ABSTRACT
INTRODUCTION: A physically active lifestyle during pregnancy improves maternal and offspring health but can be difficult to follow. In Denmark, less than 40% of pregnant women meet physical activity (PA) recommendations. The FitMum study aims to explore strategies to increase PA during pregnancy among women with low PA and assess the health effects of PA. This paper presents the FitMum protocol, which evaluates the effects of structured supervised exercise training or motivational counselling supported by health technology during pregnancy on PA level and health of mother and offspring. METHODS AND ANALYSIS: A single-site three-arm randomised controlled trial that aims to recruit 220 healthy, pregnant women with gestational age (GA) no later than week 15 and whose PA level does not exceed one hour/week. Participants are randomised to one of three groups: structured supervised exercise training consisting of three weekly exercise sessions, motivational counselling supported by health technology or a control group receiving standard care. The interventions take place from randomisation until delivery. The primary outcome is min/week of moderate-to-vigorous intensity PA (MVPA) as determined by a commercial activity tracker, collected from randomisation until GA of 28 weeks and 0-6 days, and the secondary outcome is gestational weight gain (GWG). Additional outcomes are complementary measures of PA; clinical and psychological health parameters in participant, partner and offspring; analyses of blood, placenta and breastmilk samples; process evaluation of interventions; and personal understandings of PA. ETHICS AND DISSEMINATION: The study is approved by the Danish National Committee on Health Research Ethics (# H-18011067) and the Danish Data Protection Agency (# P-2019-512). Findings will be disseminated via peer-reviewed publications, at conferences, and to health professionals via science theatre performances. TRIAL REGISTRATION NUMBER: NCT03679130. PROTOCOL VERSION: This paper was written per the study protocol version 8 dated 28 August 2019.
Subject(s)
Mothers , Motivational Interviewing , Exercise , Exercise Therapy , Female , Humans , Life Style , Pregnancy , Randomized Controlled Trials as TopicABSTRACT
BACKGROUND: Fibroblast growth factor 23 (FGF23) is known to cause left ventricular hypertrophy (LVH), but controversy exists concerning its effect in dialysis. This study evaluated associations between FGF23 levels, echocardiography and prognosis in patients on hemodialysis (HD). METHODS: Patients >18 years on chronic HD were included in this cross-sectional study. Plasma C-terminal FGF23 concentration was measured with ELISA and transthoracic echocardiography was performed, both before and after HD treatment. RESULTS: 239 haemodialysis (HD) patients were included in the study. The FGF23 was median 3560RU/ml (IQR 1447-9952). The mean left ventricular mass index (LVMI) was 110.2±26.7g/m2 and the left ventricular ejection fraction (LVEF) was 52.7±9.9%. Defined by LVMI, LVH was found in 110 patients (46%), of which 92 (84%) had hypertension (p<0.01). Patients with LVH had FGF23 levels of 5319 RU/ml (IQR 1858-12,859) and those without 2496 RU/ml (IQR 1141-7028) (p<0.01). FGF23 was significant positive correlated with LVMI (p<0.01), and negatively to LVEF (p<0.01). In a multivariate analysis, FGF23 was correlated with LVEF (p<0.01), but only marginally to LVMI (p<0.01). Cardiovascular events in the follow up period was not correlated with FGF23. Furthermore, FGF23 was independently correlated with overall mortality (p<0.001). CONCLUSION: FGF23 was positively correlated with LVH and negatively to LVEF. FGF23 was an independent predictor for overall mortality.
