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  • 1
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2015
    In:  Diabetologia Vol. 58, No. 3 ( 2015-3), p. 596-603
    In: Diabetologia, Springer Science and Business Media LLC, Vol. 58, No. 3 ( 2015-3), p. 596-603
    Type of Medium: Online Resource
    ISSN: 0012-186X , 1432-0428
    RVK:
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2015
    detail.hit.zdb_id: 1458993-X
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  • 2
    Online Resource
    Online Resource
    The Endocrine Society ; 2019
    In:  Journal of the Endocrine Society Vol. 3, No. Supplement_1 ( 2019-04-15)
    In: Journal of the Endocrine Society, The Endocrine Society, Vol. 3, No. Supplement_1 ( 2019-04-15)
    Type of Medium: Online Resource
    ISSN: 2472-1972
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2019
    detail.hit.zdb_id: 2881023-5
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  • 3
    Online Resource
    Online Resource
    Oxford University Press (OUP) ; 2019
    In:  Innovation in Aging Vol. 3, No. Supplement_1 ( 2019-11-08), p. S256-S256
    In: Innovation in Aging, Oxford University Press (OUP), Vol. 3, No. Supplement_1 ( 2019-11-08), p. S256-S256
    Abstract: Sarcopenia in aging leads to decreased muscle mass and physical-function (muscle strength and exercise capacity), but underlying mechanisms are not well understood and effective interventions are limited. We hypothesized that deficiency of the intracellular antioxidant protein Glutathione initiates a unique self-perpetuating metabolic cycle linking impaired fasted mitochondrial fuel-oxidation (fMFO) to protein catabolism and contributes to sarcopenia. We also hypothesized that supplementing the Glutathione precursor amino-acids glycine and N-acetylcysteine (GlyNAC) to correct Glutathione deficiency in older humans could reverse these defects. We tested our hypothesis in a 24-week open-label clinical-trial in 8 older-humans (74y) studied before and 24-weeks after GlyNAC supplementation, compared to 8 gender-matched unsupplemented young-controls (25y), and measured intracellular Glutathione concentrations, fMFO, physical-function, muscle-protein breakdown-rate (MPBR), gluconeogenesis, and urine nitrogen-excretion (UNE). GlyNAC supplementation in older humans corrected Glutathione deficiency and restored impaired fMFO (to levels in young controls), lowered MPBR and UNE, and increased physical-function, but did not affect gluconeogenesis or increase lean-mass, and suggest that muscle amino-acids are utilized for energy needs rather than glucose production. The absence of an increase in lean-mass suggests that GlyNAC should be combined with anabolic agents for potential benefits in combating sarcopenia. Overall, these results indicate the presence of a unique reversible metabolic cycle in older humans initiated by Glutathione deficiency which results in impaired mitochondrial fatty-acid and glucose oxidation, muscle-protein breakdown, UNE, and leads to deficiency of glycine and cysteine which re-initiate the cycle. These data have implications for improving physical-function and muscle mass in age-associated sarcopenia, and warrants further investigation.
    Type of Medium: Online Resource
    ISSN: 2399-5300
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
    detail.hit.zdb_id: 2905697-4
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  • 4
    In: Journal of Parenteral and Enteral Nutrition, Wiley, Vol. 40, No. 5 ( 2016-07), p. 656-671
    Abstract: Introduction: Parenteral nutrition (PN) in preterm infants leads to PN‐associated liver disease (PNALD). PNALD has been linked to serum accumulation of phytosterols that are abundant in plant oil but absent in fish oil emulsions. Hypothesis : Whether modifying the phytosterol and vitamin E composition of soy and fish oil lipid emulsions affects development of PNALD in preterm pigs. Methods : We measured markers of PNALD in preterm pigs that received 14 days of PN that included 1 of the following: (1) Intralipid (IL, 100% soybean oil), (2) Intralipid + vitamin E (ILE, d‐α‐tocopherol), (3) Omegaven (OV, 100% fish oil), or (4) Omegaven + phytosterols (PS, β‐sitosterol, campesterol, and stigmasterol). Results : Serum levels of direct bilirubin, gamma glutamyl transferase, serum triglyceride, low‐density lipoprotein, and hepatic triglyceride content were significantly lower ( P 〈 .05) in the ILE, OV, and PS compared to IL. Hepatic cholesterol 7‐hydroxylase and organic solute transporter–α expression was lower ( P 〈 .05) and portal plasma FGF19 higher in the ILE, OV, and PS vs IL. Hepatic expression of mitochondrial carnitine palmitoyltransferase 1A and microsomal cytochrome P450 2E1 fatty acid oxidation genes was higher in ILE, OV, and PS vs IL. In vivo 13 C‐CDCA clearance and expression of pregnane X receptor target genes, cytochrome P450 3A29 and multidrug resistance‐associated protein 2, were higher in ILE, OV, and PS vs IL. Conclusions : α‐tocopherol in Omegaven and added to Intralipid prevented serum and liver increases in biliary and lipidemic markers of PNALD in preterm piglets. The addition of phytosterols to Omegaven did not produce evidence of PNALD.
