scholarly journals Systemic, Cerebral and Skeletal Muscle Ketone Body and Energy Metabolism During Acute Hyper-D-β-Hydroxybutyratemia in Post-Absorptive Healthy Males

2015 ◽  
Vol 100 (2) ◽  
pp. 636-643 ◽  
Author(s):  
Kristian H. Mikkelsen ◽  
Thomas Seifert ◽  
Niels H. Secher ◽  
Thomas Grøndal ◽  
Gerrit van Hall
Keyword(s):  
Skeletal Muscle ◽  
Energy Metabolism ◽  
Ketone Bodies ◽  
Glucose Production ◽  
Epileptic Seizures ◽  
Energy Utilization ◽  
Glucose Turnover ◽  
Dependent Manner ◽  
Oxidation Rates ◽  
Healthy Males

Abstract Context: Ketone bodies are substrates during fasting and when on a ketogenic diet not the least for the brain and implicated in the management of epileptic seizures and dementia. Moreover, D-β-hydroxybutyrate (HOB) is suggested to reduce blood glucose and fatty acid levels. Objectives: The objectives of this study were to quantitate systemic, cerebral, and skeletal muscle HOB utilization and its effect on energy metabolism. Design: Single trial. Setting: Hospital. Participant: Healthy post-absorptive males (n = 6). Interventions: Subjects were studied under basal condition and three consecutive 1-hour periods with a 3-, 6-, and 12-fold increased HOB concentration via HOB infusion. Main Outcome Measures: Systemic, cerebral, and skeletal muscle HOB kinetics, oxidation, glucose turnover, and lipolysis via arterial, jugular, and femoral venous differences in combination with stable isotopically labeled HOB, glucose, and glycerol, infusion. Results: An increase in HOB from the basal 160–450 μmol/L elicited 14 ± 2% reduction (P = .03) in glucose appearance and 37 ± 4% decrease (P = .03) in lipolytic rate while insulin and glucagon were unchanged. Endogenous HOB appearance was reduced in a dose-dependent manner with complete inhibition at the highest HOB concentration (1.7 mmol/L). Cerebral HOB uptake and subsequent oxidation was linearly related to the arterial HOB concentration. Resting skeletal muscle HOB uptake showed saturation kinetics. Conclusion: A small increase in the HOB concentration decreases glucose production and lipolysis in post-absorptive healthy males. Moreover, cerebral HOB uptake and oxidation rates are linearly related to the arterial HOB concentration of importance for modifying brain energy utilization, potentially of relevance for patients with epileptic seizures and dementia.

Regulation on Energy Metabolism and Protection on Mitochondria of Panax Ginseng Polysaccharide

2009 ◽  
Vol 37 (06) ◽  
pp. 1139-1152 ◽  
Author(s):  
Xing-Tai Li ◽  
Rui Chen ◽  
Li-Ming Jin ◽  
Hui-Ying Chen
Keyword(s):  
Skeletal Muscle ◽  
Energy Metabolism ◽  
Panax Ginseng ◽  
Chronic Hypoxia ◽  
Energy Charge ◽  
Liver Cells ◽  
Adenylate Energy Charge ◽  
Dependent Manner ◽  
Lipid Peroxidation Product ◽  
Ginseng Polysaccharide

Panax ginseng C A Meyer (PG) is one of the most popular qi-invigorating herbal medicine and has been used to promote health, vitality, and longevity in China. Although PG has been used in traditional Chinese medicine for millennia, its qi-invigorating activities still lack convincing evidence. We investigated the effects of Panax ginseng polysaccharide (PGP) on energy metabolism and mitochondrial protection. The chronic hypoxia model was set up. Lipid peroxidation product malondialdehyde (MDA) was assayed by thiobarbituric acid (TBA) colorimetry. Mice liver mitochondria were isolated by differential centrifugation. The spectrophotometric method was used to measure the swelling of mitochondria. The levels of adenosine triphosphate (ATP), adenosine diphosphate (ADP) and adenosine monophosphate (AMP) in liver cells were determined by reversed-phase high performance liquid chromatography (RP-HPLC), adenylate energy charge (AEC), total adenylate pool (TAP), ATP/ADP and ATP/AMP ratio were calculated. The creatine kinase (CK) activities in mice skeletal muscle were determined by a commercial monitoring kit. The result showed that PGP could inhibit mitochondrial injury and swelling induced by Fe 2+-L-Cys in a concentration-dependent manner. PGP which was administered by oral gavage daily for 10 days could inhibit the formation of MDA in mice brain, increase levels of ATP, ADP, TAP and AEC, ratio of ATP/ADP and ATP/AMP in liver cells, increase CK activities in mice skeletal muscle under chronic hypoxia condition. These results indicate that PGP protect mitochondria by inhibiting mitochondrial swelling, and improving energy metabolism. PGP functions as a preventive antioxidant by increasing CK activities. Therefore, PGP had the pharmaceutical activities of antihypoxia, antioxidation and improving energy status.