Subject(s)
Fibroblast Growth Factors/blood , Hypertrophy, Left Ventricular/blood , Hypertrophy, Left Ventricular/physiopathology , Renal Dialysis , Stroke Volume , Aged , Cross-Sectional Studies , Echocardiography , Female , Fibroblast Growth Factor-23 , Humans , Hypertrophy, Left Ventricular/diagnostic imaging , Male , Middle Aged , PrognosisABSTRACT
AIMS: Poor myometrial contractility has been demonstrated in women at term with diabetes and decreased muscular mitochondrial content and/or function has been extensively implicated in the progression of type 2 diabetes. Alterations of the uterine mitochondrial phenotype in pregnant women with diabetes have yet to be investigated as a causal link to decreased myometrial contractility. METHODS: Observational study of 18 women with diabetes (type 2 and gestational) scheduled for an elective Caesarean section at term with matching controls. A uterine biopsy and fasting blood samples were taken on the day of delivery. RESULTS: Respiration rates in isolated mitochondria and myometrial mRNA levels of genes related to mitochondrial biogenesis were unaffected by diabetes. Mitochondrial quantity examined by quantification of the complexes of the respiratory chain and histology did not indicate alterations in mitochondrial quantity. Citrate syntase activity was higher (0.31 ± 0.02 vs. 0.24 ± 0.02 U/mg protein, P = 0.008), whereas protein content was lower in women with diabetes compared with the control group (94.6 ± 6.9 vs. 118.6 ± 7.4 mg/g wet wt, P = 0.027). Histological examinations did not support any structural alterations in the myometrium or its mitochondria. CONCLUSION: No indication of decreased mitochondrial function, content, morphology, or localization in the myometrium at term in women with diabetes compared with controls was observed. The increase in citrate syntase activity in the myometrium could be explained by the lower protein content in the myometrium, which we suggest is due to alterations in tissue or cellular composition.
Subject(s)
Diabetes Mellitus, Type 2/metabolism , Mitochondria/metabolism , Myometrium/metabolism , Pregnancy Complications/physiopathology , Adult , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/pathology , Diabetes Mellitus, Type 2/physiopathology , Female , Humans , Muscle Contraction , Myometrium/pathology , Myometrium/physiopathology , Phenotype , Pregnancy , Pregnancy Complications/metabolism , Pregnancy Complications/pathology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Uterus/metabolism , Uterus/pathology , Uterus/physiopathology , Young AdultABSTRACT
[This corrects the article DOI: 10.1371/journal.pone.0186755.].
ABSTRACT
INTRODUCTION: Interleukin (IL)-18 is involved in regulation of lipid and glucose metabolism. Mice lacking whole-body IL-18 signalling are prone to develop weight gain and insulin resistance, a phenotype which is associated with impaired fat oxidation and ectopic skeletal muscle lipid deposition. IL-18 mRNA is expressed in human skeletal muscle but a role for IL-18 in muscle has not been identified. Patients with HIV-infection and lipodystrophy (LD) are characterized by lipid and glucose disturbances and increased levels of circulating IL-18. We hypothesized that skeletal muscle IL-18 and IL-18 receptor (R) expression would be altered in patients with HIV-lipodystrophy. DESIGN AND METHODS: Twenty-three HIV-infected patients with LD and 15 age-matched healthy controls were included in a cross-sectional study. Biopsies from the vastus lateralis muscle were obtained and IL-18 and IL-18R mRNA expression were measured by real-time PCR and sphingolipids (ceramides, sphingosine, sphingosine-1-Phosphate, sphinganine) were measured by HPLC. Insulin resistance was assessed by HOMA and the insulin response during an OGTT. RESULTS: Patients with HIV-LD had a 60% and 54% lower level of muscular IL-18 and IL-18R mRNA expression, respectively, compared to age-matched healthy controls. Patients with HIV-LD had a trend towards increased levels of ceramide (18.3±4.7 versus 14.8±3.0,p = 0.06) and sphingosine (0.41±0.13 versus 0.32±0.07, and lower level of sphinganine (p = 0.06). Low levels of muscle IL-18 mRNA correlated to high levels of ceramides (r = -0.31, p = 0.038) and sphingosine-1P (r = -0.29, p = 0.046) in skeletal muscle, whereas such a correlation was not found in healthy controls. Low expression of IL-18 mRNA in skeletal muscle correlated to elevated concentration of circulating triglycerides (Rp = -0.73, p<0.0001). Neither muscle expression of IL-18 mRNA or ceramide correlated to parameters of insulin resistance. CONCLUSION: IL-18 (mRNA) in skeletal muscle appears to be involved in the regulation of intramuscular lipid metabolism and hypertriglyceridemia.