    Type of Medium: Online Resource
    ISSN: 0148-6071 , 1941-2444
    Language: English
    Publisher: Wiley
    Publication Date: 2016
    detail.hit.zdb_id: 2170060-6
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  • 5
    In: Journal of Parenteral and Enteral Nutrition, Wiley, Vol. 47, No. 2 ( 2023-02), p. 276-286
    Abstract: Extrauterine growth restriction is a common complication of preterm birth. Leucine (Leu) is an agonist for the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) signaling pathway that regulates translation initiation and protein synthesis in skeletal muscle. Previously, we showed that intermittent intravenous pulses of Leu to neonatal pigs born at term receiving continuous enteral nutrition increases muscle protein synthesis and lean mass accretion. Our objective was to determine the impact of intermittent intravenous pulses of Leu on muscle protein anabolism in preterm neonatal pigs administered continuous parenteral nutrition. Methods Following preterm delivery (on day 105 of 115 gestation), pigs were fitted with umbilical artery and jugular vein catheters and provided continuous parenteral nutrition. Four days after birth, pigs were assigned to receive intermittent Leu (1600 µmol kg −1  h −1 ; n  = 8) or alanine (1600 µmol kg −1  h −1 ; n  = 8) parenteral pulses every 4 h for 28 h. Anabolic signaling and fractional protein synthesis were determined in skeletal muscle. Results Leu concentration in the longissimus dorsi and gastrocnemius muscles increased in the leucine (LEU) group compared with the alanine (ALA) group ( P   〈  0.0001). Despite the Leu‐induced disruption of the Sestrin2·GATOR2 complex, which inhibits mTORC1 activation, in these muscles ( P   〈  0.01), the abundance of mTOR·RagA and mTOR·RagC was not different. Accordingly, mTORC1‐dependent activation of 4EBP1, S6K1, eIF4E·eIF4G, and protein synthesis were not different in any muscle between the LEU and ALA groups. Conclusion Intermittent pulses of Leu do not enhance muscle protein anabolism in preterm pigs supplied continuous parenteral nutrition.
    Type of Medium: Online Resource
    ISSN: 0148-6071 , 1941-2444
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2170060-6
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  • 6
    Online Resource
    Online Resource
    American Physiological Society ; 2008
    In:  Journal of Applied Physiology Vol. 104, No. 6 ( 2008-06), p. 1854-1855
    In: Journal of Applied Physiology, American Physiological Society, Vol. 104, No. 6 ( 2008-06), p. 1854-1855
    Type of Medium: Online Resource
    ISSN: 8750-7587 , 1522-1601
    RVK:
    RVK:
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2008
    detail.hit.zdb_id: 1404365-8
    SSG: 12
    SSG: 31
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  • 7
    Online Resource
    Online Resource
    American Physiological Society ; 2021
    In:  American Journal of Physiology-Endocrinology and Metabolism Vol. 321, No. 6 ( 2021-12-01), p. E795-E801
    In: American Journal of Physiology-Endocrinology and Metabolism, American Physiological Society, Vol. 321, No. 6 ( 2021-12-01), p. E795-E801
    Abstract: Gluconeogenesis (GNG), the formation of glucose from noncarbohydrate precursors, requires adenosine triphosphate (ATP). Previous studies have estimated the energetic cost of GNG in humans based on theoretical calculations of rates of GNG, moles of oxygen consumption by GNG, and average oxygen consumption. Few human studies have measured the energy expenditure (EE) due to GNG. We estimated EE attributable to GNG in patients with three insulin resistance conditions and high GNG rates (insulin receptor pathogenic variants, lipodystrophy, and type 2 diabetes) and obesity without diabetes. Fractional GNG was measured by incorporation of deuterium from body water into newly formed glucose, endogenous glucose production (EGP) as glucose appearance following administration of [6,6- 2 H 2 ]glucose, and total