bims-glecem Biomed News
on Glycogen metabolism in exercise, cancer and energy metabolism
Issue of 2022‒07‒10
eighteen papers selected by
Dipsikha Biswas, Københavns Universitet



  1. Cell Rep. 2022 Jul 05. pii: S2211-1247(22)00835-X. [Epub ahead of print]40(1): 111041
      Glycogen is the primary energy reserve in mammals, and dysregulation of glycogen metabolism can result in glycogen storage diseases (GSDs). In muscle, glycogen synthesis is initiated by the enzymes glycogenin-1 (GYG1), which seeds the molecule by autoglucosylation, and glycogen synthase-1 (GYS1), which extends the glycogen chain. Although both enzymes are required for proper glycogen production, the nature of their interaction has been enigmatic. Here, we present the human GYS1:GYG1 complex in multiple conformations representing different functional states. We observe an asymmetric conformation of GYS1 that exposes an interface for close GYG1 association, and propose this state facilitates handoff of the GYG1-associated glycogen chain to a GYS1 subunit for elongation. Full activation of GYS1 widens the GYG1-binding groove, enabling GYG1 release concomitant with glycogen chain growth. This structural mechanism connecting chain nucleation and extension explains the apparent stepwise nature of glycogen synthesis and suggests distinct states to target for GSD-modifying therapeutics.
    Keywords:  CP: Molecular biology; structural biology, cryo-EM, Pompe disease, glycogen synthesis
    DOI:  https://doi.org/10.1016/j.celrep.2022.111041
  2. Mol Genet Metab Rep. 2022 Jun;31 100872
      Glycogen storage disease type 1a (GSD Ia) is an inborn error of carbohydrate metabolism. Despite severe hyperlipidemia, GSD Ia patients show limited atherogenesis compared to age-and-gender matched controls. Employing a GSD Ia mouse model that resembles the severe hyperlipidemia in patients, we here found increased atherogenesis in GSD Ia. These data provide a rationale for investigating atherogenesis in GSD Ia in a larger patient cohort.
    Keywords:  Atherosclerosis; G6P, Glucose-6-phosphate; G6PC1, Glucose-6-phosphatase enzyme; GSD Ia, Glycogen storage disease type 1a; Glycogen storage disease type 1a; HDL, High-density lipoprotein; Hyperlipidemia; Ldlr−/−, LDL receptor deficient; PUFA, Poly-unsaturated FA; SFA, Saturated fatty acids; TG, Triglycerides; VLDL, Very-low-density lipoprotein; WTD, Western-type diet
    DOI:  https://doi.org/10.1016/j.ymgmr.2022.100872
  3. Front Pediatr. 2022 ;10 921323
      Background: Glycogen storage disease type Ia is a rare metabolic disorder that leads to excessive glycogen and fat accumulation in organs, characterized by hepatomegaly, hypoglycemia, lactic acidemia, hyperlipidemia, hyperuricemia, puberty delay, and growth retardation. Here, we report on a patient with glycogen storage disease type Ia treated with growth hormone.Case Presentation: A 10-year-old boy had growth retardation for 6 years, and was admitted to clarify the cause of his short stature. We found that his bone age was 5.5 years, significantly lower than his physical age, while his serum IGF-1 and IGFBP-3 were 23.30 and 1620.0 ng/mL, respectively, both lower than normal. His medical history revealed that he had suffered from steatohepatitis, hyperlipidemia, and hypoglycemia since he was 11 months of age. Whole exome sequencing (WES) showed compound heterozygous mutations in exons 2 and 5 of the glucose-6-phosphatase (G6PC) gene on chromosome 17: c.G248A (p.R83H) and c.G648T (p.L216L). The patient was finally diagnosed with GSD Ia. After growth hormone (GH) treatment and corn starch therapy for 14 months, his height significantly increased (by 13 cm). The serum IGF-1 level increased to the normal range but his lipid levels and liver function did not significantly increase.
    Conclusion: We describe a young patient with a compound heterozygous G6PC variant in a Chinese family; his height increased significantly after growth hormone and corn starch interventions. This case emphasizes that WES is essential for early diagnosis, and that growth hormone treatment may increase the height of patients with GSD Ia safely.