Insulin resistance, but normal basal rates of glucose production in patients with newly diagnosed mild diabetes mellitus

1991 ◽  
Vol 124 (6) ◽  
pp. 637-645 ◽  
Author(s):  
Ole Hother-Nielsen ◽  
Henning Beck-Nielsen
Keyword(s):  
Diabetes Mellitus ◽  
Plasma Glucose ◽  
Glucose Utilization ◽  
Ketone Bodies ◽  
Glucose Production ◽  
Glucose Turnover ◽  
Diabetic Patients ◽  
Newly Diagnosed ◽  
Turnover Rates ◽  
Mild Diabetes

Abstract. Fasting hyperglycemia in Type II (non-insulin-dependent) diabetes has been suggested to be due to hepatic overproduction of glucose and reduced glucose clearance. We studied 22 patients (10 lean and 12 obese) with newly diagnosed mild diabetes mellitus (fasting plasma glucose <15 mmol/l, urine ketone bodies <1 mmol/l), and two age- and weight-matched groups of non-diabetic control subjects. Glucose turnover rates and sensitivity to insulin were determined using adjusted primed-continuous [3-3H]glucose infusion and the hyperinsulinemic euglycemic clamp technique. Insulin-stimulated glucose utilization was reduced in both diabetic groups (lean patients: 313±35 vs 531±22 mg·m−2·min−1, p<0.01;obesepatients:311±28vs453±26mg·m−2·min−1, p<0.01). Basal plasma glucose concentrations decreased 0.43±0.05 mmol/l per h (p<0.01). Glucose production rates were smaller than glucose utilization rates (lean patients: 87±3 vs 94±3 mg·m−2·min−1, p<0.01; obese patients: 79±5 vs 88±5 mg·m−2 ·min−1, p<0.01), were not correlated to basal glucose or insulin concentrations, and were not different from normal (lean controls: 87±4 mg·−2·min−1; obese controls: 80±5 mg·m−2·min−1). These results suggest that the basal state in the diabetic patients is a compensated condition where glucose turnover rates are maintained near normal despite defects in insulin sensitivity.

Role of fat-derived substrates in the regulation of gluconeogenesis during fasting

1996 ◽  
Vol 270 (5) ◽  
pp. E822-E830 ◽  
Author(s):  
F. Fery ◽  
L. Plat ◽  
C. Melot ◽  
E. O. Balasse
Keyword(s):  
Ketone Body ◽  
Ketone Bodies ◽  
Glucose Turnover ◽  
Oxidation Rates ◽  
Relative Contribution ◽  
Beta Hydroxybutyrate ◽  
Hormonal Milieu ◽  
Body Concentration

To determine the role of fat-derived substrates in the regulation of glucose metabolism during fasting, glucose turnover, urea nitrogen production, alanine conversion to glucose, and substrate oxidation rates were measured in 34 normal 4-day-fasted volunteers treated with the antilipolytic drug acipimox or placebo for 8 h. The approximately 50% inhibition of lipolysis induced by acipimox increased glucose concentration and production, respectively, by approximately 35 and approximately 30%, whereas the protein breakdown and the amount of alanine converted to glucose were increased, respectively, by approximately 70 and approximately 85%. Insulin levels were reduced by approximately 40%, cortisol levels doubled, and growth hormone concentration increased sevenfold. The relative contribution of free fatty acid (FFA) and ketone body lowering to the observed response was evaluated in nine acipimox-treated subjects in whom ketone body concentration was clamped with an intravenous beta-hydroxybutyrate infusion. The results of these experiments suggest that, during fasting, both FFA and ketone bodies tend to suppress gluconceogenesis and to protect the protein stores. FFA seem to exert their effects mainly through their ability to modulate the hormonal milieu (especially insulin), whereas ketone bodies seem to act mainly by other mechanisms. Thus the widespread view according to which FFA exert a stimulatory role on gluconeogenesis does not apply to the fasting state in vivo.

