bims-glecem 2023-10-01 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2023–10–01
sixteen papers selected by
Dipsikha Biswas, Københavns Universitet

Glycogen storage disease with massive left ventricular hypertrophy and increased native T1: a case report.
Generation of three induced pluripotent stem cell lines from patients with glycogen storage disease type III.
Creation of an iPSC-Based Skeletal Muscle Model of McArdle Disease Harbouring the Mutation c.2392T>C (p.Trp798Arg) in the PYGM Gene.
Improved Enzyme Replacement Therapy with Cipaglucosidase Alfa/Miglustat in Infantile Pompe Disease.
An early onset benign myopathy with glycogen storage caused by a de novo 1.4 Mb-deletion of chromosome 14.
Cold Exposure Regulates Hepatic Glycogen and Lipid Metabolism in Newborn Goats.
Omics-Based Approaches for the Characterization of Pompe Disease Metabolic Phenotypes.
Development of a rapid simultaneous assay of two urinary tetrasaccharide metabolites using differential ion mobility and tandem mass spectrometry and its application to patients with glycogen storage disease (type Ib and II).
CARBOHYDRATES METABOLISM IN THE BLOOD OF RATS WITH IMPAIRED GLUCOSE TOLERANCE UNDER LONG TERM MELATONIN INJECTIONS.
Cytocompatibility and Osteoinductive Properties of Collagen-Fibronectin Hydrogel Impregnated with siRNA Targeting Glycogen Synthase Kinase 3β: In Vitro Study.
Can a modified ketogenic diet be a nutritional strategy for patients with McArdle disease? Results from a randomized, single-blind, placebo-controlled, cross-over study.
MicroRNAs as Potential Regulators of GSK-3β in Renal Cell Carcinoma.
Are Anti-rhGAA Antibodies a Determinant of Treatment Outcome in Adults with Late-Onset Pompe Disease? A Systematic Review.
A Comprehensive Update on Late-Onset Pompe Disease.
Diabetic Endothelial Cell Glycogen Synthase Kinase 3β Activation Induces VCAM1 Ectodomain Shedding.
The effects of postprandial exercise and meal glycemic index on plasma glucose and glucoregulatory hormone responses after Roux-en-Y gastric bypass.

Eur Heart J Case Rep. 2023 Sep;7(9): ytad458

Glycogen storage disease with massive left ventricular hypertrophy and increased native T1: a case report.

Jie Wang, Lutong Pu, Yuchi Han, Yucheng Chen.

   Background: Glycogen storage disease (GSD) type Ⅲa is a rare autosomal recessive disorder resulting in the accumulation of abnormally structured glycogen in the liver, skeletal muscle, and cardiac muscle. Cardiovascular magnetic resonance (CMR) tissue characteristics in GSD have rarely been reported.
Case summary: We report a 24-year-old male patient suffering from recurrent palpitation and atypical chest pain for 5 years with suspected hypertrophic cardiomyopathy. Laboratory tests revealed an elevated creatine kinase, and physical exam revealed hepatosplenomegaly. Cardiovascular magnetic resonance demonstrated asymmetrical massive left ventricular hypertrophy with a maximal thickness of 34.6 mm in the septum. In the regions with focal late gadolinium enhancement (LGE) in the anterior septum, both native T1 and extracellular volume (ECV) are elevated. However, in the LGE-negative regions of the myocardium, native T1 was elevated without elevation in ECV (septum, 22.7%; free wall, 20.9%). Whole exome sequencing revealed a novel pathogenic homozygous nonsense variant of the AGL gene (c.4284 T > G, p. Tyr1428*), confirming the diagnosis of the patients as GSD type Ⅲa.
Discussion: This case showed increased diffuse native T1 but not ECV on CMR in LGE-negative myocardium in GSD, which indicates that the T1 value is increased with an accumulation of glycogen in the myocardium, but the ECV space was not expanded in this process. Genetic testing should be obtained in severe LV hypertrophy when multi-organ involvement is present, and myocardial tissue characterization is discrepant between T1 elevation and normal ECV to consider glycogen storage disorder.

