Regional cerebral effects of ketone body infusion with 3-hydroxybutyrate in humans: Reduced glucose uptake, unchanged oxygen consumption and increased blood flow by positron emission tomography. A randomized, controlled trial

Svart, Mads; Gormsen, Lars Christian; Hansen, Jakob; Zeidler, D; Gejl, Michael; Vang, Kim; Aanerud, Joel; Moeller, Niels

doi:10.1371/journal.pone.0190556

Cited by 73 publications

(56 citation statements)

References 41 publications

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“…Patient baseline characteristics and six-month outcome are summarized in Table 1. GCS on site was median 6 [3][4][5][6][7][8][9][10][11][12][13][14]. Two patients had type 2 diabetes.…”

Section: Patient Characteristics and Outcomementioning

confidence: 99%

“…Lactate/pyruvate ratio (27 [17-44] vs. 27 vs. 28 ), brain tissue PO 2 (29 [19-39] vs. 29.5 [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] vs. 29 [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] mm Hg) and ICP (10 [3-20] vs. 11 [5][6][7][8][9][10][11][12][13][14][15][16][17] (Figure 3(a)), representing a median 4.7-fold decrease of blood KB from fasting to stable nutrition state. Median individual plasma/brain KB ratio was 11.…”

Section: Modulation Of Cerebral Ketone Metabolism By Nutritional Statementioning

confidence: 99%

“…44 Higher blood KB levels (4-5 mmol/L) may also be reached exogenously via intravenous infusion of sodium BHB solutions. 7,21,45 Using such approaches, supplemental KB therapy has proven efficacious in reducing brain injury in animal models of TBI and ischemia 14 and thus appears a promising avenue for future clinical investigation. 45…”

Section: Therapeutic Kb Supplementation In Patients With Tbimentioning

confidence: 99%

“…2 Production of ketone bodies (KB, including acetoacetate [AcAc] and b-hydroxybutyrate [BHB]) upon mobilization of fatty acids during fasting or adrenergic stress (endogenous ketosis or ketogenesis) provides alternative energy substrate in conditions of increased demand, 3 while simultaneously preserving limited glucose reserves. [4][5][6][7][8][9] This rescue mechanism may be an advantage in conditions of impaired glycolysis and potentially limited cerebral glucose availability, such as after traumatic brain injury (TBI). 10,11 Besides their key role in regulating cerebral energy metabolism, KB have other important neuroprotective properties, including attenuation of oxidative stress, 12,13 apoptotic cell death 14 and microglial activation.…”

Section: Introductionmentioning

confidence: 99%

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Modulation of cerebral ketone metabolism following traumatic brain injury in humans

Bernini

Masoodi

Solari

et al. 2018

J Cereb Blood Flow Metab

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Adaptive metabolic response to injury includes the utilization of alternative energy substrates -such as ketone bodies (KB) -to protect the brain against further damage. Here, we examined cerebral ketone metabolism in patients with traumatic brain injury (TBI; n ¼ 34 subjects) monitored with cerebral microdialysis to measure total brain interstitial tissue KB levels (acetoacetate and b-hydroxybutyrate). Nutrition -from fasting vs. stable nutrition state -was associated with a significant decrease of brain KB (34.7 [10th-90th percentiles 10.7-189] mmol/L vs. 13.1 [6.5-64.3] mmol/L, p < 0.001) and blood KB (668 [168.4-3824.9] vs. 129.4 [82.6-1033.8] mmol/L, p < 0.01). Blood KB correlated with brain KB (Spearman's rho 0.56, p ¼ 0.0013). Continuous feeding with medium-chain triglycerides-enriched enteral nutrition did not increase blood KB, and provided a modest increase in blood and brain free medium chain fatty acids. Higher brain KB at the acute TBI phase correlated with age and brain lactate, pyruvate and glutamate, but not brain glucose. These novel findings suggest that nutritional ketosis was the main determinant of cerebral KB metabolism following TBI. Age and cerebral metabolic distress contributed to brain KB supporting the hypothesis that ketones might act as alternative energy substrates to glucose. Further studies testing KB supplementation after TBI are warranted.

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“…Patient baseline characteristics and six-month outcome are summarized in Table 1. GCS on site was median 6 [3][4][5][6][7][8][9][10][11][12][13][14]. Two patients had type 2 diabetes.…”

Section: Patient Characteristics and Outcomementioning

confidence: 99%

Section: Modulation Of Cerebral Ketone Metabolism By Nutritional Statementioning

confidence: 99%

Section: Therapeutic Kb Supplementation In Patients With Tbimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Modulation of cerebral ketone metabolism following traumatic brain injury in humans

Bernini

Masoodi

Solari

et al. 2018

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

show abstract

“…In the mitochondria 3-HB is also known to increase the expression of neurotrophic factor that facilitates respiration [14]. Very recently the study of healthy human subjects with and without continuous infusion of 3-HB demonstrated reduced cerebral glucose uptake and neuroprotective effects [15]. There is a striking similarity between the activity of polymer in bacteria and monomeric 3-HB in eukaryotic cells.…”

mentioning

confidence: 99%

3-Hydroxybutyrate Is Active Compound in Flax that Upregulates Genes Involved in DNA Methylation