    Keywords:  G6PC gene; GSD Ia; compound heterozygous variant; growth hormone treatment; growth retardation
    DOI:  https://doi.org/10.3389/fped.2022.921323
  4. J Gen Physiol. 2022 Sep 05. pii: e202113071. [Epub ahead of print]154(9):
      Glycogen is a key energy substrate in excitable tissue, including in skeletal muscle fibers where it also contributes to local energy production. Transmission electron microscopy imaging has revealed the existence of a heterogenic subcellular distribution of three distinct glycogen pools in skeletal muscle, which are thought to reflect the requirements for local energy stores at the subcellular level. Here, we show that the three main energy-consuming ATPases in skeletal muscles (Ca2+, Na+,K+, and myosin ATPases) utilize different local pools of glycogen. These results clearly demonstrate compartmentalized glycogen metabolism and emphasize that spatially distinct pools of glycogen particles act as energy substrate for separated energy requiring processes, suggesting a new model for understanding glycogen metabolism in working muscles, muscle fatigue, and metabolic disorders. These observations suggest that the distinct glycogen pools can regulate the functional state of mammalian muscle cells and have important implications for the understanding of how the balance between ATP utilization and ATP production is regulated at the cellular level in general and in skeletal muscle fibers in particular.
    DOI:  https://doi.org/10.1085/jgp.202113071
  5. Mol Genet Metab Rep. 2022 Jun;31 100856
      Introduction: Biotinidase synthesis is needed to recycle biotin for essential metabolic reactions. Biotinidase activity is lower than normal levels in advanced liver disease but is higher in hepatic glycogen storage disorders (GSDs), however the cause of this association remains unclear.Methods: In this study, biotinidase activity was measured in plasma samples from 45 individuals with hepatic GSDs; GSDI (a, b; n = 25) and GSD III (a, b; n = 20), complemented by a chart review to associate biotinidase activity levels with clinical laboratory and imaging findings known to be implicated in these GSDs.
    Results: Our findings showed variation in biotinidase activity levels among subjects with GSD I and III; biotinidase activity correlated positively with hypertriglyceridemia in subjects with GSD I (r = 0.47, P = 0.036) and GSD III (r = 0.58, P = 0.014), and correlated negatively with age (r = -0.50, P = 0.03) in patients with GSD III. Additionally, biotinidase activity was reduced, albeit within the normal range in subjects with evidence of fibrosis/cirrhosis, as compared to subjects with hepatomegaly with or without steatosis (P = 0.002).
    Discussions: These findings suggest that abnormal lipid metabolism in GSD I and III and progressive liver disease in GSD III may influence biotinidase activity levels. We suggest that a prospective, multi-center, longitudinal study designed to assess the significance of monitoring biotinidase activity in a larger cohort with hepatic GSDs is warranted to confirm this observation.
    Take-home message: Altered lipid metabolism and advancing liver fibrosis/cirrhosis may influence biotinidase activity levels in patients with hepatic glycogen storage disease. Thus, longitudinal monitoring of biotinidase activity, when combined with clinical and other biochemical findings may be informative.
    Keywords:  Biomarker; Biotinidase; GSD type I; GSD type III; Hepatic glycogen storage disease; Long-term disease monitoring
    DOI:  https://doi.org/10.1016/j.ymgmr.2022.100856
  6. Front Cell Infect Microbiol. 2022 ;12 866729
      The obligate intracellular bacteria Chlamydia trachomatis store glycogen in the lumen of the vacuoles in which they grow. Glycogen catabolism generates glucose-1-phosphate (Glc1P), while the bacteria can take up only glucose-6-phosphate (Glc6P). We tested whether the conversion of Glc1P into Glc6P could be catalyzed by a phosphoglucomutase (PGM) of host or bacterial origin. We found no evidence for the presence of the host PGM in the vacuole. Two C. trachomatis proteins, CT295 and CT815, are potential PGMs. By reconstituting the reaction using purified proteins, and by complementing PGM deficient fibroblasts, we demonstrated that only CT295 displayed robust PGM activity. Intriguingly, we showed that glycogen accumulation in the lumen of the vacuole of a subset of Chlamydia species (C. trachomatis, C. muridarum, C. suis) correlated with the presence, in CT295 orthologs, of a secretion signal recognized by the type three secretion (T3S) machinery of Shigella. C. caviae and C. pneumoniae do not accumulate glycogen, and their CT295 orthologs lack T3S signals. In conclusion, we established that the conversion of Glc1P into Glc6P was accomplished by a bacterial PGM, through the acquisition of a T3S signal in a "housekeeping" protein. Acquisition of this signal likely contributed to shaping glycogen metabolism within Chlamydiaceae.