A comparison of fuel preferences of mitochondria from vertebrates and invertebrates

1990 ◽  
Vol 68 (7) ◽  
pp. 1337-1349 ◽  
Author(s):  
C. D. Moyes ◽  
R. K. Suarez ◽  
P. W. Hochachka ◽  
J. S. Ballantyne
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Fatty Acids ◽  
Energy Metabolism ◽  
Ketone Bodies ◽  
Mitochondrial Enzymes ◽  
Tissue Specific ◽  
Isolated Mitochondria ◽  
Mitochondrial Oxidation ◽  
Aerobic Energy Metabolism

Knowledge of tissue-specific mitochondrial properties is important in understanding cellular aerobic energy metabolism. Studies employing isolated mitochondria offer the advantage of direct and controlled manipulation of extramitochondrial conditions, while minimizing disruption of interactions between mitochondrial enzymes, transporters, and membranes. In this review, we compare the oxidative properties of mitochondria isolated from liver, heart, and skeletal muscle of vertebrates and invertebrates. The observed differences between tissues and species in the capacities for mitochondrial oxidation of fatty acids, ketone bodies, pyruvate, and amino acids reflect fundamentally different adaptations for the assimilation, storage, and utilization of metabolic fuels.

scholarly journals Minor Role of Ketone Bodies in Energy Metabolism by Skeletal Muscle Tissue During the Postoperative Course

1988 ◽  
Vol 207 (1) ◽  
pp. 95-101 ◽  
Author(s):  
WOLFGANG H. HARTL ◽  
KARL-WALTER JAUCH ◽  
RAINER KIMMIG ◽  
MATTHIAS WICKLMAYR ◽  
BERNULF GÜNTHER ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Energy Metabolism ◽  
Muscle Tissue ◽  
Ketone Bodies ◽  
Skeletal Muscle Tissue ◽  
Minor Role ◽  
Postoperative Course

Alterations of fasting glucose and fat metabolism in intrauterine growth-retarded newborn dogs

1989 ◽  
Vol 256 (3) ◽  
pp. E380-E385 ◽  
Author(s):  
R. M. Kliegman
Keyword(s):  
Growth Retardation ◽  
Ketone Bodies ◽  
Energy Charge ◽  
Glucose Production ◽  
Glucose Turnover ◽  
Hepatic Glycogen ◽  
Intrauterine Growth ◽  
Glucose Levels ◽  
Lower Glucose ◽  
Gluconeogenesis From Alanine

Maternal nutritional deprivation resulted in reduced fetal weight at term gestation (251 +/- 7 vs. 277 +/- 7 g, P less than 0.01) in newborn dogs. Growth-retarded pups developed lower blood glucose levels after 3, 6, and 9 h of neonatal fasting, reduced plasma levels of free fatty acids (FFA) at 9 and 24 h, and lower ketone bodies at 24 h compared with age-matched newborn control pups. Systemic rates of palmitate and alanine turnover were not affected, but systemic glucose turnover was reduced for 3-9 h after birth. The rate of alanine incorporation into glucose from 3 to 9 h was also reduced in growth-retarded pups compared with timed controls. Paradoxically, the rate of incorporation of palmitate into triglycerides was augmented in the smaller growth-retarded pups. Hepatic glycogen content was reduced at every time in the study among growth-retarded pups, whereas the rates of glycogenolysis between birth and 24 h were equivalent in the two pup groups. In contrast, hepatic triglyceride levels were augmented throughout the study in pups with growth retardation. Maternal starvation and lower glucose levels resulted in a lower hepatic energy charge, and augmented cytoplasmic and mitochondrial NAD-to-NADH ratios in intrauterine growth-retarded pups. These data suggest that intrauterine growth retardation in dogs results in fasting neonatal hypoglycemia that is due in part to reduced systemic glucose production. We speculate that reduced rates of gluconeogenesis from alanine and reduced oxidation of alternate fuels such as FFA contribute to hypoglycemia. FFA recycling to triglyceride synthesis rather than oxidative pathways may contribute to the observed reduction of circulating glucose levels.