Keywords:  Case report; Glycogen storage disease; Hypertrophic cardiomyopathy; Late gadolinium enhancement; T1 mapping

DOI:  https://doi.org/10.1093/ehjcr/ytad458
Stem Cell Res. 2023 Sep 23. pii: S1873-5061(23)00200-3. [Epub ahead of print]72 103214

Generation of three induced pluripotent stem cell lines from patients with glycogen storage disease type III.

Lucille Rossiaud, Emilie Pellier, Manon Benabides, Xavier Nissan, Giuseppe Ronzitti, Lucile Hoch.

Glycogen storage disease type III (GSDIII) is an autosomal recessive disorder characterized by a deficiency of glycogen debranching enzyme (GDE) leading to cytosolic glycogen accumulation and inducing liver and muscle pathology. Skin fibroblasts from three GSDIII patients were reprogrammed into induced pluripotent stem cells (iPSCs) using non-integrated Sendai virus. All of the three lines exhibited normal morphology, expression of pluripotent markers, stable karyotype, potential of trilineage differentiation and absence of GDE expression, making them valuable tools for modeling GSDIII disease in vitro, studying pathological mechanisms and investigating potential treatments.

DOI: https://doi.org/10.1016/j.scr.2023.103214
Biomedicines. 2023 Aug 31. pii: 2434. [Epub ahead of print]11(9):

Creation of an iPSC-Based Skeletal Muscle Model of McArdle Disease Harbouring the Mutation c.2392T>C (p.Trp798Arg) in the PYGM Gene.

Victoria Cerrada, Inés García-Consuegra, Joaquín Arenas, M Esther Gallardo.

  McArdle disease is a rare autosomal recessive condition caused by mutations in the PYGM gene. This gene encodes the skeletal muscle isoform of glycogen phosphorylase or myophosphorylase. Patients with McArdle disease have an inability to obtain energy from their muscle glycogen stores, which manifests as a marked exercise intolerance. Nowadays, there is no cure for this disorder and recommendations are intended to prevent and mitigate symptoms. There is great heterogeneity among the pathogenic variants found in the PYGM gene, and there is no obvious correlation between genotypes and phenotypes. Here, we present the generation of the first human iPSC-based skeletal muscle model harbouring the second most frequent mutation in PYGM in the Spanish population: NM_005609.4: c.2392T>C (p.Trp798Arg). To this end, iPSCs derived from a McArdle patient and a healthy control were both successfully differentiated into skeletal muscle cells using a small molecule-based protocol. The created McArdle skeletal muscle model was validated by confirming distinctive biochemical aspects of the disease such as the absence of myophosphorylase, the most typical biochemical feature of these patients. This model will be very valuable for use in future high-throughput pharmacological screenings.

Keywords:  McArdle disease; PYGM; disease modelling; iPSCs; induced pluripotent stem cell; skeletal muscle differentiation

DOI:  https://doi.org/10.3390/biomedicines11092434
Pharmaceuticals (Basel). 2023 Aug 23. pii: 1199. [Epub ahead of print]16(9):

Improved Enzyme Replacement Therapy with Cipaglucosidase Alfa/Miglustat in Infantile Pompe Disease.

Lina Fiege, Ibrahim Duran, Thorsten Marquardt.

  Pompe disease is a lysosomal storage disorder with impaired glycogen degradation caused by a deficiency of the enzyme acid α-glucosidase (GAA). Children with the severe infantile form do not survive beyond the first year of life without treatment. Since 2006, enzyme replacement therapy (ERT) with Alglucosidase alfa (Myozyme) has been available, which is a recombinant human GAA (rhGAA). Myozyme therapy has prolonged the life span of affected patients, but many patients showed a continuing, albeit slower, disease progression. A new generation of rhGAA, Cipaglucosidase alfa (Amicus) has a higher content of mannose-6-phosphate residues, which are necessary for efficient cellular uptake and lysosomal targeting. Cipaglucosidase alfa is co-administered with an enzyme stabilizer, Miglustat, which also optimizes the pharmacological properties. In mouse models, the superiority of Cipaglucosidase alfa/Miglustat compared to the previous standard therapy could be determined. Here, we report the disease course of a patient with severe infantile M. Pompe, who showed serious progression even with high-dose standard of care ERT. Changing the therapy to Cipaglucosidase alfa/Miglustat improved respiratory failure, cardiomyopathy, and motor functions significantly. The patient could be weaned from respiratory support and oxygen supplementation. Cardiac function was normalized. Most impressively, the patient, who had lost nearly all motor skills, acquired head control, learned to speak, and could move his wheelchair by himself. Overall, the patient's clinical situation has improved dramatically with the new ERT.