Subject(s)
HIV Infections/metabolism , Interleukin-18/metabolism , Lipid Metabolism , Lipodystrophy/metabolism , Muscle, Skeletal/metabolism , Receptors, Interleukin-18/metabolism , Adult , HIV Infections/complications , Humans , Lipodystrophy/complications , Male , Middle AgedABSTRACT
KEY POINTS: Obesity during pregnancy and childbirth is associated with labour dystocia leading to instrumental or operative delivery, but the underlying pathophysiological mechanisms remain unclear and insufficient uterine contractility has been suggested. This study examined whether reduced myometrial mitochondrial capacity or quantity could contribute as a pathophysiological mechanism to labour dystocia. Data did not support reduced myometrial mitochondrial capacity or quantity in the myometrium at term in obese women, but a reduced myocyte density with increased triglyceride content was demonstrated, which could lead to poorer uterine contractility. These results add to the understanding of systemic effects of obesity, placing also the myometrium at term as an affected non-adipose tissue. ABSTRACT: Obesity is known to increase the risk of labour dystocia and insufficient energy supply, due to reduced mitochondrial capacity or quantity, could be a possible mechanism leading to reduced efficiency of uterine contractility during labour. In the present study of 36 women having an elective Caesarean section at term, obesity did not change mitochondrial phenotype in the myometrial myocyte obtained from uterine biopsies taken at delivery. Respiration rates in isolated mitochondria were unaffected by obesity. No indication of reduced content, investigated by quantification of the complexes of the respiratory chain, or altered regulation, examined by myometrial mRNA levels of genes related to mitochondrial biogenesis and inflammation, was detected. Yet we found increased myometrial triglyceride content in the obese group (2.39 ± 0.26 vs. 1.56 ± 0.20 mm, P = 0.024), while protein content and citrate synthase activity per gram wet weight myometrium were significantly lower in the obese (109.2 ± 7.2 vs. 139.4 ± 5.6 mg g-1 , P = 0.002, and 24.8 ± 1.0 vs. 29.6 ± 1.4 U g-1 wet wt, P = 0.008, respectively). These differences were substantiated by our histological findings where staining for nuclei, cytoplasm, glycogen and collagen supported the idea of a smaller muscle content in the myometrium in obese women. In conclusion no indication of myometrial mitochondrial dysfunction in the isolated state was found, but the observed increase of lipid content might play a role in the pathophysiological mechanisms behind labour dystocia in obese women.
Subject(s)
Lipid Metabolism , Mitochondria, Muscle/metabolism , Myometrium/metabolism , Obesity/metabolism , Pregnancy Complications/metabolism , Adult , Case-Control Studies , Female , Humans , Mitochondria, Muscle/ultrastructure , Muscle Cells/metabolism , Muscle Cells/ultrastructure , Myometrium/pathology , Obesity/pathology , Phenotype , Pregnancy , Pregnancy Complications/pathologyABSTRACT
Taurine ameliorates changes occurring in newborn skeletal muscle as a result of gestational protein restriction in C57BL/6 mice, but taurine supplementation effects may be exaggerated in C57BL/6 mice due to their inherent excessive taurinuria.We examined if maternal taurine supplementation could ameliorate changes in gene expression levels, properties of mitochondria, myogenesis, and nutrient transport and sensing, in male newborn skeletal muscle caused by a maternal low protein (LP) diet in Wistar rats.LP diet resulted in an 11% non-significant decrease in birth weight, which was not rescued by taurine supplementation (LP-Tau). LP-Tau offspring had significantly lower birth weight compared to controls. Gene expression profiling revealed 895 significantly changed genes, mainly an LP-induced down-regulation of genes involved in protein translation. Taurine fully or partially rescued 32% of these changes, but with no distinct pattern as to which genes were rescued.Skeletal muscle taurine content in LP-Tau offspring was increased, but no changes in mRNA levels of the taurine synthesis pathway were observed. Taurine transporter mRNA levels, but not protein levels, were increased by LP diet.Nutrient sensing signaling pathways were largely unaffected in LP or LP-Tau groups, although taurine supplementation caused a decrease in total Akt and AMPK protein levels. PAT4 amino acid transporter mRNA was increased by LP, and normalized by taurine supplementation.In conclusion, gestational protein restriction in rats decreased genes involved in protein translation in newborn skeletal muscle and led to changes in nutrient transporters. Taurine partly rescued these changes, hence underscoring the importance of taurine in development.