Mechanisms of ageing metabolic decline revealed by targeted metabolomics and energy metabolism in NAD+ depleted skeletal muscle

2016 ◽  
Author(s):  
Rachel Fletcher ◽  
Lucy Oldacre-Bartley ◽  
Craig Doig ◽  
Charles Brenner ◽  
Gareth Lavery
Keyword(s):  
Skeletal Muscle ◽  
Energy Metabolism ◽  
Targeted Metabolomics

scholarly journals Systemic oxidative stress is associated with lower aerobic capacity and impaired skeletal muscle energy metabolism in heart failure patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Takashi Yokota ◽  
Shintaro Kinugawa ◽  
Kagami Hirabayashi ◽  
Mayumi Yamato ◽  
Shingo Takada ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Skeletal Muscle ◽  
Energy Metabolism ◽  
Aerobic Capacity ◽  
Plantar Flexion ◽  
Exercise Intolerance ◽  
Whole Body ◽  
Resonance Spectroscopy ◽  
Systemic Oxidative Stress

AbstractOxidative stress plays a role in the progression of chronic heart failure (CHF). We investigated whether systemic oxidative stress is linked to exercise intolerance and skeletal muscle abnormalities in patients with CHF. We recruited 30 males: 17 CHF patients, 13 healthy controls. All participants underwent blood testing, cardiopulmonary exercise testing, and magnetic resonance spectroscopy (MRS). The serum thiobarbituric acid reactive substances (TBARS; lipid peroxides) were significantly higher (5.1 ± 1.1 vs. 3.4 ± 0.7 μmol/L, p < 0.01) and the serum activities of superoxide dismutase (SOD), an antioxidant, were significantly lower (9.2 ± 7.1 vs. 29.4 ± 9.7 units/L, p < 0.01) in the CHF cohort versus the controls. The oxygen uptake (VO2) at both peak exercise and anaerobic threshold was significantly depressed in the CHF patients; the parameters of aerobic capacity were inversely correlated with serum TBARS and positively correlated with serum SOD activity. The phosphocreatine loss during plantar-flexion exercise and intramyocellular lipid content in the participants' leg muscle measured by 31phosphorus- and 1proton-MRS, respectively, were significantly elevated in the CHF patients, indicating abnormal intramuscular energy metabolism. Notably, the skeletal muscle abnormalities were related to the enhanced systemic oxidative stress. Our analyses revealed that systemic oxidative stress is related to lowered whole-body aerobic capacity and skeletal muscle dysfunction in CHF patients.

scholarly journals Atorvastatin impairs liver mitochondrial function in obese Göttingen Minipigs but heart and skeletal muscle are not affected

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Liselotte Bruun Christiansen ◽  
Tine Lovsø Dohlmann ◽  
Trine Pagh Ludvigsen ◽  
Ewa Parfieniuk ◽  
Michal Ciborowski ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Function ◽  
Citrate Synthase ◽  
Obese Group ◽  
Control Group ◽  
Dependent Manner ◽  
Respiratory Capacity ◽  
Protein Carbonyl Content ◽  
Functional Changes ◽  
Mitochondrial Respiratory

AbstractStatins lower the risk of cardiovascular events but have been associated with mitochondrial functional changes in a tissue-dependent manner. We investigated tissue-specific modifications of mitochondrial function in liver, heart and skeletal muscle mediated by chronic statin therapy in a Göttingen Minipig model. We hypothesized that statins enhance the mitochondrial function in heart but impair skeletal muscle and liver mitochondria. Mitochondrial respiratory capacities, citrate synthase activity, coenzyme Q10 concentrations and protein carbonyl content (PCC) were analyzed in samples of liver, heart and skeletal muscle from three groups of Göttingen Minipigs: a lean control group (CON, n = 6), an obese group (HFD, n = 7) and an obese group treated with atorvastatin for 28 weeks (HFD + ATO, n = 7). Atorvastatin concentrations were analyzed in each of the three tissues and in plasma from the Göttingen Minipigs. In treated minipigs, atorvastatin was detected in the liver and in plasma. A significant reduction in complex I + II-supported mitochondrial respiratory capacity was seen in liver of HFD + ATO compared to HFD (P = 0.022). Opposite directed but insignificant modifications of mitochondrial respiratory capacity were seen in heart versus skeletal muscle in HFD + ATO compared to the HFD group. In heart muscle, the HFD + ATO had significantly higher PCC compared to the HFD group (P = 0.0323). In the HFD group relative to CON, liver mitochondrial respiration decreased whereas in skeletal muscle, respiration increased but these changes were insignificant when normalizing for mitochondrial content. Oral atorvastatin treatment in Göttingen Minipigs is associated with a reduced mitochondrial respiratory capacity in the liver that may be linked to increased content of atorvastatin in this organ.

