bims-glecem 2023-10-08 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2023–10–08
nine papers selected by
Dipsikha Biswas, Københavns Universitet

Assessment of the diagnosis, treatment, and follow-up of a group of Turkish pediatric glycogen storage disease type 1b patients with varying clinical presentations and a novel mutation.
Crohn-like disease long remission in a pediatric patient with glycogen storage disease type Ib treated with empagliflozin: a case report.
Aberrant glucose metabolism underlies impaired macrophage differentiation in glycogen storage disease type Ib.
A splice-switching oligonucleotide treatment ameliorates glycogen storage disease type 1a with G6PC c.648G>T.
The role of glycogen synthase kinase 3 beta in neurodegenerative diseases.
AR-A014418, a glycogen synthase kinase-3β inhibitor, mitigates lipopolysaccharide-induced inflammation in rat dental pulp stem cells via NLR family pyrin domain containing 3 inflammasome impairment.
Clinical significance of glycogen synthase kinase 3 (GSK-3) expression and tumor budding grade in colorectal cancer: Implications for targeted therapy.
Novel Role of Glycogen Synthase Kinase-3β in Determining Cancer Cell Response to Genotoxic Stress through Regulation of 53BP1 Function.
Rapid ultra-performance liquid chromatography-tandem mass spectrometry method for the simultaneous determination of three characteristic urinary saccharide metabolites in patients with glycogen storage diseases (type Ⅰb and Ⅱ).

J Pediatr Endocrinol Metab. 2023 Oct 05.

Assessment of the diagnosis, treatment, and follow-up of a group of Turkish pediatric glycogen storage disease type 1b patients with varying clinical presentations and a novel mutation.

Aynur Küçükçongar Yavaş, Ayşenur Engin Erdal, Berrak Bilginer Gürbüz, Aysel Ünlüsoy Aksu, Çiğdem Seher Kasapkara.

   OBJECTIVES: Glycogen storage disease (GSD) type 1b is a multisystemic disease in which immune and infectious complications are present, different from GSD type 1a. Treatment with granulocyte-colony stimulating factor (G-CSF) is often required in the management of neutropenia and inflammatory bowel disease. Recently, an alternative treatment option to G-CSF has been preferred, like empagliflozin. To report on the demographics, genotype, clinical presentation, management, and complications of pediatric patients with glycogen storage disease type 1b (GSD 1b).
METHODS: A retrospective analysis of the clinical course of eight patients with GSD type 1b whose diagnosis was confirmed by molecular testing.
RESULTS: The mean age at referral was four months. The diagnosis of GSD 1b was based on clinical and laboratory findings and supported by genetic studies. One patient presented with an atypical clinical finding in the form of hydrocephalus at the time of first admission. The first symptom was abscess formation on the scalp due to neutropenia in another patient. Other patients had hypoglycemia at the time of admission. All patients presented suffered from neutropenia, which was managed with G-CSF, except one. Hospitalizations for infections were frequent. One patient developed chronic diarrhea and severe infections, which have been brought under control with empagliflozin.
CONCLUSIONS: Neutropenia is an essential finding in GSD 1b and responsible for complications. The coexistence of hypoglycemia and neutropenia should bring to mind GSD 1b. Empagliflozin can be a treatment option for neutropenia, which is resistant to G-CSF treatment.

Keywords:  empagliflozin; glycogen storage disease type 1b; hepatomegaly; neutropenia

DOI:  https://doi.org/10.1515/jpem-2023-0336
Therap Adv Gastroenterol. 2023 ;16 17562848231202138

Crohn-like disease long remission in a pediatric patient with glycogen storage disease type Ib treated with empagliflozin: a case report.

Margherita Calia, Andrea Mario Luciano Arosio, Viola Crescitelli, Anna Fornari, Roberta Pretese, Serena Gasperini, Giovanna Zuin.