    Keywords:  Chlamydia; glycogen, metabolism; phosphoglucomutase (PGM); secretion signal; type 3 secreted effectors
    DOI:  https://doi.org/10.3389/fcimb.2022.866729
  7. Front Mol Neurosci. 2022 ;15 852171
      Glycogen synthase kinase-3 (GSK3) mediates phosphorylation of several hundred proteins, and its aberrant activity is associated with an array of prevalent disorders. The two paralogs, GSK3α and GSK3β, are expressed ubiquitously and fulfill common as well as unique tasks throughout the body. In the CNS, it is established that GSK3 is involved in synaptic plasticity. However, the relative roles of GSK3 paralogs in synaptic plasticity remains controversial. Here, we used hippocampal slices obtained from adult mice to determine the role of each paralog in CA3-CA1 long-term potentiation (LTP) of synaptic transmission, a form of plasticity critically required in learning and memory. Conditional Camk2a Cre-driven neuronal deletion of the Gsk3a gene, but not Gsk3b, resulted in enhanced LTP. There were no changes in basal synaptic function in either of the paralog-specific knockouts, including several measures of presynaptic function. Therefore, GSK3α has a specific role in serving to limit LTP in adult CA1, a postsynaptic function that is not compensated by GSK3β.
    Keywords:  CA3-CA1 synapses; GSK-3 (glycogen synthase kinase 3); GSK-3α; GSK-3β; LTP (long term potentiation); conditional knock out mice; synaptic function; synaptic plasticity
    DOI:  https://doi.org/10.3389/fnmol.2022.852171
  8. Front Endocrinol (Lausanne). 2022 ;13 858832
      Hypoglycemia results from an imbalance between glucose entering the blood compartment and glucose demand, caused by a defect in the mechanisms regulating postprandial glucose homeostasis. Hypoglycemia represents one of the most common metabolic emergencies in childhood, potentially leading to serious neurologic sequelae, including death. Therefore, appropriate investigation of its specific etiology is paramount to provide adequate diagnosis, specific therapy and prevent its recurrence. In the absence of critical samples for biochemical studies, etiological assessment of children with hypoglycemia may include dynamic methods, such as in vivo functional tests, and continuous glucose monitoring. By providing detailed information on actual glucose fluxes in vivo, proof-of-concept studies have illustrated the potential (clinical) application of dynamic stable isotope techniques to define biochemical and clinical phenotypes of inherited metabolic diseases associated with hypoglycemia. According to the textbooks, individuals with glycogen storage disease type I (GSD I) display the most severe hypoglycemia/fasting intolerance. In this review, three dynamic methods are discussed which may be considered during both diagnostic work-up and monitoring of children with hypoglycemia: 1) functional in vivo tests; 2) in vivo metabolic profiling by continuous glucose monitoring (CGM); 3) stable isotope techniques. Future applications and benefits of dynamic methods in children with hypoglycemia are also discussed.
    Keywords:  children; continuous glucose monitoring; fasting challenge; functional tests; hepatic glycogen storage diseases; hypoglycemia; stable isotopes
    DOI:  https://doi.org/10.3389/fendo.2022.858832
  9. Fundam Clin Pharmacol. 2022 Jul 08.
      BACKGROUND: Histamine participates in a variety of physiological functions. The local effects of histamine have a role to provide metabolic energy for the tissues.OBJECTIVES: To study the mechanism whereby histamine affects serum glucose and liver glycogen fractions.
    METHODS: Six groups of ten male rats received two injections with histamine, H1-agonist (dipyridylethylamine), H2-agonist (dimaprit), H1-agonist plus H1-antagonist (cetirizine) or H2-agonist plus H2-antagonist (famotidine). Serum glucose and liver glycogen fractions were measured.
    RESULTS: Histamine caused a significant increase in serum glucose (163.7 ± 5.4 vs. 153.2 ± 3.3 mg/dL, p= 0.023). The effect of histamine was mimicked by selective H1-agonist (164.2 ± 3.5 vs. 152.8 ± 2.9 mg/dL, p= 0.005), but not with H2-agonist (159.3 ± 3.7 vs. 156.3 ± 4.8 mg/dL, p= 0.281). The effect of H1- agonist was abolished in the presence of selective H1- antagonist. Treatment by H1- but not H2-agonist decreased total glycogen by about 35% (30.6 ± 0.5 vs. 47.3 ± 2.8 mg/g wet weight of liver, p= 0.003). The decrease happened wholly in ASG fraction (26.8 ± 1.2 vs. 43.7 ± 3.2 mg/g wet weight of liver, p=0.004), while AIG did not change significantly (4.2 ± 0.5 vs. 4.5 ± 0.4 mg/g wet weight of liver, p=0.724).