Keywords:  Cipaglucosidase alfa; Myozyme; Pompe disease; enzyme replacement therapy; glycogen storage disease type II

DOI:  https://doi.org/10.3390/ph16091199
Neuromuscul Disord. 2023 Aug 25. pii: S0960-8966(23)00706-X. [Epub ahead of print]

An early onset benign myopathy with glycogen storage caused by a de novo 1.4 Mb-deletion of chromosome 14.

Gianmarco Severa, Alessandra Pennisi, Christine Barnerias, Chiara Fiorillo, Marcello Scala, Valentina Taglietti, Andreea Iuliana Cojocaru, Dima Jouni, Lucie Tosca, Gérard Tachdjian, Isabelle Desguerre, François-Jérome Authier, Robert-Yves Carlier, Corinne Metay, Camille Verebi, Edoardo Malfatti.

  Early onset myopathies are a clinically and histologically heterogeneous monogenic diseases linked to approximately 90 genes. Molecular diagnosis is challenging, especially in patients with a mild phenotype. We describe a 26-year-old man with neonatal hypotonia, motor delay and seizures during infancy, and non-progressive, mild muscular weakness in adulthood. Serum Creatine kinase level was normal. Whole-body muscle MRI showed thin muscles, and brain MRI was unremarkable. A deltoid muscle biopsy showed glycogen storage. WGS revealed a de novo 1.4 Mb-deletion of chromosome 14, confirmed by Array-CGH. This microdeletion causes the loss of ten genes including RALGAPA1, encoding for RalA, a regulator of glucose transporter 4 (GLUT4) expression at the membrane of myofibers. GLUT4 was overexpressed in patient's muscle. Here we highlight the importance to search for chromosomal alterations in the diagnostic workup of early onset myopathies.

Keywords:  Early onset myopathies; GLUT4; Glycogen storage; RALGAPA1; WES, aCGH

DOI:  https://doi.org/10.1016/j.nmd.2023.08.011
Int J Mol Sci. 2023 Sep 20. pii: 14330. [Epub ahead of print]24(18):

Cold Exposure Regulates Hepatic Glycogen and Lipid Metabolism in Newborn Goats.

Duo Su, Tianhui Zhou, Yan Wang, Linjie Wang.

  Cold exposure influences liver metabolism, thereby affecting energy homeostasis. However, the gene regulatory network of the liver after cold exposure remains poorly understood. In this study, we found that 24 h cold exposure (COLD, 6 °C) increased plasma glucose (GLU) levels, while reducing plasma non-esterified fatty acid (NEFA) and triglyceride (TG) levels compared to the room temperature (RT, 25 °C) group. Cold exposure increased hepatic glycogen content and decreased hepatic lipid content in the livers of newborn goats. We conducted RNA-seq analysis on the livers of newborn goats in both the RT and cold exposure groups. A total of 1600 genes were identified as differentially expressed genes (DEGs), of which 555 genes were up-regulated and 1045 genes were down-regulated in the cold exposure group compared with the RT group. Cold exposure increased the expression of genes involved in glycolysis, glycogen synthesis, and fatty acid degradation pathways. These results can provide a reference for hepatic lipid and glycogen metabolism in newborn goats after cold exposure.

Keywords:  cold exposure; glycogen metabolism; goats; lipid metabolism; liver

DOI:  https://doi.org/10.3390/ijms241814330
Biology (Basel). 2023 Aug 23. pii: 1159. [Epub ahead of print]12(9):

Omics-Based Approaches for the Characterization of Pompe Disease Metabolic Phenotypes.

Nuria Gómez-Cebrián, Elena Gras-Colomer, José Luis Poveda Andrés, Antonio Pineda-Lucena, Leonor Puchades-Carrasco.

