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  • Proceedings of the National Academy of Sciences  (4)
  • 1
    Online Resource
    Online Resource
    Effect of a ketogenic diet on hepatic steatosis and hepatic mitochondrial metabolism in nonalcoholic fatty liver disease
    Proceedings of the National Academy of Sciences ; 2020
    In:  Proceedings of the National Academy of Sciences Vol. 117, No. 13 ( 2020-03-31), p. 7347-7354
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 117, No. 13 ( 2020-03-31), p. 7347-7354
    Abstract: Weight loss by ketogenic diet (KD) has gained popularity in management of nonalcoholic fatty liver disease (NAFLD). KD rapidly reverses NAFLD and insulin resistance despite increasing circulating nonesterified fatty acids (NEFA), the main substrate for synthesis of intrahepatic triglycerides (IHTG). To explore the underlying mechanism, we quantified hepatic mitochondrial fluxes and their regulators in humans by using positional isotopomer NMR tracer analysis. Ten overweight/obese subjects received stable isotope infusions of: [D 7 ]glucose, [ 13 C 4 ]β-hydroxybutyrate and [3- 13 C]lactate before and after a 6-d KD. IHTG was determined by proton magnetic resonance spectroscopy ( 1 H-MRS). The KD diet decreased IHTG by 31% in the face of a 3% decrease in body weight and decreased hepatic insulin resistance (−58%) despite an increase in NEFA concentrations (+35%). These changes were attributed to increased net hydrolysis of IHTG and partitioning of the resulting fatty acids toward ketogenesis (+232%) due to reductions in serum insulin concentrations (−53%) and hepatic citrate synthase flux (−38%), respectively. The former was attributed to decreased hepatic insulin resistance and the latter to increased hepatic mitochondrial redox state (+167%) and decreased plasma leptin (−45%) and triiodothyronine (−21%) concentrations. These data demonstrate heretofore undescribed adaptations underlying the reversal of NAFLD by KD: That is, markedly altered hepatic mitochondrial fluxes and redox state to promote ketogenesis rather than synthesis of IHTG.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1922344117
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2020
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Reversal of muscle insulin resistance by weight reduction in young, lean, insulin-resistant offspring of parents with type 2 diabetes
    Proceedings of the National Academy of Sciences ; 2012
    In:  Proceedings of the National Academy of Sciences Vol. 109, No. 21 ( 2012-05-22), p. 8236-8240
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 21 ( 2012-05-22), p. 8236-8240
    Abstract: To examine the role of intramyocellular lipid (IMCL) accumulation as well as circulating cytokines, branched-chain amino acids and acylcarnitines in the pathogenesis of muscle insulin resistance in healthy, young, lean insulin-resistant offspring of parents with type 2 diabetes (IR offspring), we measured these factors in plasma and used 1 H magnetic resonance spectroscopy to assess IMCL content and hyperinsulinemic-euglycemic clamps using [6,6- 2 H 2 ] glucose to assess rates of insulin-stimulated peripheral glucose metabolism before and after weight reduction. Seven lean (body mass index 〈 25 kg/m 2 ), young, sedentary IR offspring were studied before and after weight stabilization following a hypocaloric (1,200 Kcal) diet for ∼9 wks. This diet resulted in an average weight loss of 4.1 ± 0.6 kg ( P 〈 0.0005), which was associated with an ∼30% reduction of IMCL from 1.1 ± 0.2% to 0.8 ± 0.1% ( P = 0.045) and an ∼30% improvement in insulin-stimulated muscle glucose uptake [3.7 ± 0.3 vs. 4.8 ± 0.1 mg/(kg–min), P = 0.01]. This marked improvement in insulin-stimulated peripheral insulin responsiveness occurred independently of changes in plasma concentrations of TNF-α, IL-6, total adiponectin, C-reactive protein, acylcarnitines, and branched-chain amino acids. In conclusion, these data support the hypothesis that IMCL accumulation plays an important role in causing muscle insulin resistance in young, lean IR offspring, and that both are reversible with modest weight loss.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1205675109
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2012
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 3
    Online Resource
    Online Resource
    The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome
