .003). Adjusted for multiple variables, each 1% increase in weight loss was associated with 0.21-micromol/L (+/- standard error 0.027) increase in men (P < .0001) and 0.11-micromol/L (+/-0.024) increase in women (P < .0001). Short-term weight loss during administration of sibutramine in combination with diet and exercise advice is effective in increasing bilirubin levels within the reference range, with bilirubin increasing as a linear function of weight change. The effect is greater in men than in women.
Bilirubin inhibits experimental atherosclerosis, is inversely associated with carotid plaque burden, and confers neuroprotection in experimental stroke. Clinical data addressing the association of bilirubin with stroke are not available. We hypothesized that higher bilirubin levels would be associated with reduced stroke prevalence and improved stroke outcomes.
We used the National Health and Nutrition Examination Survey 1999 to 2004, a nationally representative cross-sectional examination of the United States civilian population, to examine the association of bilirubin with stroke. Of 13,214 adult participants with data on stroke history, serum total bilirubin level, and stroke risk factors, 453 reported a history of stroke. Of these, 138 participants reported an adverse stroke outcome, defined as a long-term health problem or disability due to stroke. We performed multivariable logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) with adjustment for demographic characteristics and stroke risk factors.
After multivariable adjustment, a 1.71 micromol/L (0.1 mg/dL) increment in bilirubin level was associated with a 9% reduced odds of stroke (OR 0.91; 95% CI, 0.86-0.96) among all participants and with a 10% reduced odds of an adverse stroke outcome (OR 0.90; 95% CI, 0.80-1.00) among participants with a history of stroke.
These results suggest that a higher serum total bilirubin level is associated with reduced stroke prevalence and improved stroke outcomes. Our findings support the hypothesis that bilirubin may protect from stroke events and from neurologic damage in stroke.
Obesity and physical inactivity are independent risk factors for the development of nonalcoholic fatty liver disease (NAFLD). We determined the effect of endurance exercise training on hepatic lipid content and hepatic enzyme concentration in men and women. Waist circumference (WC), percent body fat (BF), computed tomography (CT) scans for liver attenuation (inverse relationship with hepatic lipid), bilirubin, alanine aminotransferase (ALT), and gamma-glutamyltransferase (GGT) plasma concentrations were measured before and after 12 weeks of endurance training in 41 lean and obese men and women. Exercise training did not change liver attenuation, body weight, percent BF, bilirubin, or ALT concentration, but did lower WC (P < 0.0001), and decreased GGT in men only (P = 0.01). Obese subjects had a lower liver attenuation than lean subjects (P = 0.04). Obese women had lower ALT than obese men (P = 0.03). GGT was lower in women before and after training. WC was positively correlated with GGT (r = 0.32, P = 0.003) and ALT (r = 0.320, P = 0.004) and negatively correlated with liver attenuation (r = -0.340, P = 0.03). Percent BF was negatively correlated with bilirubin (r = -0.374, P = 0.005). Liver attenuation was negatively correlated with ALT (r = -0.405, P = 0.003). Short-term endurance training without weight loss does not alter hepatic lipid content. There was a strong relationship between GGT/ALT and body composition (percent BF) as well as between ALT and hepatic lipid content.
The relation of menopause to cardiovascular disease incidence was examined in women less than 55 years old from the cohort of 2873 women in the initial Framingham examination. Although the number of person-years of experience during the 20 years of observation was nearly the same for premenopausal and postmenopausal status, there were only 20 cardiovascular events among the premenopausal women in this age group whereas 70 events occurred among the postmenopausal women of the same age. In each specific age group studied incidence rates were lower in premenopausal than postmenopausal women. This was also true for coronary heart disease. Contrast for "hard" diagnoses of cardiovascular disease (excluding diagnoses of angina pectoris and intermittent claudication) was in the same direction. Although cholesterol and hemoglobin did rise somewhat more steeply in women undergoing the menopause, this greater incidence of cardiovascular disease in postmenopausal women could not be explained by the influence of the menopause on the usual cardiovascular risk factors.
The steady-state basal plasma glucose and insulin concentrations are determined by their interaction in a feedback loop. A computer-solved model has been used to predict the homeostatic concentrations which arise from varying degrees beta-cell deficiency and insulin resistance. Comparison of a patient's fasting values with the model's predictions allows a quantitative assessment of the contributions of insulin resistance and deficient beta-cell function to the fasting hyperglycaemia (homeostasis model assessment, HOMA). The accuracy and precision of the estimate have been determined by comparison with independent measures of insulin resistance and beta-cell function using hyperglycaemic and euglycaemic clamps and an intravenous glucose tolerance test. The estimate of insulin resistance obtained by homeostasis model assessment correlated with estimates obtained by use of the euglycaemic clamp (Rs = 0.88, p less than 0.0001), the fasting insulin concentration (Rs = 0.81, p less than 0.0001), and the hyperglycaemic clamp, (Rs = 0.69, p less than 0.01). There was no correlation with any aspect of insulin-receptor binding. The estimate of deficient beta-cell function obtained by homeostasis model assessment correlated with that derived using the hyperglycaemic clamp (Rs = 0.61, p less than 0.01) and with the estimate from the intravenous glucose tolerance test (Rs = 0.64, p less than 0.05). The low precision of the estimates from the model (coefficients of variation: 31% for insulin resistance and 32% for beta-cell deficit) limits its use, but the correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop.