GNG as fractional GNG × EGP. EE was measured by indirect calorimetry and compared with predicted EE from the Mifflin St. Jeor equation. EE attributable to GNG was estimated using linear regression after accounting for age and fat-free mass (FFM). EE in patients with insulin resistance was significantly higher than predicted by the Mifflin St. Jeor equation. GNG correlated with resting EE (REE). EE attributable to GNG in patients with insulin resistance was almost one-third of REE, substantially higher than theorized in healthy subjects. Our findings demonstrate that GNG is a significant contributor to EE in insulin-resistant states. Prediction equations may underestimate caloric needs in patients with insulin resistance. Therefore, targeting caloric needs to account for higher EE due to increased GNG should be considered in energy balance studies in patients with insulin resistance. NEW & NOTEWORTHY Gluconeogenesis is an energy-requiring process that is upregulated in diabetes, contributing to hyperglycemia. Previous studies have estimated that gluconeogenesis accounts for less than 10% of resting energy expenditure. This study estimates the energy expenditure attributable to gluconeogenesis in uncommon and severe forms of insulin resistance and common, milder forms of insulin resistance. In these populations, gluconeogenesis accounts for almost one-third of resting energy expenditure, substantially higher than previously theorized in the literature.
    Type of Medium: Online Resource
    ISSN: 0193-1849 , 1522-1555
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2021
    detail.hit.zdb_id: 1477331-4
    SSG: 12
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  • 8
    Online Resource
    Online Resource
    American Physiological Society ; 2009
    In:  American Journal of Physiology-Endocrinology and Metabolism Vol. 296, No. 6 ( 2009-06), p. E1239-E1250
    In: American Journal of Physiology-Endocrinology and Metabolism, American Physiological Society, Vol. 296, No. 6 ( 2009-06), p. E1239-E1250
    Abstract: We recently showed that the developing gut is a significant site of methionine transmethylation to homocysteine and transsulfuration to cysteine. We hypothesized that sulfur amino acid (SAA) deficiency would preferentially reduce mucosal growth and antioxidant function in neonatal pigs. Neonatal pigs were enterally fed a control or an SAA-free diet for 7 days, and then whole body methionine and cysteine kinetics were measured using an intravenous infusion of [1- 13 C;methyl- 2 H 3 ]methionine and [ 15 N]cysteine. Body weight gain and plasma methionine, cysteine, homocysteine, and taurine and total erythrocyte glutathione concentrations were markedly decreased (−46% to −85%) in SAA-free compared with control pigs. Whole body methionine and cysteine fluxes were reduced, yet methionine utilization for protein synthesis and methionine remethylation were relatively preserved at the expense of methionine transsulfuration, in response to SAA deficiency. Intestinal tissue concentrations of methionine and cysteine were markedly reduced and hepatic levels were maintained in SAA-free compared with control pigs. SAA deficiency increased the activity of methionine metabolic enzymes, i.e., methionine adenosyltransferase, methionine synthase, and cystathionine β-synthase, and S-adenosylmethionine concentration in the jejunum, whereas methionine synthase activity increased and S-adenosylmethionine level decreased in the liver. Small intestine weight and protein and DNA mass were lower, whereas liver weight and DNA mass were unchanged, in SAA-free compared with control pigs. Dietary SAA deficiency induced small intestinal villus atrophy, lower goblet cell numbers, and Ki-67-positive proliferative crypt cells in association with lower tissue glutathione, especially in the jejunum. We conclude that SAA deficiency upregulates intestinal methionine cycle activity and suppresses epithelial growth in neonatal pigs.
