bims-glecem 2023-10-29 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2023–10–29
seven papers selected by
Dipsikha Biswas, Københavns Universitet

Diet-induced diabetes is associated with lower hippocampal glycogen and reduced glycogenolysis following local exogenous insulin.
Hydration, Hyperthermia, Glycogen, and Recovery: Crucial Factors in Exercise Performance-A Systematic Review and Meta-Analysis.
Ginsenoside Rb1 Promotes Hepatic Glycogen Synthesis to Ameliorate T2DM Through 15-PGDH/PGE2/EP4 Signaling Pathway.
In Silico Approaches to Developing Novel Glycogen Synthase Kinase 3β (GSK-3β).
Massive Splenomegaly with Pancytopenia in an Adult: Gaucher's Disease.
A fingerprint of 2-[18F]FDG radiometabolites - How tissue-specific metabolism beyond 2-[18F]FDG-6-P could affect tracer accumulation.
No Net-Utilization of Intramuscular Lipid Droplets during Repeated High-Intensity Intermittent Exercise.

J Neurochem. 2023 Oct 26.

Diet-induced diabetes is associated with lower hippocampal glycogen and reduced glycogenolysis following local exogenous insulin.

Ewan C McNay.

  Brain fuel (specifically, glucose) supply and metabolism are well-established to be limiting factors for cognitive performance, with the largest body of data being for hippocampally mediated tasks. Consistent with this, disease states such as Alzheimer's disease and insulin-resistant diabetes, that impair cognitive metabolism, impair cognition with this being shown again most prominently for hippocampally mediated processes. In addition to glucose supplied from the blood, brain oxidative metabolism can use local glycogen stores (within astrocytes) as a fuel source via conversion to lactate; both lactate and glycogen have been shown to be important contributors to regulation of cognitive metabolism. Insulin has been shown to be a key regulator of hippocampal cognitive and metabolic processes; in the periphery, insulin facilitates glycogen synthesis and storage, but the impact on brain glycogen is unclear. Furthermore, the impact of diet-induced diabetes on hippocampal glycogen levels and/or metabolism is unknown. Here, we show that in rats with high-fat diet-induced diabetes, hippocampal glycogen is reduced and is less responsive to acute intrahippocampal administration of insulin, which significantly reduces glycogen in the hippocampi of control animals: Our data suggest that impaired fuel availability from glycogen may be a contributing factor to the cognitive impairment seen in disease states that include central insulin resistance.

Keywords:  AD; T2DM; glycogen; hippocampus; insulin

DOI:  https://doi.org/10.1111/jnc.16001
Nutrients. 2023 Oct 19. pii: 4442. [Epub ahead of print]15(20):

Hydration, Hyperthermia, Glycogen, and Recovery: Crucial Factors in Exercise Performance-A Systematic Review and Meta-Analysis.

Olga López-Torres, Celia Rodríguez-Longobardo, Rodrigo Escribano-Tabernero, Valentín E Fernández-Elías.

  Hyperthermia accelerates dehydration and can lead to a glycolysis malfunction. Therefore, to deeply understand the relationship between dehydration and hyperthermia during exercise, as well as in the recovery time, there might be important factors to improve athletic performance. A systematic review was carried out in different databases using the words "hydration" OR "dehydration" AND "glycogen" OR "glycogenesis" OR "glycogenolysis" AND "muscle" OR "muscle metabolism" OR "cardiovascular system" and adding them to the "topic section" in Web of Science, to "Title/Abstract" in PubMed and to "Abstract" in SPORTDiscus. A total of 18 studies were included in the review and 13 in the meta-analysis. The free statistical software Jamovi was used to run the meta-analysis (version 1.6.15). A total sample of 158 people was included in the qualitative analysis, with a mean age of 23.5 years. Ten studies compared muscle glycogen content after hydration vs. remaining dehydrated (SMD -4.77 to 3.71, positive 80% of estimates, \hat{\mu} = 0.79 (95% CI: -0.54 to 2.12), z = 1.17, p = 0.24, Q-test (Q(9) = 66.38, p < 0.0001, tau2 = 4.14, I2 = 91.88%). Four studies examined the effect of temperature on postexercise muscle glycogen content (SMD -3.14 to -0.63, 100% of estimates being negative, \hat{\mu} = -1.52 (95% CI: -2.52 to -0.53), (z = -3.00, p = 0.003, Q-test (Q(3) = 8.40, p = 0.038, tau2 = 0.68, I2 = 66.81%). In conclusion, both hyperthermia and dehydration may contribute to elevated glycogenolysis during exercise and poor glycogen resynthesis during recovery. Although core and muscle hyperthermia are the key factors in glycogen impairments, they are also directly related to dehydration.

Keywords:  athletic performance; dehydration; glycogen recovery; muscle temperature

DOI:  https://doi.org/10.3390/nu15204442
Diabetes Metab Syndr Obes. 2023 ;16 3223-3234

Ginsenoside Rb1 Promotes Hepatic Glycogen Synthesis to Ameliorate T2DM Through 15-PGDH/PGE2/EP4 Signaling Pathway.