  Lysosomal storage disorders (LSDs) constitute a large group of rare, multisystemic, inherited disorders of metabolism, characterized by defects in lysosomal enzymes, accessory proteins, membrane transporters or trafficking proteins. Pompe disease (PD) is produced by mutations in the acid alpha-glucosidase (GAA) lysosomal enzyme. This enzymatic deficiency leads to the aberrant accumulation of glycogen in the lysosome. The onset of symptoms, including a variety of neurological and multiple-organ pathologies, can range from birth to adulthood, and disease severity can vary between individuals. Although very significant advances related to the development of new treatments, and also to the improvement of newborn screening programs and tools for a more accurate diagnosis and follow-up of patients, have occurred over recent years, there exists an unmet need for further understanding the molecular mechanisms underlying the progression of the disease. Also, the reason why currently available treatments lose effectiveness over time in some patients is not completely understood. In this scenario, characterization of the metabolic phenotype is a valuable approach to gain insights into the global impact of lysosomal dysfunction, and its potential correlation with clinical progression and response to therapies. These approaches represent a discovery tool for investigating disease-induced modifications in the complete metabolic profile, including large numbers of metabolites that are simultaneously analyzed, enabling the identification of novel potential biomarkers associated with these conditions. This review aims to highlight the most relevant findings of recently published omics-based studies with a particular focus on describing the clinical potential of the specific metabolic phenotypes associated to different subgroups of PD patients.

Keywords:  Pompe disease; glycogen storage disease; lysosomal storage disorders; metabolic phenotype; multi-omics; omics

DOI:  https://doi.org/10.3390/biology12091159
Anal Bioanal Chem. 2023 Sep 29.

Development of a rapid simultaneous assay of two urinary tetrasaccharide metabolites using differential ion mobility and tandem mass spectrometry and its application to patients with glycogen storage disease (type Ib and II).

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

  Glucose tetrasaccharide (Glc4) and maltotetraose (M4) are important biomarkers for Pompe disease and other glycogen storage diseases (GSDs). With the development of new treatments for GSDs, more specific and sensitive bioanalytical methods are needed to determine biomarkers. In recent years, differential mobility spectrometry (DMS) has become an effective analytical technique with high selectivity and specificity. This study aimed to develop an efficient analytical method for the two urinary tetrasaccharide metabolites using DMS and apply it to patients with GSDs (type Ib and II). Urine samples were directly diluted and injected into liquid chromatography-differential mobility spectrometry tandem mass spectrometry (LC-DMS-MS/MS). Chromatographic separation was performed on an Acquity™ UPLC BEH Amide column (2.1 × 50 mm, 1.7 μm) with a short gradient elution of 2.6 min. DMS-MS/MS was used to detect two urinary tetrasaccharide metabolites in a negative multiple reaction monitoring mode with isopropanol as a modifier. A total of 20 urine samples from 6 healthy volunteers and 10 patients with GSDs (type Ib and II) were collected for analysis. The method was linear over a concentration range of 0.5~100.0 µg/mL for each urinary tetrasaccharide (r≥0.99). The intra- and inter-day precision RSD% were less than 14.3%, and the accuracy RE% were in the range of -14.3~13.4%. The relative matrix effect was between 86.6 and 114.3%. No carryover or interference was observed. Patients with GSDs (type Ib and II) had significantly higher median urinary Glc4 (P=0.001) and M4 (P=0.012) excretion than healthy subjects. The developed method was simple, rapid, sensitive, and specific. It was successfully applied to healthy volunteers and patients with GSDs (type Ib and II). DMS technology greatly improved analysis efficiency and provided high sensitivity and specificity.

Keywords:  Biomarkers; Differential mobility spectrometry; Glucose tetrasaccharide; Glycogen storage diseases; Maltotetraose

DOI:  https://doi.org/10.1007/s00216-023-04964-5
Wiad Lek. 2023 ;76(8): 1761-1767

CARBOHYDRATES METABOLISM IN THE BLOOD OF RATS WITH IMPAIRED GLUCOSE TOLERANCE UNDER LONG TERM MELATONIN INJECTIONS.

Oleksandra Yu Kushnir, Iryna M Yaremii, Kyrylo A Pantsiuk, Volodymyr V Vivsyannuk, Diana M Tymkul, Kateryna V Vlasova, Olena V Vlasova.

