bims-glecem 2024-01-28 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2024–01–28
nine papers selected by
Dipsikha Biswas, Københavns Universitet

Treatment recommendations for glycogen storage disease type IB- associated neutropenia and neutrophil dysfunction with empagliflozin: Consensus from an international workshop.
McArdle's, a Rare Disease That Every Family Doctor Can Manage: A Case Report.
Regulatory Role of GgaR (YegW) for Glycogen Accumulation in Escherichia coli K-12.
Immunophenotype associated with high sustained antibody titers against enzyme replacement therapy in infantile-onset Pompe disease.
Evaluating avalglucosidase alfa for the management of late-onset Pompe disease.
Glycogen Synthase Kinase-3 Inhibition by CHIR99021 Promotes Alveolar Epithelial Cell Proliferation and Lung Regeneration in the Lipopolysaccharide-Induced Acute Lung Injury Mouse Model.
Sucrose-Enriched and Carbohydrate-Free High-Fat Diets Distinctly Affect Substrate Metabolism in Oxidative and Glycolytic Muscles of Rats.
An analysis of Pompe newborn screening data: a new prevalence at birth, insight and discussion.
A Five-Week Periodized Carbohydrate Diet Does Not Improve Maximal Lactate Steady-State Exercise Capacity and Substrate Oxidation in Well-Trained Cyclists compared to a High-Carbohydrate Diet.

Mol Genet Metab. 2024 Jan 17. pii: S1096-7192(24)00028-3. [Epub ahead of print]141(3): 108144

Treatment recommendations for glycogen storage disease type IB- associated neutropenia and neutrophil dysfunction with empagliflozin: Consensus from an international workshop.

Sarah C Grünert, Terry G J Derks, Helen Mundy, R Neil Dalton, Jean Donadieu, Peter Hofbauer, Neil Jones, Sema Kalkan Uçar, Jamas LaFreniere, Enrique Landelino Contreras, Surekha Pendyal, Alessandro Rossi, Blair Schneider, Ronen Spiegel, Karolina M Stepien, Dorota Wesol-Kucharska, Maria Veiga-da-Cunha, Saskia B Wortmann.

  Glycogen storage disease type Ib (GSD Ib, biallelic variants in SLC37A4) is a rare disorder of glycogen metabolism complicated by neutropenia/neutrophil dysfunction. Since 2019, the SGLT2-inhibitor empagliflozin has provided a mechanism-based treatment option for the symptoms caused by neutropenia/neutrophil dysfunction (e.g. mucosal lesions, inflammatory bowel disease). Because of the rarity of GSD Ib, the published evidence on safety and efficacy of empagliflozin is still limited and does not allow to develop evidence-based guidelines. Here, an international group of experts provides 14 best practice consensus treatment recommendations based on expert practice and review of the published evidence. We recommend to start empagliflozin in all GSD Ib individuals with clinical or laboratory signs related to neutropenia/neutrophil dysfunction with a dose of 0.3-0.4 mg/kg/d given as a single dose in the morning. Treatment can be started in an outpatient setting. The dose should be adapted to the weight and in case of inadequate clinical treatment response or side effects. We strongly recommend to pause empagliflozin immediately in case of threatening dehydration and before planned longer surgeries. Discontinuation of G-CSF therapy should be attempted in all individuals. If available, 1,5-AG should be monitored. Individuals who have previously not tolerated starches should be encouraged to make a new attempt to introduce starch in their diet after initiation of empagliflozin treatment. We advise to monitor certain safety and efficacy parameters and recommend continuous, alternatively frequent glucose measurements during the introduction of empagliflozin. We provide specific recommendations for special circumstances like pregnancy and liver transplantation.

Keywords:  Dapagliflozin; Empagliflozin; Glycogen storage disorder 1b; Hypoglycemia; Inflammatory bowel disease; Neutrophil dysfunction; SGLT2-inhibitor; SGLT2i; Treatment, neutropenia

DOI:  https://doi.org/10.1016/j.ymgme.2024.108144
Cureus. 2023 Dec;15(12): e50892

McArdle's, a Rare Disease That Every Family Doctor Can Manage: A Case Report.

João R Oliveira, João P Pereira, Mariana F Branco, Luísa C Leite, Ana I Patrício.