Subject(s)
Diet, Protein-Restricted/adverse effects , Muscle, Skeletal/drug effects , Prenatal Exposure Delayed Effects , Taurine/pharmacology , Transcriptome/genetics , Animals , Female , Male , Mitochondria/drug effects , Muscle, Skeletal/metabolism , Pregnancy , Rats , Rats, WistarSubject(s)
Diet, High-Fat , Glucose/metabolism , Lipid Metabolism/drug effects , Mitochondria, Muscle/drug effects , Taurine/pharmacology , Animals , Blood Glucose/drug effects , Blood Glucose/metabolism , Cell Respiration/drug effects , Dietary Supplements , Glucose Intolerance/etiology , Glucose Intolerance/metabolism , Lipids/blood , Male , Mitochondria, Muscle/physiology , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Rats , Rats, WistarSubject(s)
Fructose/pharmacology , Homeostasis/drug effects , Taurine/metabolism , Animals , Diet , Dietary Carbohydrates/pharmacology , Dietary Supplements , Drinking/drug effects , Eating/drug effects , Eating/physiology , Liver/drug effects , Liver/metabolism , Male , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Rats , Rats, Wistar , Taurine/pharmacologyABSTRACT
To characterize mechanisms responsible for fat accumulation we used a selectively bred obesity-prone (OP) and obesity-resistant (OR) rat model where the rats were fed a Western diet for 76 days. Body composition was assessed by magnetic resonance imaging scans, and as expected, the OP rats developed a higher degree of fat accumulation compared with OR rats. Indirect calorimetry showed that the OP rats had higher respiratory exchange ratio (RER) compared with OR rats, indicating an impaired ability to oxidize fat. The OP rats had lower expression of carnitine palmitoyltransferase 1b in intra-abdominal fat, and higher expression of stearoyl-CoA desaturase 1 in subcutaneous fat compared with OR rats, which could explain the higher fat accumulation and RER values. Basal metabolic parameters were also examined in juvenile OP and OR rats before and during the introduction of the Western diet. Juvenile OP rats likewise had higher RER values, indicating that this trait may be a primary and contributing factor to their obese phenotype. When the adult obese rats were exposed to the orexigenic and adipogenic hormone ghrelin, we observed increased RER values in both OP and OR rats, while OR rats were more sensitive to the orexigenic effects of ghrelin as well as ghrelin-induced attenuation of activity and energy expenditure. Thus increased fat accumulation characterizing obesity may be caused by impaired oxidative capacity due to decreased carnitine palmitoyltransferase 1b levels in the white adipose tissue, whereas ghrelin sensitivity did not seem to be a contributing factor.
Subject(s)
Adiposity , Carnitine O-Palmitoyltransferase/metabolism , Energy Metabolism , Intra-Abdominal Fat/enzymology , Obesity/enzymology , Subcutaneous Fat/enzymology , Adiposity/drug effects , Animals , Calorimetry, Indirect , Carnitine O-Palmitoyltransferase/genetics , Diet, High-Fat , Disease Models, Animal , Down-Regulation , Eating , Energy Metabolism/drug effects , Gene Expression Regulation , Ghrelin/administration & dosage , Hypothalamus/enzymology , Insulin/blood , Intra-Abdominal Fat/drug effects , Intra-Abdominal Fat/physiopathology , Leptin/blood , Magnetic Resonance Imaging , Male , Muscle, Skeletal/enzymology , Obesity/blood , Obesity/etiology , Obesity/genetics , Obesity/physiopathology , Oxidation-Reduction , Rats , Subcutaneous Fat/drug effects , Subcutaneous Fat/physiopathology , Time Factors , Weight GainABSTRACT
BACKGROUND: Vitamin A has widespread effects on immune function and is therefore interesting in HIV-infection. Retinol-binding protein (RBP or RBP4) is a negative acute-phase protein and a marker of vitamin A status. Our aim was to investigate the association of RBP with HIV progression, infection with schistosomiasis, inflammatory cytokines, and mortality. METHODS: The study included 192 HIV-infected and 177 HIV-uninfected individuals from Mupfure in rural Zimbabwe. Of these, 208 were infected with Schistosoma haematobium, 27 with S. mansoni and 48 with both. Plasma RBP, HIV-RNA, CD4 cell count, haemoglobin, cytokines, clinical staging (CDC category), self-reported level of function (Karnoffsky Performance Score, KPS) and schistosomiasis status were assessed at baseline. Participants were followed up for survival 3-4 years post-enrolment. RESULTS: RBP levels were lower in HIV-infected individuals(p<0.0001). Among HIV-infected individuals, multivariable analysis showed RBP to be positively correlated with CD4 cell count(p=0.050), KPS(p=0.003), and haemoglobin(p<0.0001) and negatively correlated with HIV-RNA(p<0.0001), CDC category(p<0.0001), tumor necrosis factor-receptor II(p<0.0001) and interleukin(IL)-6(p=0.004), as well as with IL-8(p=0.005) and IL-10(p=0.003) for HIV-infected men. Furthermore, among HIV-infected individuals RBP correlated negatively with schistosomiasis(p=0.038) and intensity of infection: circulating anodic antigen(p=0.014), circulating cathodic antigen(p<0.0001) and faecal egg output(p=0.004). CONCLUSIONS: In HIV-infected individuals, RBP was negatively associated with levels of inflammatory markers, markers of HIV progression, infection with schistosomiasis and markers of schistosomal intensity.