  Glycogen storage disease type Ib (GSD Ib) is a rare hereditary glycogen disorder that results in inadequate maintenance of glucose homeostasis, accumulation of glycogen in different organs, loss and dysfunction of neutrophils. Crohn's-like disease is observed in up to 24-77% of GDS Ib cases. Recently, empagliflozin has been recommended as a treatment for neutrophil dysfunction in GDS Ib patients with or without Crohn's-like disease. There are no guidelines for the treatment of inflammatory bowel disease (IBD) manifestation in GSD Ib patients, although some cases have been treated with granulocyte colony-stimulating factor and others with IBD conventional therapy, resulting in partial IBD remission. Herein, we describe a child with GDS Ib and Crohn's-like disease who was treated with empagliflozin and achieved complete remission after 2 years of treatment. This case is the first one with such a long follow-up evaluation including endoscopic and magnetic resonance enterography assessment. Our clinical evidence of remission of IBD manifestation in our GSD Ib patient and the role of neutrophils in GDS Ib described in the literature suggest a strong association with IBD pathophysiology and neutrophil function. The use of empagliflozin resulted in significant improvements in gastrointestinal symptoms, reduced drug usage, and enhanced quality of life in the patient, with a favorable safety profile, offering a promising new therapeutic option for this population.

Keywords:  case report; empagliflozin; glycogen storage disease type Ib; inflammatory bowel disease; pediatric

DOI:  https://doi.org/10.1177/17562848231202138
FASEB J. 2023 Nov;37(11): e23216

Aberrant glucose metabolism underlies impaired macrophage differentiation in glycogen storage disease type Ib.

Yuyeon Jang, Tae Sub Park, Byung-Chul Park, Young Mok Lee, Tae-Hwe Heo, Hyun Sik Jun.

  Glycogen storage disease type Ib (GSD-Ib) is an autosomal recessive disorder caused by a deficiency in the glucose-6-phosphate (G6P) transporter (G6PT) that is responsible for transporting G6P into the endoplasmic reticulum. GSD-Ib is characterized by disturbances in glucose homeostasis, neutropenia, and neutrophil dysfunction. Although some studies have explored neutrophils abnormalities in GSD-Ib, investigations regarding monocytes/macrophages remain limited so far. In this study, we examined the impact of G6PT deficiency on monocyte-to-macrophage differentiation using bone marrow-derived monocytes from G6pt-/- mice as well as G6PT-deficient human THP-1 monocytes. Our findings revealed that G6PT-deficient monocytes exhibited immature differentiation into macrophages. Notably, the impaired differentiation observed in G6PT-deficient monocytes seemed to be associated with abnormal glucose metabolism, characterized by enhanced glucose consumption through glycolysis, even under quiescent conditions with oxidative phosphorylation. Furthermore, we observed a reduced secretion of inflammatory cytokines in G6PT-deficient THP-1 monocytes during the inflammatory response, despite their elevated glucose consumption. In conclusion, this study sheds light on the significance of G6PT in monocyte-to-macrophage differentiation and underscores its importance in maintaining glucose homeostasis and supporting immune response in GSD-Ib. These findings may contribute to a better understanding of the pathogenesis of GSD-Ib and potentially pave the way for the development of targeted therapeutic interventions.

Keywords:  differentiation; glucose metabolism; glucose-6-phosphate transporter; macrophages; metabolic reprogramming; monocytes

DOI:  https://doi.org/10.1096/fj.202300592RR
J Clin Invest. 2023 Oct 03. pii: e163464. [Epub ahead of print]

A splice-switching oligonucleotide treatment ameliorates glycogen storage disease type 1a with G6PC c.648G>T.

Kentaro Ito, Go Tajima, Chikako Kamisato, Miyuki Tsumura, Mitsuhiro Iwamoto, Yukiko Sekiguchi, Yukinobu Numata, Kyoko Watanabe, Yoshiyuki Yabe, Satomi Kanki, Yusuke Fujieda, Koichi Goto, Yoshitaka Sogawa, Masataka Oitate, Hiroyuki Nagase, Shinnosuke Tsuji, Tomohiro Nishizawa, Masayo Kakuta, Takeshi Masuda, Yoshiyuki Onishi, Makoto Koizumi, Hidefumi Nakamura, Satoshi Okada, Masafumi Matsuo, Kiyosumi Takaishi.