  McArdle's disease is a rare autosomal recessive disorder that affects glycogen storage. It typically manifests in adolescence or early adulthood with presenting symptoms, such as fatigue, myalgia, exercise intolerance, and cramps, which can be easily overlooked. This case report seeks to offer a comprehensive overview of the perspective of a patient living with McArdle's disease, emphasizing the importance of treatment encouragement. The report documents the case of a 25-year-old male presenting with myalgia and fatigue exacerbated by strenuous exercise, illustrating the diagnostic challenges associated with McArdle's disease, primarily attributable to clinician unawareness. Furthermore, the case highlights the importance of adhering to lifestyle modifications to mitigate symptoms and prevent flare-ups, as well as the crucial role of the family doctor in such lifestyle maintenance.

Keywords:  creatine kinase; exercise intolerance; fatigue; glycogen; glycogen storage disorder type v; high carbohydrate diet; mcardle; myalgia; rhabdomyolysis

DOI:  https://doi.org/10.7759/cureus.50892
Microorganisms. 2024 Jan 05. pii: 115. [Epub ahead of print]12(1):

Regulatory Role of GgaR (YegW) for Glycogen Accumulation in Escherichia coli K-12.

Shunsuke Saito, Ikki Kobayashi, Motoki Hoshina, Emi Uenaka, Atsushi Sakurai, Sousuke Imamura, Tomohiro Shimada.

  Glycogen, the stored form of glucose, accumulates upon growth arrest in the presence of an excess carbon source in Escherichia coli and other bacteria. Chromatin immunoprecipitation screening for the binding site of a functionally unknown GntR family transcription factor, YegW, revealed that the yegTUV operon was a single target of the E. coli genome. Although none of the genes in the yegTUV operon have a clear function, a previous study suggested their involvement in the production of ADP-glucose (ADPG), a glycogen precursor. Various validation through in vivo and in vitro experiments showed that YegW is a single-target transcription factor that acts as a repressor of yegTUV, with an intracellular concentration of consistently approximately 10 molecules, and senses ADPG as an effector. Further analysis revealed that YegW repressed glycogen accumulation in response to increased glucose concentration, which was not accompanied by changes in the growth phase. In minimal glucose medium, yegW-deficient E. coli promoted glycogen accumulation, at the expense of poor cell proliferation. We concluded that YegW is a single-target transcription factor that senses ADPG and represses glycogen accumulation in response to the amount of glucose available to the cell. We propose renaming YegW to GgaR (repressor of glycogen accumulation).

Keywords:  ADP-glucose; Escherichia coli; gene regulation; glycogen; transcription factor

DOI:  https://doi.org/10.3390/microorganisms12010115
Front Immunol. 2023 ;14 1301912

Immunophenotype associated with high sustained antibody titers against enzyme replacement therapy in infantile-onset Pompe disease.

Ankit K Desai, P Brian Smith, John S Yi, Amy S Rosenberg, Trevor D Burt, Priya S Kishnani.

   Introduction: The efficacy of enzyme replacement therapy (ERT) with alglucosidase alfa for infantile-onset Pompe disease (IOPD) is limited in some patients due to the development of high and sustained antibody titers (HSAT; ≥12,800).
Methods: We carried out detailed immunophenotyping of IOPD patients (n=40), including analysis of circulating cell populations by flow cytometry and plasma cytokines by multiplex array, to determine whether patients with HSAT have unique immunological characteristics compared to those with low titers (LT; <12,800).
Results: Compared to patients with LT, patients who develop HSAT were skewed toward a type 2 immune profile, with an increased frequency of Th2 cells that was positively correlated with levels of Th2 (IL-4, IL-5, IL-13) and pro-inflammatory (IL-6, TNF-α, MIP-1α, MIP-1β) cytokines. B cells were increased in HSAT patients with a decreased fraction of unswitched memory B cells. Plasma GM-CSF concentrations were lower on average in HSAT patients, while CXCL11 was elevated. Finally, using principal components analysis, we derived an HSAT Signature Score that successfully stratified patients according to their antibody titers.
Discussion: The immune profiles revealed in this study not only identify potential biomarkers of patients that developed HSAT but also provide insights into the pathophysiology of HSAT that will ultimately lead to improved immunotherapy strategies.

Keywords:  anti-drug antibodies; enzyme replacement therapy; immune activation; immune profiling; immunophenotyping; infantile-onset Pompe disease

DOI:  https://doi.org/10.3389/fimmu.2023.1301912
Expert Rev Neurother. 2024 Jan 23. 1-8

Evaluating avalglucosidase alfa for the management of late-onset Pompe disease.

Corrado Angelini.