Subject(s)
HIV Infections/diagnosis , HIV Infections/mortality , Inflammation/virology , Retinol-Binding Proteins, Plasma/analysis , Schistosomiasis/complications , Adult , Biomarkers/blood , Coinfection/diagnosis , Coinfection/mortality , Cytokines/blood , Disease Progression , Female , HIV Infections/complications , Humans , Inflammation/immunology , Male , Middle Aged , Rural Population , Schistosomiasis/diagnosis , Young Adult , Zimbabwe/epidemiologyABSTRACT
Laboring women with elevated body mass index (BMI) have an increased risk of inefficient uterine labor contractions, and despite the significance of mitochondria in the production of energy to drive uterine contractions, mitochondrial function in the myometrium with reference to the BMI has not been explored. The objective of this study was to determine whether obesity prior to and during gestation affects oxidative capacity and/or morphology of mitochondria in the myometrium at term in an animal model. Rat dams were fed for 47 days prior to impregnation and during gestation with either (1) a regular chow diet, (2) a low-fat high-carbohydrate diet, or (3) a high-fat low-carbohydrate diet (n = 10 in each group). On day 20 of gestation, corresponding to term pregnancy, total hysterectomy was performed with subsequent examination of the function and morphology of myometrial mitochondria. Body composition was regularly assessed by quantitative magnetic resonance imaging, and blood sampling was done prior to diet assignment, impregnation, and hysterectomy. Dams on the high-fat low-carbohydrate diet achieved higher fat percentage compared to rats on the regular chow diet (p < 0.05). Maximal oxygen consumption, phosphate/oxygen ratio, or the amount of mitochondria per gram of myometrium did not differ between the three feeding groups. Electron microscopic examinations did not reveal any morphological differences in mitochondria between groups; however, a previously undescribed subsarcolemmal localization of the mitochondria in the myocyte was identified. We did not find evidence of altered myometrial mitochondrial function or morphology in this animal model of obesity prior to and during pregnancy.
Subject(s)
Mitochondria/metabolism , Myometrium/metabolism , Obesity/metabolism , Pregnancy Complications/metabolism , Animals , Diet, High-Fat/adverse effects , Female , Mitochondria/ultrastructure , Myometrium/pathology , Oxygen Consumption , Pregnancy , Rats , Rats, WistarABSTRACT
The nonprotein amino acid taurine has been shown to counteract the negative effects of a high-fructose diet in rats with regard to insulin resistance and dyslipidemia. Here we examined the long-term (26 weeks) effects of oral taurine supplementation (2% in the drinking water) in fructose-fed Wistar rats.The combination of fructose and taurine caused a significant increase in fasting glucose compared to the control diet without changing hepatic phosphoenol pyruvate carboxykinase mRNA levels. The combination of fructose and taurine also improved glucose tolerance compared to control. Neither a high-fructose diet nor taurine supplementation induced significant changes in body weight, body fat or total calorie intake, fasting insulin levels, HOMA-IR, or insulin-induced Akt phosphorylation in skeletal muscle.Fructose alone caused a decrease in liver triglyceride content, with taurine supplementation preventing this. There was no effect of long-term fructose diet and/or taurine supplementation on plasma triglycerides, plasma nonesterified fatty acids, as well as plasma HDL, LDL, and total cholesterol.In conclusion, the study suggests that long-term taurine supplementation improves glucose tolerance and normalize hepatic triglyceride content following long-term fructose feeding. However, as the combination of taurine and fructose also increased fasting glucose levels, the beneficial effect of taurine supplementation towards amelioration of glucose intolerance and insulin resistance may be questionable.