   OBJECTIVE: The aim: To determine the influence of melatonin on the glucose level and content of malondialdehyde, activities of pyruvate kinase and glucose-6-phosphate dehydrogenase enzymes in the blood; histochemical features of glycogen distribution in liver of rats with impaired glucose tolerance.
PATIENTS AND METHODS: Materials and methods: Diabetes in rats was induced by intra-abdominal injection of a 5% solution of alloxan monohydrate at the rate of 170 mg/kg of body weight. Four days after animals were divided into rats with impaired glucose tolerance and melatonin-group with impaired glucose tolerance (5 mg/ kg «Sigma» USA, daily and intraperitoneal for 42 days starting from 5th day). Impaired glucose tolerance was determined by measurement of glucose profiles - fasting <5.6 mmol/l; postprandial (2h post-load) 7.8 - 11.0 mmol/l. Histochemical examination of the liver was performed according to the standard method of PAS-reaction staining. Statistical analysis was performed using Statistica 10 StatSoft Inc.
RESULTS: Results: Pyruvate kinase activity in erythrocytes and optical density of glycogen in hepatocytes of animals with impaired glucose tolerance decreased on 18% and 11%, activity of glucose-6-phosphate dehydrogenase and content of malondialdehyde increased on 35% and 23%, respectively compared with the control. We have reached the recovery of the pyruvate kinase and normalization of glucose-6-phosphate dehydrogenase activities, malondialdehyde levels, glucose profiles in the blood as well as glycogen distribution in the liver caused by melatonin injections.
CONCLUSION: Conclusions: We have determined that long term melatonin injections did better glucose tolerance in rats.

Keywords:   alloxan-induced diabetes mellitus ; antioxidant ; glucose concentration

DOI:  https://doi.org/10.36740/WLek202308109
Biomedicines. 2023 Aug 24. pii: 2363. [Epub ahead of print]11(9):

Cytocompatibility and Osteoinductive Properties of Collagen-Fibronectin Hydrogel Impregnated with siRNA Targeting Glycogen Synthase Kinase 3β: In Vitro Study.

Elena V Galitsyna, Anastasiia A Buianova, Vadim I Kozhukhov, Sergey P Domogatsky, Tatiana B Bukharova, Dmitriy V Goldshtein.

  In this study, we developed an osteoplastic material based on collagen-fibronectin hydrogel impregnated with siRNA molecules targeting glycogen synthase kinase 3β (GSK3β), which inhibits the osteogenic differentiation of mesenchymal stem cells. The hydrogel impregnated with polyplexes containing siRNA GSK3β and polyethylenimine has been shown to have no cytotoxic effect: there was no statistically significant change in the cell's viability after 7 days of incubation in its presence compared to the control group. On days 2 and 7, an increase in the level of expression of markers of osteogenic differentiation was observed, which confirms the osteoinductive qualities of the material. It has been demonstrated that the hydrogel maintains cell adhesion. Our results obtained in vitro indicate cytocompatibility and osteoinductive properties of collagen-fibronectin hydrogel impregnated with siRNA GSK3β molecules.

Keywords:  GSK3β; MSCs; PEI; collagen–fibronectin hydrogel; osteogenic differentiation; siRNA

DOI:  https://doi.org/10.3390/biomedicines11092363
Clin Nutr. 2023 Sep 20. pii: S0261-5614(23)00293-5. [Epub ahead of print]42(11): 2124-2137

Can a modified ketogenic diet be a nutritional strategy for patients with McArdle disease? Results from a randomized, single-blind, placebo-controlled, cross-over study.

Nicoline Løkken, Maja Risager Nielsen, Mads Godtfeldt Stemmerik, Charlotte Ellerton, Karoline Lolk Revsbech, Margaret Macrae, Anna Slipsager, Bjørg Krett, Gry Hatting Beha, Frida Emanuelsson, Gerrit van Hall, Rosaline Quinlivan, John Vissing.