   INTRODUCTION: Glycogenosis type II (GSDII) is a rare autosomal disorder that is caused by the deficiency of alpha-glucosidase, a lysosomal enzyme that hydrolyzes glycogen to glucose. Autophagy dysregulation plays a critical role. Importantly, since 2006, both patients with infantile (classic Pompe disease) and adult GSDII (late-onset Pompe disease or LOPD) have been treated with enzyme replacement therapy (ERT). To support this use, several double-blind and observational studies including large cohorts of GSDII patients have been undertaken and have shown ERT to be effective in modifying the natural course of disease. Indeed, most LOPD cases improve in the first 20 months of treatment in a six-minute walk test (6MWT), while those who are untreated do not; instead, their response declines over time.
AREAS COVERED: The author reviews avalglucosidase alpha, a therapy approved by both the FDA and European regulatory agencies. Herein, the author considers the pathophysiological approaches such as the role of enzyme entry, autophagy, and the response to ERT treatment of motor and respiratory components.
EXPERT OPINION: There has been a notable drive toward the research of various aspects of this disease regarding the role of new enzyme penetration and immune adverse events. Consequently, avalglucosidase alpha might be a further step forward.

Keywords:  Pompe disease; acid alpha-glucosidase; autophagy; enzyme replacement therapy; glycogenosis type 2

DOI:  https://doi.org/10.1080/14737175.2024.2306855
Int J Mol Sci. 2024 Jan 20. pii: 1279. [Epub ahead of print]25(2):

Glycogen Synthase Kinase-3 Inhibition by CHIR99021 Promotes Alveolar Epithelial Cell Proliferation and Lung Regeneration in the Lipopolysaccharide-Induced Acute Lung Injury Mouse Model.

Raquel Fernandes, Catarina Barbosa-Matos, Caroline Borges-Pereira, Ana Luísa Rodrigues Toste de Carvalho, Sandra Costa.

  Acute respiratory distress syndrome (ARDS) is a life-threatening lung injury that currently lacks effective clinical treatments. Evidence highlights the potential role of glycogen synthase kinase-3 (GSK-3) inhibition in mitigating severe inflammation. The inhibition of GSK-3α/β by CHIR99021 promoted fetal lung progenitor proliferation and maturation of alveolar epithelial cells (AECs). The precise impact of CHIR99021 in lung repair and regeneration during acute lung injury (ALI) remains unexplored. This study intends to elucidate the influence of CHIR99021 on AEC behaviour during the peak of the inflammatory phase of ALI and, after its attenuation, during the repair and regeneration stage. Furthermore, a long-term evaluation was conducted post CHIR99021 treatment at a late phase of the disease. Our results disclosed the role of GSK-3α/β inhibition in promoting AECI and AECII proliferation. Later administration of CHIR99021 during ALI progression contributed to the transdifferentiation of AECII into AECI and an AECI/AECII increase, suggesting its contribution to the renewal of the alveolar epithelial population and lung regeneration. This effect was confirmed to be maintained histologically in the long term. These findings underscore the potential of targeted therapies that modulate GSK-3α/β inhibition, offering innovative approaches for managing acute lung diseases, mostly in later stages where no treatment is available.

Keywords:  acute lung injury; alveolar epithelial cells; cell proliferation; glycogen synthase kinase-3; lung regeneration

DOI:  https://doi.org/10.3390/ijms25021279
Nutrients. 2024 Jan 18. pii: 286. [Epub ahead of print]16(2):

Sucrose-Enriched and Carbohydrate-Free High-Fat Diets Distinctly Affect Substrate Metabolism in Oxidative and Glycolytic Muscles of Rats.

Daniel Da Eira, Shailee Jani, Mateja Stefanovic, Rolando B Ceddia.

  Skeletal muscle substrate preference for fuel is largely influenced by dietary macronutrient availability. The abundance of dietary carbohydrates promotes the utilization of glucose as a substrate for energy production, whereas an abundant dietary fat supply elevates rates of fatty acid (FA) oxidation. The objective of this study was to determine whether an obesogenic, high-fat, sucrose-enriched (HFS) diet or a carbohydrate-free ketogenic diet (KD) exert distinct effects on fat, glucose, and ketone metabolism in oxidative and glycolytic skeletal muscles. Male Wistar rats were fed either a HFS diet or a KD for 16 weeks. Subsequently, the soleus (Sol), extensor digitorum longus (EDL), and epitrochlearis (Epit) muscles were extracted to measure palmitate oxidation, insulin-stimulated glucose metabolism, and markers of mitochondrial biogenesis, ketolytic capacity, and cataplerotic and anaplerotic machinery. Sol, EDL, and Epit muscles from KD-fed rats preserved their ability to elevate glycogen synthesis and lactate production in response to insulin, whereas all muscles from rats fed with the HFS diet displayed blunted responses to insulin. The maintenance of metabolic flexibility with the KD was accompanied by muscle-fiber-type-specific adaptive responses. This was characterized by the Sol muscle in KD-fed rats enhancing mitochondrial biogenesis and ketolytic capacity without elevating its rates of FA oxidation in comparison with that in HFS feeding. Conversely, in the Epit muscle, rates of FA oxidation were increased, whereas the ketolytic capacity was markedly reduced by the KD in comparison with that by HFS feeding. In the EDL muscle, the KD also increased rates of FA oxidation, although it did so without altering its ketolytic capacity when compared to HFS feeding. In conclusion, even though obesogenic and ketogenic diets have elevated contents of fat and alter whole-body substrate partitioning, these two dietary interventions are associated with opposite outcomes with respect to skeletal muscle metabolic flexibility.