Subject(s)
Feeding Behavior/drug effects , Fructose/pharmacology , Glucose/metabolism , Homeostasis/drug effects , Lipid Metabolism/drug effects , Taurine/pharmacology , Animals , Body Weight/drug effects , Dietary Supplements , Drinking Behavior/drug effects , Fructose/administration & dosage , Glucose Tolerance Test , Insulin/metabolism , Male , Rats , Rats, Wistar , Signal Transduction/drug effects , Taurine/administration & dosage , Time FactorsABSTRACT
BACKGROUND: Low birth weight is associated with an increased risk of developing impaired glucose tolerance, and eventually type 2 diabetes in adult life. Gestational protein restriction in rodents gives rise to a low birth weight phenotype in the offspring. RESULTS: We examined gene expression changes in liver and skeletal muscle of mice subjected to gestational protein restriction (LP) or not (NP), with or without taurine supplementation in the drinking water. LP offspring had a 40% lower birth weight than NP offspring, with taurine preventing half the decrease. Microarray gene expression analysis of newborn mice revealed significant changes in 2012 genes in liver and 967 genes in skeletal muscle of LP offspring. Taurine prevented 30% and 46% of these expression changes, respectively. Mitochondrial genes, especially those involved with oxidative phosphorylation, were more abundantly changed than other genes. The mitochondrial genes were mainly upregulated in liver, but downregulated in skeletal muscle, despite no change in citrate synthase activity in either tissue. Taurine preferentially rescued genes concerned with fatty acid metabolism in liver and with oxidative phosphorylation and TCA cycle in skeletal muscle. A mitochondrial signature was seen in the liver of NP offspring with taurine supplementation, as gene sets for mitochondrial ribosome as well as lipid metabolism were over represented in 4-week-old offspring subjected to gestational taurine supplementation. Likewise, 11 mitochondrial genes were significantly upregulated by gestational taurine supplementation in 4-week-old NP offspring. CONCLUSIONS: Gestational protein restriction resulted in lower birth weight associated with significant gene expression changes, which was different in liver and muscle of offspring. However, a major part of the birth weight decrease and the expression changes were prevented by maternal taurine supplementation, implying taurine is a key factor in determining expression patterns during development and in that respect also an important component in metabolic fetal programming.
Subject(s)
Diet, Protein-Restricted/adverse effects , Gene Expression Regulation , Genes, Mitochondrial , Liver , Mitochondria/genetics , Muscle, Skeletal , Taurine/administration & dosage , Animals , Animals, Newborn , Birth Weight , Body Weight/physiology , Citrate (si)-Synthase/metabolism , Female , Liver/cytology , Liver/physiology , Male , Mice , Mice, Inbred C57BL , Microarray Analysis , Mitochondria/metabolism , Muscle, Skeletal/cytology , Muscle, Skeletal/physiology , Pregnancy , Prenatal Exposure Delayed EffectsABSTRACT
US adults take between approximately 2,000 and approximately 12,000 steps per day, a wide range of ambulatory activity that at the low range could increase risk for developing chronic metabolic diseases. Dramatic reductions in physical activity induce insulin resistance; however, it is uncertain if and how low ambulatory activity would influence peripheral insulin sensitivity. We aimed to explore if healthy, nonexercising subjects who went from a normal to a low level of ambulatory activity for 2 wk would display metabolic alterations including reduced peripheral insulin sensitivity. To do this, ten healthy young men decreased their daily activity level from a mean of 10,501+/-808 to 1,344+/-33 steps/day for 2 wk. Hyperinsulinemic-euglycemic clamps with stable isotopes and muscle biopsies, maximal oxygen consumption (VO2 max) tests, and blood samples were performed pre- and postintervention. A reduced number of daily steps induced a significant reduction of 17% in the glucose infusion rate (GIR) during the clamp. This reduction was due to a decline in peripheral insulin sensitivity with no effect on hepatic endogenous glucose production. The insulin-stimulated ratio of pAktthr308/total Akt decreased after step reduction, with a post hoc analysis revealing the most pronounced effect after 4 h of insulin infusion. In addition, the 2-wk period induced a 7% decline in VO2 max (ml/min; cardiovascular fitness). Lean mass of legs, but not arms and trunk, decreased concurrently. Taken together, one possible biological cause for the public health problem of Type 2 diabetes has been identified. Reduced ambulatory activity for 2 wk in healthy, nonexercising young men significantly reduced peripheral insulin sensitivity, cardiovascular fitness, and lean leg mass.