   BACKGROUND: McArdle disease is caused by myophosphorylase deficiency leading to blocked glycogenolysis in skeletal muscle. Consequently, individuals with McArdle disease have intolerance to physical activity, muscle fatigue, and pain. These symptoms vary according to the availability of alternative fuels for muscle contraction. In theory, a modified ketogenic diet (mKD) can provide alternative fuels in the form of ketone bodies and potentially boost fat oxidation.
METHODS: This randomized, single-blind, placebo-controlled, cross-over study aimed to investigate if a mKD improves exercise capacity in individuals with McArdle disease. Participants were randomized to follow a mKD (75-80% fat, 15% protein, 5-10% carbohydrates) or placebo diet (PD) first for three weeks, followed by a wash-out period, and then the opposite diet. The primary outcome was change in heart rate during constant-load cycling. Secondary outcomes included change in plasma metabolites, perceived exertion, indirect calorimetry measures, maximal exercise capacity, and patient-reported outcomes.
RESULTS: Fifteen out of 20 patients with genetically verified McArdle disease completed all study visits, and 14 were included in the data analyses. We found that the mKD induced a metabolic shift towards increased fat oxidation (∼60% increase), and a 19-fold increase in plasma β-hydroxybutyrate (p < 0.05). The mKD did not improve heart rate responses during constant-load cycling but did improve patient-reported outcomes and maximal exercise capacity (∼20% increase) compared to the PD.
CONCLUSION: The mKD did not alleviate all McArdle disease-related symptoms but did induce some positive changes. To date, no satisfactory treatment options exist other than exercise training. To that end, a mKD can be a possible nutritional strategy for some individuals with McArdle disease who are motivated to undertake a restrictive diet.
CLINICAL TRIAL REGISTRATION: clinical trials.gov: NCT04044508.

Keywords:  Glycogen storage disease type V; McArdle disease; Modified ketogenic diet; Randomized clinical trial

DOI:  https://doi.org/10.1016/j.clnu.2023.09.006
Curr Issues Mol Biol. 2023 Sep 11. 45(9): 7432-7448

MicroRNAs as Potential Regulators of GSK-3β in Renal Cell Carcinoma.

Masaki Murata, Vladimir Bilim, Yuko Shirono, Akira Kazama, Kaede Hiruma, Masayuki Tasaki, Yoshihiko Tomita.

  The prognosis of patients with advanced renal cell carcinoma (RCC) has improved with newer therapies, including molecular-targeted therapies and immuno-oncology agents. Despite these therapeutic advances, many patients with metastatic disease remain uncured. Inhibition of glycogen synthase kinase-3β (GSK-3β) is a promising new therapeutic strategy for RCC; however, the precise regulatory mechanism has not yet been fully elucidated. MicroRNAs (miRNAs) act as post-translational regulators of target genes, and we investigated the potential regulation of miRNAs on GSK-3β in RCC. We selected nine candidate miRNAs from three databases that could potentially regulate GSK-3β. Among these, hsa-miR-4465 (miR-4465) was downregulated in RCC cell lines and renal cancer tissues. Furthermore, luciferase assays revealed that miR-4465 directly interacted with the 3' untranslated region of GSK-3β, and Western blot analysis showed that overexpression of miR-4465 significantly decreased GSK-3β protein expression. Functional assays showed that miR-4465 overexpression significantly suppressed cell invasion of A498 and Caki-1 cells; however, cell proliferation and migration were suppressed only in Caki-1 and A498 cells, respectively, with no effect on cell cycle and apoptosis. In conclusion, miR-4465 regulates GSK-3β expression but does not consistently affect RCC cell function as a single molecule. Further comprehensive investigation of regulatory networks is required in this field.

Keywords:  GSK-3β; competing endogenous RNA; hsa-miR-4465; microRNA; renal cell carcinoma

DOI:  https://doi.org/10.3390/cimb45090470
Biomolecules. 2023 09 19. pii: 1414. [Epub ahead of print]13(9):

Are Anti-rhGAA Antibodies a Determinant of Treatment Outcome in Adults with Late-Onset Pompe Disease? A Systematic Review.

Imke A M Ditters, Harmke A van Kooten, Nadine A M E van der Beek, Ans T van der Ploeg, Hidde H Huidekoper, Johanna M P van den Hout.