Keywords:  ACAT1; OXCT; PGC-1α; TFAM; anaplerosis; insulin resistance; ketogenic diet; ketolysis

DOI:  https://doi.org/10.3390/nu16020286
Front Pediatr. 2023 ;11 1221140

An analysis of Pompe newborn screening data: a new prevalence at birth, insight and discussion.

Ryan Colburn, David Lapidus.

  This study includes over 11.6M newborns screened (NBS) for Pompe Disease (PD) from 29 distinct universal screening programs across 8 countries and 4 continents. The birth prevalence of PD is 1:18,711, with no evidence of difference across populations of European, Latin American, or Asian ancestry, though differences may exist for PD subtypes. This study also compares these results, based on direct detection of disease and analyzed using a binomial method along with power analysis, with other methods for estimating the 'frequency' of rare genetic diseases (such as utilizing Hardy-Weinberg equilibrium on allele frequency and confidence interval analysis). This comparison demonstrates the implications of sample size and frames a discussion on its influence on the reliability of results when extrapolating to a population beyond the study dataset.
Objectives: Primary: Establish a new figure for prevalence at birth for Pompe disease by collecting and analyzing the largest relevant dataset to date and using that result to project population prevalence at birth in a novel way. Secondary: Compare these results to previous analyses to offer a framework for evaluating 'frequency' data that can be applied to other rare, genetic diseases, along with methods to assess quality of estimates.

Keywords:  Pompe (glycogen storage disease type 2/II); autosomal recessive inheritance; diagnosis/diagnostic yield; genetic prevalence; gnomAD; lysosomal storage disorder/disease (LSD); newborn screening (NBS); rare disease epidemiology

DOI:  https://doi.org/10.3389/fped.2023.1221140
Nutrients. 2024 Jan 21. pii: 318. [Epub ahead of print]16(2):

A Five-Week Periodized Carbohydrate Diet Does Not Improve Maximal Lactate Steady-State Exercise Capacity and Substrate Oxidation in Well-Trained Cyclists compared to a High-Carbohydrate Diet.

Gorka Prieto-Bellver, Javier Diaz-Lara, David J Bishop, José Fernández-Sáez, Javier Abián-Vicén, Iñigo San-Millan, Jordan Santos-Concejero.

  There is a growing interest in studies involving carbohydrate (CHO) manipulation and subsequent adaptations to endurance training. This study aimed to analyze whether a periodized carbohydrate feeding strategy based on a daily training session has any advantages compared to a high-carbohydrate diet in well-trained cyclists. Seventeen trained cyclists (VO2peak = 70.8 ± 6.5 mL·kg-1·min-1) were divided into two groups, a periodized (PCHO) group and a high-carbohydrate (HCHO) group. Both groups performed the same training sessions for five weeks. In the PCHO group, 13 training sessions were performed with low carbohydrate availability. In the HCHO group, all sessions were completed following previous carbohydrate intake to ensure high pre-exercise glycogen levels. In both groups, there was an increase in the maximal lactate steady state (MLSS) (PCHO: 244.1 ± 29.9 W to 253.2 ± 28.4 W; p = 0.008; HCHO: 235.8 ± 21.4 W to 246.9 ± 16.7 W; p = 0.012) but not in the time to exhaustion at MLSS intensity. Both groups increased the percentage of muscle mass (PCHO: p = 0.021; HCHO: p = 0.042) and decreased the percent body fat (PCHO: p = 0.021; HCHO: p = 0.012). We found no differences in carbohydrate or lipid oxidation, heart rate, and post-exercise lactate concentration. Periodizing the CHO intake in well-trained cyclists during a 5-week intervention did not elicit superior results to an energy intake-matched high-carbohydrate diet in any of the measured outcomes.

Keywords:  body composition; carbohydrates; cycling; fat oxidation; performance; train low

DOI:  https://doi.org/10.3390/nu16020318