Mierziak

Wojtasik

Kulma

et al. 2020

IJMS

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In mammalian cells, 3-hydroxybutyrate (3-HB) is not only an intermediate metabolite during the oxidation of fatty acids, but also an important signaling molecule. On the other hand, the information about the metabolism or function of this compound in plants is scarce. In our study, we show for the first time that this compound naturally occurs in flax. The expression of bacterial β-ketothiolase in flax affects expression of endogenous genes of the 3-HB biosynthesis pathway and the compound content. The increase in 3-HB content in transgenic plants or after control plants treatment with 3-HB resulted in upregulation of genes involved in chromatin remodeling. The observation that 3-HB is an endogenous activator of methyltransferase 3 (CMT3), decreased DNA methylation I (DDM1), DEMETER DNA glycosylase (DME), and an inhibitor of sirtuin 1 (SRT1) provides an example of integration of different genes in chromatin remodeling. The changes in chromatin remodeling gene expression concomitant with those involved in phenolics and the lignin biosynthesis pathway suggest potential integration of secondary metabolic status with epigenetic changes.Initially, investigated degradation assays carried out with isolated PHB granules revealed, as a first step, the release of 3-hydroxybutyrate (3-HB) in a hydrolytic reaction, then conversion to 3-hydroxybutyryl coenzyme A and further to acetyl-CoA via acetoacetyl-CoA in the reverse direction and by the same enzymes of the synthesis pathway. In a more recent study, the intracellular degradation of PHB by PHB depolymerase PhaZ1 to (n)-3-HB-CoA and its conversion to crotonyl-CoA converted to acetoacetyl-CoA finally cleaved by a 3-ketoacyl-CoA thiolase to two molecules of acetyl-CoA was shown [6,7].In vertebrates, 3-HB is a product of the normal metabolism of fatty acid oxidation. However the possibility that part of 3-HB derives from bacterial PHB metabolism cannot be excluded as gut microbiota can be a source of PHB [8]. The possibility that part of 3-HB derives from bacterial PHB metabolism cannot be excluded. The 3-HB in humans serves as a metabolic fuel in tissues and its synthesis is increased during metabolic stress conditions, such as exercise, fasting, and severe acute illness. Furthermore, 3-HB has been reported to lower reactive oxygen species (ROS) dependent oxidative stress [9], to inhibit histone deacetylase (HDAC) induced by oxidative stress [10] and to promote the expression of brain-derived neurotrophic factor [11]. It has also been reported that specific supplementation with 3-HB increases lifespan in C. elegans roundworms by 20% [12]. A more recent study reported that 3-HB infusion in ischemia in mice reduced infarct size, mediated by histone deacetylase sirtuin 3, and reduced ROS production [13]. In the mitochondria 3-HB is also known to increase the expression of neurotrophic factor that facilitates respiration [14]. Very recently the study of healthy human subjects with and without continuous infusion of 3-HB demonstrated reduced cerebral glucose uptake and neuroprote...

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Brain energy failure in dementia syndromes: Opportunities and challenges for glucagon‐like peptide‐1 receptor agonists

Yassine

Solomon

Thakral

et al. 2021

Alzheimer's & Dementia

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Medications for type 2 diabetes (T2DM) offer a promising path for discovery and development of effective interventions for dementia syndromes. A common feature of dementia syndromes is an energy failure due to reduced energy supply to neurons and is associated with synaptic loss and results in cognitive decline and behavioral changes. Among diabetes medications, glucagon‐like peptide‐1 (GLP‐1) receptor agonists (RAs) promote protective effects on vascular, microglial, and neuronal functions. In this review, we present evidence from animal models, imaging studies, and clinical trials that support developing GLP‐1 RAs for dementia syndromes. The review examines how changes in brain energy metabolism differ in conditions of insulin resistance and T2DM from dementia and underscores the challenges that arise from the heterogeneity of dementia syndromes. The development of GLP‐1 RAs as dementia therapies requires a deeper understanding of the regional changes in brain energy homeostasis guided by novel imaging biomarkers.

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Regional cerebral effects of ketone body infusion with 3-hydroxybutyrate in humans: Reduced glucose uptake, unchanged oxygen consumption and increased blood flow by positron emission tomography. A randomized, controlled trial

Cited by 73 publications

References 41 publications

Modulation of cerebral ketone metabolism following traumatic brain injury in humans

Modulation of cerebral ketone metabolism following traumatic brain injury in humans

3-Hydroxybutyrate Is Active Compound in Flax that Upregulates Genes Involved in DNA Methylation

Brain energy failure in dementia syndromes: Opportunities and challenges for glucagon‐like peptide‐1 receptor agonists

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