Mingjie Liang, Wenjing Zhan, Lexun Wang, Weijian Bei, Weixuan Wang.

   Purpose: Ginsenoside Rb1 (Rb1), one of the crucial bioactive constituents in Panax ginseng C. A. Mey., possesses anti-type 2 diabetes mellitus (T2DM) property. Nevertheless, the precise mechanism, particularly the impact of Rb1 on hepatic glycogen production, a crucial process in the advancement of T2DM, remains poorly understood. 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is responsible for prostaglandin E2 (PGE2) inactivation. A recent study has reported that inhibition of 15-PGDH promoted hepatic glycogen synthesis and improved T2DM. Therefore, herein, we aimed to investigate whether Rb1 ameliorated T2DM through 15-PGDH/PGE2-regulated hepatic glycogen synthesis.
Methods: By combining streptozotocin with a high-fat diet, we successfully established a mouse model for T2DM. Afterward, these mice were administered Rb1 or metformin for 8 weeks. An insulin-resistant cell model was established by incubating LO2 cells with palmitic acid. Liver glycogen and PGE2 levels, the expression levels of 15-PGDH, serine/threonine kinase AKT (AKT), and glycogen synthase kinase 3 beta (GSK3β) were measured. Molecular docking was used to predict the binding affinity between 15-PGDH and Rb1.
Results: Rb1 administration increased the phosphorylation levels of AKT and GSK3β to enhance glycogen synthesis in the liver of T2DM mice. Molecular docking indicated that Rb1 had a high affinity for 15-PGDH. Moreover, Rb1 treatment resulted in the suppression of elevated 15-PGDH levels and the elevation of decreased PGE2 levels in the liver of T2DM mice. Furthermore, in vitro experiments showed that Rb1 administration might enhance glycogen production by modulating the 15-PGDH/PGE2/PGE2 receptor EP4 pathway.
Conclusion: Our findings indicate that Rb1 may enhance liver glycogen production through a 15-PGDH-dependent pathway to ameliorate T2DM, thereby offering a new explanation for the positive impact of Rb1 on T2DM and supporting its potential as an effective therapeutic approach for T2DM.

Keywords:  15-hydroxyprostaglandin dehydrogenase; ginsenoside Rb1; hepatic glycogen synthesis; prostaglandin E2; type 2 diabetes mellitus

DOI:  https://doi.org/10.2147/DMSO.S431423
Biomedicines. 2023 Oct 13. pii: 2784. [Epub ahead of print]11(10):

In Silico Approaches to Developing Novel Glycogen Synthase Kinase 3β (GSK-3β).

Shuchi Goyal, Manjinder Singh, Divya Thirumal, Pratibha Sharma, Somdutt Mujwar, Krishna Kumar Mishra, Thakur Gurjeet Singh, Ravinder Singh, Varinder Singh, Tanveer Singh, Sheikh F Ahmad.

  Alzheimer's disease (AD) is caused by plaque agglomeration and entanglement in several areas of the neural cells, which leads to apoptosis. The main etiology of AD is senile dementia, which is linked to amyloid-beta (Aβ) deregulation and tau perivascular pathogeny. Hyperphosphorylated tau has a propensity for microtubules, which elevate the instability and tau-protein congregates, leading to accumulation of neurofibrillary tangles (NFTs). Tau hyperphosphorylation is susceptible to GSK-3, which has led to an emerging hypothesis regarding the pathogenesis of AD. Accordingly, attempts have been made to conduct investigations and achieve further advancements on new analogues capable of inhibiting the GSK-3 protein, which are currently in the clinical trials. In this analysis, we have evaluated certain GSK-3 inhibitor variants utilising scaffolding and framework devised techniques with pharmacological characteristics, accompanied by computational screenings (pharmacokinetics and docking). The structure-based designed analogues interacted effectively with the active amino acids of GSK-3β target protein. The in silico pharmacokinetic studies revealed their drug-like properties. The analogues with best interactions and binding scores will be considered in the future to completely demonstrate their potential relevance as viable GSK-3 inhibitors.

Keywords:  Alzheimer’s disease; GSK-3β; amyloid-beta; docking; molecular dynamics; morphing; neurofibrillary tangles; scaffold

DOI:  https://doi.org/10.3390/biomedicines11102784
Cardiovasc Hematol Disord Drug Targets. 2023 Oct 24.

Massive Splenomegaly with Pancytopenia in an Adult: Gaucher's Disease.

Farid Alam, Jitendra Singh, Nilesh Kumar, Kailash Kumar, Anju Dinkar.