We examined serum bilirubin and various liver-function enzymes as possible risk factors for angiographically documented coronary artery disease (CAD). The studies involved a "training" set of 619 men for whom complete data on all risk factors considered were available, and a "test" set of 258 men for whom some risk factor data were not available. In both study groups, the liver enzymes were not related to CAD; however, In[total bilirubin] was inversely and statistically significantly related to the presence of CAD, both univariately and multivariately after adjustment for the established risk factors of age, total cholesterol, high-density lipoprotein cholesterol, smoking history, and systolic blood pressure. A 50% decrease in total bilirubin was associated with a 47% increase in the odds of being in a more severe CAD category. Our data suggest that serum bilirubin is an inverse and independent risk factor for CAD, with an association equivalent in degree to that of systolic blood pressure.
There is evidence that bilirubin functions as an endogenous tissue protector by its antioxidant and anti-complement actions, properties that are relevant to atherogenesis. Serum bilirubin distribution and its relation to cardiovascular risk were examined in 4156 individuals aged 5-30 years from a biracial (black white) community. Bilirubin levels showed significant differences related to race (whites > blacks) and sex (males > females, except in 5-10 year olds). In males the levels increased with age up to 24 years, while in females the changes were less conspicuous. Both adiposity and cigarette smoking associated independently and inversely with bilirubin. In addition, serum bilirubin correlated positively with HDL cholesterol and inversely with triglycerides, VLDL cholesterol, LDL cholesterol, insulin, glucose and systolic blood pressure although these correlations were significant only in certain age-race-sex groups. Offspring with a parental history of heart attack or hypertension had consistently lower bilirubin levels than those without such parental history. Thus, bilirubin may be an inverse risk factor for cardiovascular disease.
The association between bilirubin and cardiovascular disease is controversial. In a prospective study of 4.276 subjects, we demonstrated that a higher concentration of serum bilirubin was associated with lower risk of myocardial infarction and cardiovascular disease in men, but the pattern was not clear in women.
Bilirubin, a major intravascular product of heme catabolism, is a potent antioxidant compound. Numerous studies have been published showing the relationship between serum bilirubin levels and atherosclerosis. In the present investigation all the epidemiological studies available on the effect of serum bilirubin levels and atherosclerotic disease were analyzed. Studies on the epidemiology of atherosclerotic diseases in relation to serum bilirubin levels were searched in the MEDLINE database. Selected studies were subdivided according to serum bilirubin levels and severity of atherosclerotic disease. Because of the limited number of females involved in the studies, only males were included into meta-analysis. Associations for ordered categorical variables (bilirubin and natural history of graded atherosclerosis) were assessed to find correlation and linear trend between analyzed variables. A stratified analysis was conducted to compare risks of clinical outcomes. Eleven relevant studies were used for analysis. A close negative relationship was found between serum bilirubin levels and severity of atherosclerosis (Spearman rank coefficient r = -0.31,P < 0.0001). The linear trend was confirmed in analysis of proportions with x(2) values for both disease conditions to be very significant (P < 0.0001). Unambiguous inverse relationship between serum bilirubin levels and atherosclerosis was demonstrated in this preliminary meta-analytic study. These results indicate the importance of hem oxygenase-related products in the prevention of oxidative stress-mediated diseases.
Bilirubin, with recently recognized antioxidant and antiinflammatory activity, has emerged as a candidate for atheroprotection. We hypothesized that higher levels of bilirubin would reduce susceptibility to peripheral arterial disease (PAD).
We analyzed 7075 adults with data available on the ankle brachial index, serum total bilirubin level, and PAD risk factors in the National Health and Nutrition Examination Survey (1999 to 2004), a nationally representative cross-sectional examination of the United States population. A 0.1 mg/dL increase in bilirubin level was associated with a 6% reduction in the odds of PAD (OR 0.94 [95% CI 0.90 to 0.98]) after adjustment for age, gender, race/ethnicity, smoking status, diabetes, hypertension, hypercholesterolemia, chronic kidney disease, CRP, and homocysteine. This result was not dependent on bilirubin levels above the reference range, liver disease, or alcohol intake. The inverse association of bilirubin with PAD tended to be stronger among men (OR 0.90 [95% CI 0.85 to 0.96]) compared with women (OR 0.97 [95% CI 0.91 to 1.04]; P(interaction)=0.05), and was stronger among active smokers (OR 0.81 [95% CI 0.73 to 0.90]) compared with nonsmokers (OR 0.97 [95% CI 0.93 to 1.02]; P(interaction)<0.01).
Increased serum total bilirubin level is associated with reduced PAD prevalence. This result is consistent with the hypothesis that bilirubin is protective from PAD.
This review is intended to stimulate interest in the effect of increased expression of heme oxygenase-1 (HO-1) protein and increased levels of HO activity on normal and pathological states. The HO system includes the heme catabolic pathway, comprising HO and biliverdin reductase, and the products of heme degradation, carbon monoxide (CO), iron, and biliverdin/bilirubin. The role of the HO system in diabetes, inflammation, heart disease, hypertension, neurological disorders, transplantation, endotoxemia and other pathologies is a burgeoning area of research. This review focuses on the clinical potential of increased levels of HO-1 protein and HO activity to ameliorate tissue injury. The use of pharmacological and genetic probes to manipulate HO, leading to new insights into the complex relationship of the HO system with biological and pathological phenomena under investigation, is reviewed. This information is critical in both drug development and the implementation of clinical approaches to moderate and to alleviate the numerous chronic disorders in humans affected by perturbations in the HO system.
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