    CONCLUSIONS: Histamine causes to decrease glycogen in the liver and increased serum glucose. The effects of histamine were mediated via H1- receptors. ASG was metabolically active fraction of liver glycogen in this process. The results confirm the role of histamine in providing metabolic energy of the tissues.
    Keywords:  Dimaprit; Dipyridylethylamine; Glycogen; Histamine; Liver
    DOI:  https://doi.org/10.1111/fcp.12814
  10. J Clin Endocrinol Metab. 2022 Jul 04. pii: dgac411. [Epub ahead of print]
      CONTEXT: Although previous research has shown the benefit of continuous glucose monitoring (CGM) for hepatic glycogen storage diseases (GSDs), current lack of prospectively collected CGM metrics and glycemic targets for CGM-derived outcomes in the hepatic GSD population limits its use.OBJECTIVE: To assess CGM metrics for glycemic variation and glycemic control in adult patients with GSDIa as compared to matched healthy volunteers.
    DESIGN: Prospective CGM data were collected during the ENGLUPRO GSDIa trial (NCT04311307) in which a Dexcom G6 device was used. Ten adult patients with GSDIa and 10 age-, gender- and BMI-matched healthy volunteers were enrolled. Capillary blood glucose (CBG) was concurrently measured during two standardized 2-hour time intervals. Descriptive (e.g., glycemic variability (GV), time-below-range (TBR), time-in-range (TIR), time-above-range (TAR)) and advanced (i.e., 1 st and 2 nd order derivatives, Fourier analysis) CGM outcomes were calculated. For each descriptive CGM outcome measure 95%CI were computed in patients with GSDIa and healthy volunteers, respectively.
    RESULTS: CGM overestimation was higher under preprandial and level 1 hypoglycemia (i.e. capillary glucose values ≥3.0 mmol/L and < 3.9 mmol/L) conditions. GV and TAR were higher while TIR was lower in patients with GSDIa compared to healthy volunteers (p<0.05). Three patients with GSDIa showed descriptive CGM outcomes outside the calculated 95%CI in GSDIa patients. Advanced CGM analysis revealed a distinct pattern (i.e. 1 st and 2 nd order derivatives and glucose curve amplitude) in each of these 3 patients within the patients group.
    CONCLUSIONS: This is the first study to prospectively compare CGM outcomes between adult patients with GSDIa and matched healthy volunteers. The generation of a set of CGM metrics will provide guidance in using and interpreting CGM data in GSDIa and will be useful for the definition of glycemic targets for CGM in patients with GSDIa. Future studies should investigate the prognostic value of CGM outcomes and their major determinants in patients with GSDIa.
    Keywords:  continuous glucose monitoring; diet; glycogen storage disease type Ia; management; monitoring; precision medicine
    DOI:  https://doi.org/10.1210/clinem/dgac411
  11. Plant Biotechnol (Tokyo). 2022 Mar 25. 39(1): 65-72
      Plants precisely coordinate the balance between cell proliferation and differentiation to ensure the continuous development. In Arabidopsis thaliana, members of glycogen synthase kinase 3 (GSK3) family, which are highly conserved serine/threonine protein kinases among eukaryotes, play important roles in regulating cell proliferation and differentiation during various developmental processes. However, functional roles of GSK3s in the plant lineages except angiosperms remain to be elucidated. Here, we utilized a model liverwort, Marchantia polymorpha, for studies of GSK3, because it has a single GSK3-like kinase, MpGSK. When M. polymorpha was treated with a chemical compound, bikinin, which is known as a specific inhibitor for GSK3-like kinases, growth and morphologies were altered with an expansion of the meristematic region. Similarly, Mpgsk loss-of-function mutants accumulated undifferentiated cell mass with no differentiated tissues. By contrast, overexpression of MpGSK reduced the size of the meristem region. These results suggest that MpGSK plays important roles as a regulator for the balance between cell differentiation and proliferation in M. polymorpha.