    Proceedings of the National Academy of Sciences ; 2007
    In:  Proceedings of the National Academy of Sciences Vol. 104, No. 31 ( 2007-07-31), p. 12587-12594
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 104, No. 31 ( 2007-07-31), p. 12587-12594
    Abstract: We examined the hypothesis that insulin resistance in skeletal muscle promotes the development of atherogenic dyslipidemia, associated with the metabolic syndrome, by altering the distribution pattern of postprandial energy storage. Following ingestion of two high carbohydrate mixed meals, net muscle glycogen synthesis was reduced by ≈60% in young, lean, insulin-resistant subjects compared with a similar cohort of age–weight–body mass index–activity-matched, insulin-sensitive, control subjects. In contrast, hepatic de novo lipogenesis and hepatic triglyceride synthesis were both increased by 〉 2-fold in the insulin-resistant subjects. These changes were associated with a 60% increase in plasma triglyceride concentrations and an ≈20% reduction in plasma high-density lipoprotein concentrations but no differences in plasma concentrations of TNF-α, IL-6, adiponectin, resistin, retinol binding protein-4, or intraabdominal fat volume. These data demonstrate that insulin resistance in skeletal muscle, due to decreased muscle glycogen synthesis, can promote atherogenic dyslipidemia by changing the pattern of ingested carbohydrate away from skeletal muscle glycogen synthesis into hepatic de novo lipogenesis, resulting in an increase in plasma triglyceride concentrations and a reduction in plasma high-density lipoprotein concentrations. Furthermore, insulin resistance in these subjects was independent of changes in the plasma concentrations of TNF-α, IL-6, high-molecular-weight adiponectin, resistin, retinol binding protein-4, or intraabdominal obesity, suggesting that these factors do not play a primary role in causing insulin resistance in the early stages of the metabolic syndrome.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0705408104
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2007
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 4
    Online Resource
    Online Resource
    Effect of aging on muscle mitochondrial substrate utilization in humans
    Proceedings of the National Academy of Sciences ; 2015
    In:  Proceedings of the National Academy of Sciences Vol. 112, No. 36 ( 2015-09-08), p. 11330-11334
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 112, No. 36 ( 2015-09-08), p. 11330-11334
    Abstract: Previous studies have implicated age-associated reductions in mitochondrial oxidative phosphorylation activity in skeletal muscle as a predisposing factor for intramyocellular lipid (IMCL) accumulation and muscle insulin resistance (IR) in the elderly. To further investigate potential alterations in muscle mitochondrial function associated with aging, we assessed basal and insulin-stimulated rates of muscle pyruvate dehydrogenase (V PDH ) flux relative to citrate synthase flux (V CS ) in healthy lean, elderly subjects and healthy young body mass index- and activity-matched subjects. V PDH /V CS flux was assessed from the 13 C incorporation from of infused [1- 13 C] glucose into glutamate [4- 13 C] relative to alanine [3- 13 C] assessed by LC-tandem MS in muscle biopsies. Insulin-stimulated rates of muscle glucose uptake were reduced by 25% ( P 〈 0.01) in the elderly subjects and were associated with ∼70% ( P 〈 0.04) increase in IMCL, assessed by 1 H magnetic resonance spectroscopy. Basal V PDH /V CS fluxes were similar between the groups (young: 0.20 ± 0.03; elderly: 0.14 ± 0.03) and increased approximately threefold in the young subjects following insulin stimulation. However, this increase was severely blunted in the elderly subjects (young: 0.55 ± 0.04; elderly: 0.18 ± 0.02, P = 0.0002) and was associated with an ∼40% ( P = 0.004) reduction in insulin activation of Akt. These results provide new insights into acquired mitochondrial abnormalities associated with aging and demonstrate that age-associated reductions in muscle mitochondrial function and increased IMCL are associated with a marked inability of mitochondria to switch from lipid to glucose oxidation during insulin stimulation.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1514844112
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2015
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
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