   BACKGROUND: Pompe disease is a lysosomal storage disease characterised by skeletal and respiratory muscle weakness. Since 2006, enzyme replacement therapy (ERT) with alglucosidase alfa has been available. ERT significantly improves the prognosis of patients with Pompe disease. The effect of high antibody titres on treatment response in adults with late-onset Pompe disease (LOPD) remains unclear but may contribute to interpatient variation. We therefore conducted a systematic review on this subject.
METHODS: A systematic search was performed in Embase, Medline Ovid, Web of Science, Psych Info Ovid, Cochrane (Clinical Trials only), and Google Scholar (random top-200). Articles were included if they involved adults with LOPD treated with alglucosidase alfa and mentioned anti-rhGAA antibodies or antibody titres. In addition, articles mentioning dosages different from the standard recommended dosage were included.
RESULTS: Our literature search retrieved 2562 publications, and 17 fulfilled our selection criteria, describing 443 cases. Seven publications reported on anti-rhGAA antibody titres on a group level, with the percentage of patients with a high titre as defined in the included articles ranging from 0-33%. Six publications reported on the effect of anti-rhGAA antibody titre on clinical course, and four found no correlation. Two studies reported a negative effect on treatment. The first study found a greater improvement in Medical Research Council (MRC) score in patients with no detectable antibody titre. In the second study, a patient discontinued ERT due to a declining neuromuscular state as a result of high anti-rhGAA antibody titres. Seven publications reported on 17 individual patients with a high antibody titre (range 1:12,800-1:3,906,250). In only two cases were high-sustained neutralising antibodies reported to interfere with treatment efficacy.
CONCLUSIONS: No clear effect of anti-rhGAA IgG antibodies on treatment response could be established for the majority of LOPD patients with a high antibody titre. In a minority of patients, a clinical decline related to (possible) interference of anti-rhGAA antibodies was described.

Keywords:  anti-rhGAA antibodies; enzyme replacement therapy; late-onset Pompe disease; systematic review

DOI:  https://doi.org/10.3390/biom13091414
Biomolecules. 2023 Aug 22. pii: 1279. [Epub ahead of print]13(9):

A Comprehensive Update on Late-Onset Pompe Disease.

Beatrice Labella, Stefano Cotti Piccinelli, Barbara Risi, Filomena Caria, Simona Damioli, Enrica Bertella, Loris Poli, Alessandro Padovani, Massimiliano Filosto.

  Pompe disease (PD) is an autosomal recessive disorder caused by mutations in the GAA gene that lead to a deficiency in the acid alpha-glucosidase enzyme. Two clinical presentations are usually considered, named infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD), which differ in age of onset, organ involvement, and severity of disease. Assessment of acid alpha-glucosidase activity on a dried blood spot is the first-line screening test, which needs to be confirmed by genetic analysis in case of suspected deficiency. LOPD is a multi-system disease, thus requiring a multidisciplinary approach for efficacious management. Enzyme replacement therapy (ERT), which was introduced over 15 years ago, changes the natural progression of the disease. However, it has limitations, including a reduction in efficacy over time and heterogeneous therapeutic responses among patients. Novel therapeutic approaches, such as gene therapy, are currently under study. We provide a comprehensive review of diagnostic advances in LOPD and a critical discussion about the advantages and limitations of current and future treatments.

Keywords:  chaperone; diagnosis; enzyme replacement therapy; gene therapy; late-onset Pompe disease; multi-system disease; myopathy

DOI:  https://doi.org/10.3390/biom13091279
Int J Mol Sci. 2023 Sep 14. pii: 14105. [Epub ahead of print]24(18):

Diabetic Endothelial Cell Glycogen Synthase Kinase 3β Activation Induces VCAM1 Ectodomain Shedding.

Masuma Akter Brishti, Somasundaram Raghavan, Kennedy Lamar, Udai P Singh, Daniel M Collier, M Dennis Leo.