Subject(s)
Blood Glucose/metabolism , Diabetes Mellitus, Type 2/etiology , Insulin Resistance , Insulin/metabolism , Motor Activity , Muscle, Skeletal/metabolism , Sedentary Behavior , Actigraphy/instrumentation , Adult , Biomarkers/blood , Biopsy , Body Composition , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/physiopathology , Energy Metabolism , Glucose Clamp Technique , Humans , Inflammation/etiology , Inflammation/metabolism , Inflammation/physiopathology , Inflammation Mediators/blood , Insulin/administration & dosage , Liver/metabolism , Liver/physiopathology , Male , Muscle, Skeletal/physiopathology , Oxygen Consumption , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Time Factors , Young AdultABSTRACT
UNLABELLED: We examined gene expression changes in liver and skeletal muscle of newborn mice subjected to a maternal low protein (LP) or normal protein (NP) diet during pregnancy, with or without taurine supplementation in the drinking water. LP offspring had a 40% lower birthweight than NP offspring, whereas it was reduced by only 20% with taurine supplementation. Microarray gene expression analysis revealed significant changes in 2012 genes in liver and 967 genes in skeletal muscle of LP offspring. By unknown mechanisms, taurine partially or fully prevented 30 and 46% of these expression changes, respectively. Mitochondrial genes, in particular genes associated with oxidative phosphorylation, were more abundantly changed in LP offspring, with primarily up-regulation in liver but down-regulation in skeletal muscle. In both tissues, citrate synthase activity remained unchanged. Taurine preferentially rescued changes in genes concerned with fatty acid metabolism in liver and with oxidative phoshorylation and tri carboxylic acid (TCA) cycle in skeletal muscle. ABBREVIATIONS: Gestational protein restriction resulted in lower birthweight associated with significant gene expression changes, which was different in liver and muscle of offspring. However, a major part of the birthweight decrease and the expression changes were prevented by maternal taurine supplementation, implying taurine is a key component in metabolic fetal programming.
Subject(s)
Animals, Newborn , Dietary Proteins/administration & dosage , Gene Expression Regulation , Liver/metabolism , Muscle, Skeletal/metabolism , Taurine/administration & dosage , Animals , Female , Mice , Mice, Inbred C57BL , PregnancyABSTRACT
BACKGROUND: The two inflammatory molecules, S100A8 and S100A9, form a heterodimer, calprotectin. Plasma calprotectin levels are elevated in various inflammatory disorders. We hypothesized that plasma calprotectin levels would be increased in subjects with low-grade systemic inflammation i.e. either obese subjects or subjects with type 2 diabetes. METHODOLOGY/PRINCIPAL FINDINGS: Plasma calprotectin and skeletal muscle S100A8 mRNA levels were measured in a cohort consisting of 199 subjects divided into four groups depending on presence or absence of type 2 diabetes (T2D), and presence or absence of obesity. There was a significant interaction between obesity and T2D (p = 0.012). Plasma calprotectin was increased in obese relative to non-obese controls (p<0.0001), whereas it did not differ between obese and non-obese patients with T2D (p = 0.62). S100A8 mRNA levels in skeletal muscle were not influenced by obesity or T2D. Multivariate regression analysis (adjusting for age, sex, smoking and HOMA2-IR) showed plasma calprotectin to be strongly associated with BMI, even when further adjusted for fitness, CRP, TNF-alpha or neutrophil number. CONCLUSIONS/SIGNIFICANCE: Plasma calprotectin is a marker of obesity in individuals without type 2 diabetes.