  Glycogen storage disease type 1a (GSD1a) is caused by a congenital deficiency of glucose-6-phosphatase-alpha (G6Pase-α, encoded by G6PC), primarily associated with life-threatening hypoglycemia. Although strict dietary management substantially improves the life expectancy, patients still suffer from intermittent hypoglycemia and develop hepatic complications. Emerging therapies utilizing new modalities such as adeno-associated virus and mRNA with lipid nanoparticles are under development for GSD1a, but potentially require complicated glycemic management throughout life. Here, we present a oligonucleotide-based therapy to produce intact G6Pase-α from a pathogenic human variant, G6PC c.648G>T, the most prevalent variant in East Asia causing aberrant splicing of G6PC. DS-4108b, a splice-switching oligonucleotide, was designed to correct this aberrant splicing, especially in liver. A generated mouse strain with homozygous knock-in of this variant well reflected the pathophysiology of GSD1a patients. DS-4108b recovered hepatic G6Pase activity through splicing correction and prevented hypoglycemia and various hepatic abnormalities in the mice. Moreover, DS-4108b exhibited long-lasting efficacy for more than 12 weeks in the mice with a single dose and favorable pharmacokinetics and tolerability in mice and monkeys. Taking these findings together, this oligonucleotide-based therapy could provide a sustainable and curative therapeutic option under easy disease management for GSD1a patients with G6PC c.648G>T.

Keywords:  Gene therapy; Genetic diseases; Glucose metabolism; Metabolism; Therapeutics

DOI:  https://doi.org/10.1172/JCI163464
Front Mol Neurosci. 2023 ;16 1209703

The role of glycogen synthase kinase 3 beta in neurodegenerative diseases.

Honglu Yu, Min Xiong, Zhentao Zhang.

  Neurodegenerative diseases (NDDs) pose an increasingly prevalent threat to the well-being and survival of elderly individuals worldwide. NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and so on. They are characterized by progressive loss or dysfunction of neurons in the central or peripheral nervous system and share several cellular and molecular mechanisms, including protein aggregation, mitochondrial dysfunction, gene mutations, and chronic neuroinflammation. Glycogen synthase kinase-3 beta (GSK-3β) is a serine/threonine kinase that is believed to play a pivotal role in the pathogenesis of NDDs. Here we summarize the structure and physiological functions of GSK3β and explore its involvement in NDDs. We also discussed its potential as a therapeutic target.

Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; protein aggregation

DOI:  https://doi.org/10.3389/fnmol.2023.1209703
J Dent Sci. 2023 Oct;18(4): 1534-1543

AR-A014418, a glycogen synthase kinase-3β inhibitor, mitigates lipopolysaccharide-induced inflammation in rat dental pulp stem cells via NLR family pyrin domain containing 3 inflammasome impairment.

Huilan Xie, Yi Lin, Fang Fang.

   Background/purpose: Cell pyroptosis and gingival inflammation have been implicated in periodontitis progression. Our previous study revealed that AR-A014418, a pharmacological inhibitor of glycogen synthase kinase-3β (GSK-3β), can enhance the migratory and osteogenic differentiation abilities of rat dental pulp stem cells (rDPSCs). The present study aimed to explore the effect of AR on the inflammation of rDPSCs.
Materials and methods: The primary rDPSCs were isolated and identified by flow cytometry, as well as Oil red O and Alizarin Red S staining. The rDPSCs were cultured and exposed to lipopolysaccharide (LPS) before treating them with different concentrations of AR-A014418. The cell viability was detected using the CCK-8 assay. The generation and secretion of pro-inflammatory cytokines (IL-18, TNF-α, L-1β, and IL-6) were examined by qPCR and ELISA, respectively. To investigate the activation of the NLRP3 inflammasome, the expression levels of pro-caspase 1, cleaved caspase 1, as well as NLRP3 were analyzed by western blotting and immunofluorescence, respectively.
Results: In the rDPSCs, LPS prohibited cell viability and enhanced the generation and secretion of pro-inflammatory cytokines. LPS upregulated NLRP3 and cleaved caspase-1 protein levels and promoted ASC speck formation in the rDPSCs. AR-A014418 administration effectively blocked the LPS-induced inflammation of the rDPSCs in a dose-dependent way. Mechanistically, AR-A014418 significantly restrained the up-regulation of NLRP3 and cleaved caspase-1 in LPS-treated rDPSCs.
Conclusion: Collectively, our findings suggest that AR-A014418 significantly mitigates LPS-induced inflammation of rDPSCs by blocking the activation of the NLRP3 inflammasome.