734 A novel NQO1 specific anti-tumor agent, SBSC-S3001, selectively regresses the growth of tumors with high NQO1 expression

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A778-A778
Author(s):  
Minhyuk Yun ◽  
Goo-Young Kim ◽  
Sang Woo Jo ◽  
Changhoon In ◽  
Gyu-Young Moon ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Cancer Cells ◽  
Poor Prognosis ◽  
High Expression ◽  
List Type ◽  
Dependent Manner ◽  
Breast Cancers ◽  
Quinone Oxidoreductase ◽  
Key Enzymes

BackgroundNAD(P)H-quinone oxidoreductase 1 (NQO1) is a cytosolic two-electron oxidoreductase overexpressed in many types of cancers, including breast cancer, pancreatic cancer, colorectal cancer, cholangiocarcinoma, uterine cervical cancer, melanoma, and lung cancer.1Up-regulation of NQO1 protects cells from oxidative stress and various cytotoxic quinones and is associated with late clinical stage, poor prognosis and lymph node metastasis.2 3 NQO1 increases stability of HIF-1α protein, which has been implicated in survival, proliferation, and malignance of cancer.1 Therefore, accumulating evidences suggest NQO1 as a promising therapeutic target for cancer. Accordingly, we have characterized the effect of a novel synthetic NQO1 substrate SBSC-S3001, and demonstrated its selective cytotoxic effects in cancer cells with high expression of NQO1.MethodsIn vitro cytotoxicity was determined by sulforhodamine B (SRB) assay in cancer cells with high NQO1 expression and CRISPR-mediated NQO1 knockout cells. The effect of SBSC-S3001 on the energy metabolism pathway was evaluated by western blot analysis of metabolism associated proteins from NQO1-overexpressed cancer cells treated with the compound for 24 hours. In vivo anti-tumor activity was evaluated in MC38 syngeneic and DLD-1 orthotopic mice models.ResultsSBSC-S3001 exhibited selective cytotoxicity in cancer cells with high expression of NQO1 in a dose-dependent manner. The cytotoxicity was observed in both normoxia and hypoxia conditions, correlating with the energy metabolism, mitochondrial biogenesis, and cancer proliferative pathways. Also, stronger cytotoxicity was observed in NQO1-overexpressed cancer cells treated with SBSC-S3001 compared to beta-lapachone and analogue treatment.4 When evaluated in vivo, SBSC-S3001 effectively inhibited the growth of syngeneic and orthotopic tumors when administered as a monotherapy. SBSC-S3001 treatment associated with reduction in key enzymes of the glycolytic pathway (LDHa and GAPDH) and HIF-1α and increase in levels of mitochondrial oxidative phosphorylation (OXPHOS) complex.ConclusionsTreatment of SBSC-S3001, a novel, NQO1-specific substrate reduces HIF-1α and key enzymes associated with glycolysis and suppresses the growth of tumors overexpressing NQO1. Further characterization of SBSC-S3001 as a novel metabolic anti-cancer agent for cancers with NQO1 overexpression is warranted.Ethics ApprovalThe study was approved by Samyang Biopharmaceuticals Institution’s Ethics Board, approval number SYAU2031.ReferencesOh ET, Kim JW, Kim JMet. al., NQO1 inhibits proteasome-mediated degradation of HIF-1α. Nat Commun 2016; 14:13593.Ma, Y. et al. NQO1 overexpression is associated with poor prognosis in squamous cell carcinoma of the uterine cervix. BMC Cancer 2014;14: 414Yang, Y. et al. Clinical implications of high NQO1 expression in breast cancers. J. Exp. Clin. Cancer Res 2014;33:144.Yang Y, Zhou X, Xu M, et al., β-lapachone suppresses tumour progression by inhibiting epithelial-to-mesenchymal transition in NQO1-positive breast cancers. Sci Rep 2017;7:2681.

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