Subject(s)
Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/metabolism , Leukocyte L1 Antigen Complex/blood , Leukocyte L1 Antigen Complex/metabolism , Muscle, Skeletal/metabolism , Obesity/blood , Obesity/metabolism , Body Mass Index , Cross-Sectional Studies , Dimerization , Female , Humans , Inflammation , Male , Middle Aged , Multivariate Analysis , Neutrophils/metabolism , SmokingABSTRACT
In a sheep model, we investigated diet effects on skeletal muscle mitochondria to look for fetal programming. During pregnancy, ewes were fed normally (N) or were 50% food restricted (L) during the last trimester, and lambs born to these ewes received a normal (N) or a high-fat diet (H) for the first 6 mo of life. We examined mitochondrial function in permeabilized muscle fibers from the lambs at 6 mo of age (adolescence) and after 24 mo of age (adulthood). The postpartum H diet for the lambs induced an approximately 30% increase (P < 0.05) of mitochondrial VO(2max) and an approximately 50% increase (P < 0.05) of the respiratory coupling ratio (RCR) combined with lower levels of UCP3 and PGC-1alpha mRNA levels (P < 0.05). These effects proved to be reversible by a normal diet from 6 to 24 mo of age. However, at 24 mo, a long-term effect of the maternal gestational diet restriction (fetal programming) became evident as a lower VO(2max) (approximately 40%, P < 0.05), a lower state 4 respiration (approximately 40%, P < 0.05), and lower RCR ( approximately 15%, P < 0.05). Both PGC-1alpha and UCP3 mRNA levels were increased (P < 0.05). Two analyzed muscles were affected differently, and muscle rich in type I fibers was more susceptible to fetal programming. We conclude that fetal programming, seen as a reduced VO(2max) in adulthood, results from gestational undernutrition. Postnatal high-fat diet results in a pronounced RCR and VO(2max) increase in adolescence. However, these effects are reversible by diet correction and are not maintained in adulthood.
Subject(s)
Fetal Development/physiology , Maternal Nutritional Physiological Phenomena/physiology , Mitochondria, Muscle/physiology , Muscle, Skeletal/physiology , Sheep/physiology , Animals , Animals, Newborn , Biopsy , DNA, Mitochondrial/chemistry , DNA, Mitochondrial/genetics , Female , Malnutrition/metabolism , Mitochondria, Muscle/metabolism , Muscle Fibers, Skeletal/metabolism , Muscle Fibers, Skeletal/physiology , Muscle, Skeletal/metabolism , Oxygen Consumption/physiology , PPAR delta/genetics , PPAR delta/metabolism , Pregnancy , RNA, Messenger/chemistry , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction , Transcription Factors/genetics , Transcription Factors/physiology , Uncoupling Agents/metabolismABSTRACT
INTRODUCTION: Glutamine supplementation has beneficial effects on morbidity and mortality in critically ill patients, possibly in part through an attenuation of the proinflammatory cytokine response and a stimulation of heat shock protein (HSP)70. We infused either alanine-glutamine or saline during endotoxin challenge and measured plasma cytokines and HSP70 protein expression. METHODS: This crossover study, conducted in eight healthy young men, was double-blind, randomized and placebo-controlled. It was performed on 2 trial days, separated by a 4-week washout period. The volunteers received an infusion of alanine-glutamine at a rate of 0.025 g/(kg body weight x hour) or saline for 10 hours. After 2 hours, an intravenous bolus of Escherichia coli endotoxin (0.3 ng/kg) was administered. Blood samples were collected hourly for the following 8 hours. HSP70 protein content in isolated blood mononuclear cells (BMNCs) was measured by Western blotting. RESULTS: Plasma glutamine increased during alanine-glutamine infusion. Endotoxin reduced plasma glutamine during both trials, but plasma glutamine levels remained above baseline with alanine-glutamine supplementation. Endotoxin injection was associated with alterations in white blood cell and differential counts, tumour necrosis factor-alpha, IL-6, temperature and heart rate, but glutamine affected neither the endotoxin-induced change in these variables nor the expression of HSP70 in BMNCs. CONCLUSIONS: Endotoxin reduced plasma glutamine independently of alanine-glutamine infusion, but supplementation allows plasma levels to be maintained above baseline. Glutamine alters neither endotoxin-induced systemic inflammation nor early expression of HSP70 in BMNCs. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT 00780520.