Keywords:  Dental pulp stem cell; Glycogen synthase kinase-3β inhibitor; Inflammation; Lipopolysaccharide; NLRP3 inflammasome

DOI:  https://doi.org/10.1016/j.jds.2023.03.010
Biomed Pharmacother. 2023 Sep 28. pii: S0753-3322(23)01390-2. [Epub ahead of print]167 115592

Clinical significance of glycogen synthase kinase 3 (GSK-3) expression and tumor budding grade in colorectal cancer: Implications for targeted therapy.

Silvia Guil-Luna, Aurora Rivas-Crespo, Carmen Navarrete-Sirvent, Ana Mantrana, Alejandra Pera, Rafael Mena-Osuna, Marta Toledano-Fonseca, María Victoria García-Ortíz, Carlos Villar, Maria Teresa Sánchez-Montero, Janna Krueger, Francisco Javier Medina-Fernández, Juan De La Haba-Rodríguez, Auxiliadora Gómez-España, Enrique Aranda, Christopher E Rudd, Antonio Rodríguez-Ariza.

   INTRODUCTION: Glycogen synthase kinase 3 (GSK-3) has been proposed as a novel cancer target due to its regulating role in both tumor and immune cells. However, the connection between GSK-3 and immunoevasive contexture, including tumor budding (TB) has not been previously examined.
METHODS: we investigated the expression levels of total GSK-3 as well as its isoforms (GSK-3β and GSK-3α) and examined their potential correlation with TB grade and the programmed cell death-ligand 1 (PD-L1) in colorectal cancer (CRC) tumor samples. Additionally, we compared the efficacy of GSK-3-inhibition with PD-1/PD-L1 blockade in humanized patient-derived (PDXs) xenografts models of high-grade TB CRC.
RESULTS: we show that high-grade (BD3) TB CRC is associated with elevated expression levels of total GSK-3, specifically the GSK-3β isoform, along with increased expression of PD-L1 in tumor cells. Moreover, we define an improved risk stratification of CRC patients based on the presence of GSK-3+/PD-L1+/BD3 tumors, which are associated with a worse prognosis. Significantly, in contrast to the PD-L1/PD-1 blockade approach, the inhibition GSK-3 demonstrated a remarkable enhancement in the antitumor response. This was achieved through the reduction of tumor buds via necrosis and apoptosis pathways, along with a notable increase of activated tumor-infiltrating CD8+ T cells, NK cells, and CD4- CD8- T cells.
CONCLUSIONS: our study provides compelling evidence for the clinical significance of GSK-3 expression and TB grade in risk stratification of CRC patients. Moreover, our findings strongly support GSK-3 inhibition as an effective therapy specifically targeting high-grade TB in CRC.

Keywords:  Colorectal cancer; GSK-3; Humanized PDXs; PD-L1; Tumor budding

DOI:  https://doi.org/10.1016/j.biopha.2023.115592
Int J Radiat Oncol Biol Phys. 2023 Oct 01. pii: S0360-3016(23)04984-2. [Epub ahead of print]117(2S): S140-S141

Novel Role of Glycogen Synthase Kinase-3β in Determining Cancer Cell Response to Genotoxic Stress through Regulation of 53BP1 Function.

H Allam, S Acklin, M Patra, R Kiss, J Leung, F Xia.