  Soluble cell adhesion molecules (sCAMs) are secreted ectodomain fragments of surface adhesion molecules, ICAM1 and VCAM1. sCAMs have diverse immune functions beyond their primary function, impacting immune cell recruitment and activation. Elevated sVCAM1 levels have been found to be associated with poor cardiovascular disease (CVD) outcomes, supporting VCAM1's role as a potential diagnostic marker and therapeutic target. Inhibiting sVCAM1's release or its interaction with immune cells could offer cardioprotection in conditions such as diabetes. Membrane-bound surface adhesion molecules are widely expressed in a wide variety of cell types with higher expression in endothelial cells (ECs). Still, the source of sCAMs in the circulation is not clear. Hypothesizing that endothelial cells (ECs) could be a potential source of sCAMs, this study investigated whether dysfunctional EC signaling mechanisms during diabetes cause VCAM1 ectodomain shedding. Our results from samples from an inducible diabetic mouse model revealed increased sVCAM1 plasma levels in diabetes. Protein analysis indicated upregulated VCAM1 expression and metalloproteases ADAM10 and ADAM17 in diabetic ECs. ADAMs are known for proteolytic cleavage of adhesion molecules, contributing to inflammation. GSK3β, implicated in EC VCAM1 expression, was found to be activated in diabetic ECs. GSK3β activation in control ECs increased ADAM10/17 and VCAM1. A GSK3β inhibitor reduced active GSK3β and VCAM1 ectodomain shedding. These findings suggest diabetic ECs with elevated GSK3β activity led to VCAM1 upregulation and ADAM10/17-mediated sVCAM1 shedding. This mechanism underscores the potential therapeutic role of GSK3β inhibition in reducing the levels of circulating sVCAM1. The complex roles of sCAMs extend well beyond CVD. Thus, unraveling the intricate involvement of sCAMs in the initiation and progression of vascular disease, particularly in diabetes, holds significant therapeutic potential.

Keywords:  diabetic vascular disease; endothelial cells; soluble vascular cell adhesion molecule 1

DOI:  https://doi.org/10.3390/ijms241814105
Am J Physiol Endocrinol Metab. 2023 Sep 27.

The effects of postprandial exercise and meal glycemic index on plasma glucose and glucoregulatory hormone responses after Roux-en-Y gastric bypass.

Tummas Ternhamar, Andreas Møller, Christoffer Martinussen, Maria S Svane, Morten Hindsø, Nils B Jørgensen, Carsten Dirksen, Jens-Erik Beck Jensen, Bolette Hartmann, Jens J Holst, Bente Kiens, Sten Madsbad, Kirstine N Bojsen-Møller.

  Postprandial hypoglycemia is a complication to Roux-en-Y gastric bypass (RYGB), but the effects of postprandial exercise and meal glycemic index (GI) on postprandial glucose and glucoregulatory hormone responses are unknown. Ten RYGB-operated and ten age and weight-matched unoperated women completed four test days in random order ingesting mixed meals with high GI (HGI, GI=93) or low GI (LGI, GI=54), but matched on energy and macronutrient content. Ten minutes after meal completion, participants rested or cycled for 30 minutes at 70% of maximum oxygen uptake (VO2-max). Blood was collected for 4 hours. Postprandial exercise did not lower plasma nadir glucose in RYGB after HGI (HGI/rest 3.7±0.5 versus HGI/Ex 4.1±0.4mmol/L, p=0.070). Replacing HGI with LGI meals raised glucose nadir in RYGB (LGI/rest 4.1±0.5mmol/L, p=0.034) and reduced glucose excursions (Δpeak-nadir) but less so in RYGB (-14% [95%CI: -27; -1]) compared with controls (-33% [-51; -14]). Insulin responses mirrored glucose concentrations. Glucagon-like peptide-1 (GLP-1) responses were greater in RYGB versus controls, and higher with HGI versus LGI. Glucose-dependent insulinotropic polypeptide (GIP) responses were greater after HGI versus LGI in both groups. Post-exercise glucagon responses were lower in RYGB than controls, and noradrenaline responses tended to be lower in RYGB, while adrenaline responses were similar between groups. In conclusion, moderate intensity cycling shortly after meal intake did not increase the risk of postprandial hypoglycemia after RYGB. The low GI meal increased nadir glucose and reduced glucose excursions compared with the high GI meal. RYGB participants had lower post-exercise glucagon responses compared with controls.

Keywords:  Exercise; Glycemic Index; Mixed meal test; Postprandial hypoglycemia; Roux-en-Y gastric bypass

DOI:  https://doi.org/10.1152/ajpendo.00176.2023