    Type of Medium: Online Resource
    ISSN: 0193-1849 , 1522-1555
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2009
    detail.hit.zdb_id: 1477331-4
    SSG: 12
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  • 9
    Online Resource
    Online Resource
    American Physiological Society ; 2009
    In:  American Journal of Physiology-Endocrinology and Metabolism Vol. 297, No. 5 ( 2009-11), p. E1046-E1055
    In: American Journal of Physiology-Endocrinology and Metabolism, American Physiological Society, Vol. 297, No. 5 ( 2009-11), p. E1046-E1055
    Abstract: To determine the rates of methionine splanchnic uptake and utilization in critically ill pediatric patients we used two kinetic models: the plasma methionine enrichment and the “intracellular” homocysteine enrichment. Twenty four patients, eight infants, eight children, and eight adolescents, were studied. They received simultaneous, primed, constant, intravenous infusions of l-[ 2 H 3 ]methylmethionine and enteral l-[1- 13 C]methionine. The ratio of [ 13 C]homocysteine to [ 13 C]methionine enrichment was 1.0 ± 0.15, 0.80 ± 0.20, and 0.66 ± 0.10, respectively, for the infants, children, and adolescents, and it was different between the infants and adolescents ( P 〈 0.01). Methionine splanchnic uptake was 63, 45, and 36%, respectively, in the infants, children, and adolescents, and it was higher ( P 〈 0.01) in the infants compared with the adolescents. The infants utilized 73% of methionine flux for nonoxidative disposal, while 27% was used for transulfuration ( P 〈 0.001). Conversely, in the adolescents, 40% was utilized for nonoxidative disposal, while 60% was used for transulfuration. There is ontogeny on the rates of methionine splanchnic uptake and on the fate of methionine utilization in critically ill children, with greater methionine utilization for synthesis of proteins and methionine-derived compounds ( P 〈 0.01) and decreased transulfuration rates in the infants ( P 〈 0.01), while the opposite was observed in the adolescents. The plasma model underestimated methionine kinetics in children and adolescents but not in the infants, suggesting lesser dilution and greater compartmentation of methionine metabolism in the infant population. All patients were in negative methionine balance, indicating that the current enteral nutritional support is inadequate in these patients.
    Type of Medium: Online Resource
    ISSN: 0193-1849 , 1522-1555
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2009
    detail.hit.zdb_id: 1477331-4
    SSG: 12
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  • 10
    Online Resource
    Online Resource
    American Physiological Society ; 2022
    In:  American Journal of Physiology-Gastrointestinal and Liver Physiology Vol. 322, No. 1 ( 2022-01-01), p. G117-G133
    In: American Journal of Physiology-Gastrointestinal and Liver Physiology, American Physiological Society, Vol. 322, No. 1 ( 2022-01-01), p. G117-G133
    Abstract: The tissue-specific molecular mechanisms involved in perinatal liver and intestinal farnesoid X receptor (FXR)-fibroblast growth factor 19 (FGF19) signaling are poorly defined. Our aim was to establish how gestational age and feeding status affect bile acid synthesis pathway, bile acid pool size, ileal response to bile acid stimulation, genes involved in bile acid-FXR-FGF19 signaling and plasma FGF19 in neonatal pigs. Term ( n = 23) and preterm ( n = 33) pigs were born via cesarean section at 100% and 90% gestation, respectively. Plasma FGF19, hepatic bile acid and oxysterol profiles, and FXR target gene expression were assessed in pigs at birth and after a bolus feed on day 3 of life. Pig ileal tissue explants were used to measure signaling response to bile acids. Preterm pigs had smaller, more hydrophobic bile acid pools, lower plasma FGF19, and blunted FXR-mediated ileal response to bile acid stimulation than term pigs. GATA binding protein 4 (GATA-4) expression was higher in jejunum than ileum and was higher in preterm than term pig ileum. Hepatic oxysterol analysis suggested dominance of the alternative pathway of bile acid synthesis in neonates, regardless of gestational age and persists in preterm pigs after feeding on day 3. These results highlight the tissue-specific molecular basis for the immature enterohepatic bile acid signaling via FXR-FGF19 in preterm pigs and may have implications for disturbances of bile acid homeostasis and metabolism in preterm infants. NEW & NOTEWORTHY Our results show that the lower hepatic bile acid synthesis and ileum FXR-FGF19 pathway responsiveness to bile acids contribute to low-circulating FGF19 in preterm compared with term neonatal pigs. The molecular mechanism explaining immature or low-ileum FXR-FGF19 signaling may be linked to developmental patterning effects of GATA-4.
    Type of Medium: Online Resource
    ISSN: 0193-1857 , 1522-1547
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2022
    detail.hit.zdb_id: 1477329-6
    SSG: 12
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