PURPOSE/OBJECTIVE(S): Glycogen synthase kinase-3β (GSK3β) is a multifunctional serine/threonine kinase involved in various cellular processes and signaling pathways. Accumulating evidence suggests GSK3β plays a role in cancer treatment with effects on tumorigenesis and treatment response. We have previously shown that inhibition of GSK3β protects neurons from ionizing radiation-induced apoptosis through upregulation of non-homologous end joining (NHEJ) mediated repair of double strand breaks (DSBs). Here, we investigate the molecular mechanism underlying GSK3β regulation of NHEJ.
MATERIALS/METHODS: Using biochemical, molecular, and genetic approaches, we investigated the physical and functional interaction between GSK3β and 53BP1. Cultured human tumor cells were utilized as model system to further characterize how GSK3β controls 53BP1 function in DNA DSB recognition and repair. Finally, we employed a cell biology approach to genetically and pharmacologically manipulate GSK3β activity and test how the GSK3β-53BP1 axis impacts tumor cytotoxic response to PARP inhibitor (PARPi) and radiation therapy.
RESULTS: We illustrate that GSK3β directly interacts with 53BP1 and phosphorylates 53BP1 at threonine 334 amino acid (T334) within a region heavily phosphorylated by several stress kinases. Phosphorylation at T334 inhibits 53BP1's function in recruitment to DNA DSB sites as well as canonical NHEJ. Furthermore, our results identify GSK3β regulation of 53BP1 function in NHEJ is achieved through suppression of downstream mediators, RIF1 and PTIP, and their function. In contrast, GSK3β enhances single strand DNA resection and promotes homologous recombination (HR) repair. Most importantly, genetic and pharmacologic inhibition of GSK3β-53BP1 signaling axis dramatically enhances the cytotoxic response of BRCA1-deficit cancer cells to PARPi. The assessment of the effect of GSK3β-53BP1 axis on tumor cell response to radiation treatment is underway.
CONCLUSION: This study establishes the connection between GSK3β and DSB repair through its phosphorylation and regulation of 53BP1 pathways. Moreover, it demonstrates that GSK3β kinase activity uniquely results in inhibition of 53BP1 as opposed to other kinases that enhance 53BP1 function. Importantly, this novel signaling axis provides a strategy for targeting cancer cell resistance to PARPi.

DOI: https://doi.org/10.1016/j.ijrobp.2023.06.550
J Chromatogr B Analyt Technol Biomed Life Sci. 2023 Oct 01. pii: S1570-0232(23)00310-0. [Epub ahead of print]1229 123900

Rapid ultra-performance liquid chromatography-tandem mass spectrometry method for the simultaneous determination of three characteristic urinary saccharide metabolites in patients with glycogen storage diseases (type Ⅰb and Ⅱ).

Jianwei Ren, Yufang Ma, Mingsheng Ma, Juan Ding, Jingjing Jiang, Xin Zheng, Xiaohong Han.

  Urinary 1,5-anhydroglucitol (1, 5-AG), 6-α-D-glucopyranosyl-maltotriose (Glc4) and maltotetraose (M4) are important biomarkers for glycogen storage disease (types Ib and Ⅱ). This study aimed to develop and validate an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to detect these three urinary saccharide metabolites. Urine samples were diluted and then analyzed. Chromatographic separation was performed on an Acquity™ UPLC Amide column (2.1 × 100 mm, 1.7 μm) with gradient elution. The quantitation of analytes was achieved on a 5500 Qtrap mass spectrometer using negative multiple reaction monitoring (MRM) mode. The calibration curves for all analytes were linear over the range of 0.500 to 100 μg/mL with a correlation coefficient, R2 ≥ 0.999. The percent relative standard deviations (RSD%) were ≤12.8%, and the percent relative errors (RE%) were in the range of -11.7%-11.0%. The relative matrix effects of all analytes were between 87.2% and 104% with RSD% < 3.10% across three concentrations. The developed analytical method was simple, accurate, and reliable for rapid and simultaneous analysis of these three urinary saccharide metabolites. It was applied to healthy volunteers and patients. To our knowledge, it was the first validated assay for urinary maltotetraose quantification. This work provides support for exploring the potential of maltotetraose as a biomarker for Pompe disease.

Keywords:  Glycogen storage disease; Saccharide metabolites; UPLC-MS/MS; Urine

DOI:  https://doi.org/10.1016/j.jchromb.2023.123900