   INTRODUCTION: Gaucher's disease (GD) is a rare lysosomal storage disease. It is characterized by the deposition of glucocerebroside in cells of the macrophage-monocyte system. GD presents a broad clinical expression, including hematologic abnormalities (such as pancytopenia), massive hepatosplenomegaly, diffuse infiltrative pulmonary disease, renal involvement in the form of nephropathy and glomerulonephritis, skeletal involvement in the form of bone pain, bony infarct, osteopenia, and pathological fracture. Based on the presence or absence of neurologic involvement, it is differentiated into type 1, type 2, and type 3. Gaucher's disease type 1 is the most common form, having the nonneuropathic form and carrying autosomal recessive traits. Gaucher's disease affects all racial and ethnic groups, while type 1 GD is most prevalent among Ashkenazi Jews.
CASE PRESENTATION: A 20-year-old female was admitted to the medicine department with complaints of generalized weakness and easy fatigability, menorrhagia, and a dragging sensation in the abdomen. On clinical evaluation, she had bone marrow failure syndrome features along with massive splenomegaly. Later, she was confirmed with Gaucher disease type 1 disease by clinical and investigation (low β-glucosidase level) evaluation.
CONCLUSION: This case emphasizes keeping a differential diagnosis of glycogen storage disorder while evaluating a case of unexplained pancytopenia with massive splenomegaly in adulthood for an extended period. Currently, enzyme replacement therapy and substrate reduction therapy are the mainstay therapeutic options for GD.

Keywords:  Gaucher cells; Glucocerebrosidase; Pancytopenia; Severe splenomegaly

DOI:  https://doi.org/10.2174/011871529X253966230922110202
iScience. 2023 Nov 17. 26(11): 108137

A fingerprint of 2-[18F]FDG radiometabolites - How tissue-specific metabolism beyond 2-[18F]FDG-6-P could affect tracer accumulation.

Eva-Maria Patronas, Theresa Balber, Anne Miller, Barbara Katharina Geist, Antje Michligk, Chrysoula Vraka, Maximilian Krisch, Nataliya Rohr-Udilova, Arvand Haschemi, Helmut Viernstein, Marcus Hacker, Markus Mitterhauser.

  Studies indicate that the radiotracer 2-[18F]fluoro-2-deoxy-D-glucose (2-[18F]FDG) can be metabolized beyond 2-[18F]FDG-6-phosphate (2-[18F]FDG-6-P), but its metabolism is incompletely understood. Most importantly, it remains unclear whether downstream metabolism affects tracer accumulation in vivo. Here we present a fingerprint of 2-[18F]FDG radiometabolites over time in cancer cells, corresponding tumor xenografts and murine organs. Strikingly, radiometabolites representing glycogen metabolism or the oxPPP correlated inversely with tracer accumulation across all examined tissues. Recent studies suggest that not only hexokinase, but also hexose-6-phosphate dehydrogenase (H6PD), an enzyme of the oxidative pentose phosphate pathway (oxPPP), determines 2-[18F]FDG accumulation. However, little is known about the corresponding enzyme glucose-6-phosphate dehydrogenase (G6PD). Our mechanistic in vitro experiments on the role of the oxPPP propose that 2-[18F]FDG can be metabolized via both G6PD and H6PD, but data from separate enzyme knockdown suggest diverging roles in downstream tracer metabolism. Overall, we propose that tissue-specific metabolism beyond 2-[18F]FDG-6-P could matter for imaging.

Keywords:  cancer; nuclear medicine; radiochemicals

DOI:  https://doi.org/10.1016/j.isci.2023.108137
Am J Physiol Endocrinol Metab. 2023 Oct 25.

No Net-Utilization of Intramuscular Lipid Droplets during Repeated High-Intensity Intermittent Exercise.

Christian B Knudsen, Joachim Nielsen, Niels Ørtenblad, Magni Mohr, Kristian Overgaard, Jeppe F Vigh-Larsen.

  Intramuscular lipids are stored as subsarcolemmal or intramyofibrillar droplets with potential diverse roles in energy metabolism. We examined intramuscular lipid utilization through transmission electron microscopy during repeated high-intensity intermittent exercise, an aspect that is hitherto unexplored. Seventeen moderately-to-well-trained males underwent three periods (EX1-EX3) of 10 x 45-s high-intensity cycling (~100-120% watt max) combined with maximal repeated sprints (~250-300% watt max). M. vastus lateralis biopsies were obtained at baseline, after EX1, and EX3. During the complete exercise session, no net decline in neither subsarcolemmal nor intermyofibrillar lipid volume density occurred. However, a temporal relationship emerged for subsarcolemmal lipids with an ~11% increase in droplet size after EX1 (P=0.024), which reverted to baseline levels after EX3 accompanied by a ~30% reduction in the numerical density of subsarcolemmal lipid droplets compared to both baseline (P=0.019) and after EX1 (P=0.018). Baseline distinctions were demonstrated with a ~2-fold higher intermyofibrillar lipid volume in type 1 vs. type 2 fibers (P=0.008), mediated solely by a higher number rather than size of lipid droplets (P<0.001). No fiber type-specific differences were observed in subsarcolemmal lipid volume although type 2 fibers exhibited ~17% larger droplets (P=0.034) but a lower numerical density (main effect; P=0.010) including 3% less droplets at baseline. Collectively, these findings suggest that intramuscular lipids do not serve as an important substrate during high-intensity intermittent exercise, however, the repeated exercise pattern mediated a temporal remodeling of the subsarcolemmal lipid pool. Furthermore, fiber type- and compartment-specific differences were found at baseline underscoring the heterogeneity in lipid droplet deposition.

Keywords:  electron microscopy; fat; metabolism; subcellular; substrate

DOI:  https://doi.org/10.1152/ajpendo.00298.2023