    Keywords:  bryophyte; cell differentiation; cell proliferation; glycogen synthase kinase 3; inhibitor
    DOI:  https://doi.org/10.5511/plantbiotechnology.21.1219a
  12. J Biol Chem. 2022 Jun 30. pii: S0021-9258(22)00663-9. [Epub ahead of print] 102221
      Pah1 phosphatidate (PA) phosphatase plays a major role in triacylglycerol synthesis in Saccharomyces cerevisiae by producing its precursor diacylglycerol, and concurrently regulates de novo phospholipid synthesis by consuming its precursor PA. The function of Pah1 requires its membrane localization, which is controlled by its phosphorylation state. Whereas Pah1 is dephosphorylated by the Nem1-Spo7 protein phosphatase, its phosphorylation occurs by multiple known and unknown protein kinases. In this work, we show that Rim11, a yeast homolog of mammalian glycogen synthase kinase-3β, is a protein kinase that phosphorylates Pah1 on serine (Ser-12, Ser-602, and Ser-818) and threonine (Thr-163, Thr-164, Thr-522) residues. Enzymological characterization of Rim11 showed that its Km for Pah1 (0.4 μM) is similar to those of other Pah1-phosphorylating protein kinases, but its Km for ATP (30 μM) is significantly higher than those of these same kinases. Furthermore, we demonstrate Rim11 phosphorylation of Pah1 does not require substrate prephosphorylation, but was increased ∼2-fold upon its prephosphorylation by the Pho85-Pho80 protein kinase. In addition, we show Rim11-phosphorylated Pah1 was a substrate for dephosphorylation by Nem1-Spo7. Finally, we demonstrate the Rim11 phosphorylation of Pah1 exerted an inhibitory effect on its PA phosphatase activity by reduction of its catalytic efficiency. Mutational analysis of the major phosphorylation sites (Thr-163, Thr-164, and Ser-602) indicated that Rim11-mediated phosphorylation at these sites was required to ensure Nem1-Spo7-dependent localization of the enzyme to the membrane. Overall, these findings advance our understanding of the phosphorylation-mediated regulation of Pah1 function in lipid synthesis.
    DOI:  https://doi.org/10.1016/j.jbc.2022.102221
  13. Cardiovasc Diagn Ther. 2022 Jun;12(3): 360-369
      Background: Protein kinase AMP-activated non-catalytic subunit gamma 2 gene (PRKAG2) cardiac syndrome, caused by mutations in PRKAG2, often shows myocardial hypertrophy and abnormal glycogen deposition in cardiomyocytes. However, it remains incurable due to a lack of a management guideline for treatment.Methods: We constructed a fluorescently labeled adenovirus carrying the wild-type or R302Q mutant of the PRKAG2 gene, infected neonatal rat cardiomyocytes (NRCMs) and H9C2 cell lines, and then analyzed changes in AMP-activated protein kinase (AMPK) activity, cell hypertrophy, glycogen storage, and cell proliferation when presence or absence of metoprolol or protein kinase A (PKA) inhibition H89, and then analyzed the changes in AKT-mTOR signal transduction activity.
    Results: Overexpression of PRKAG2 R302Q in primary cardiomyocytes increased the activity of AMPK, induced cellular hypertrophy and glycogen storage, and promoted the phosphorylation levels of AKT-mTOR signaling pathway. Application of either β1-adrenergic receptor (β1-AR) blocker metoprolol or PKA inhibitor H89 to the cardiomyocytes rescued the hypertrophic cardiomyopathy (HCM)-like phenotypes induced by PRKAG2 R302Q, including suppression of both AKT-mTOR phosphorylation and AMPK activity.
    Conclusions: The current study not only determined the mechanism regulating HCM induced by PRKAG2 R302Q mutant, but also demonstrated a therapeutic strategy using β1-AR blocker to treat the patients with PRKAG2 cardiac syndrome.
    Keywords:  PRKAG2; R302Q; hypertrophic cardiomyopathy (HCM); β-adrenergic receptor blocker (β-AR blocker)
    DOI:  https://doi.org/10.21037/cdt-22-81
  14. Biomol Ther (Seoul). 2022 Jul 05.
      Glycogen synthase kinase-3β (GSK-3β) is an important serine/threonine kinase that implicates in multiple cellular processes and links with the neurodegenerative diseases including Alzheimer's disease (AD). In this study, structure-based virtual screening was performed to search database for compounds targeting GSK-3β from Enamine's screening collection. Of the top-ranked compounds, 7 primary hits underwent a luminescent kinase assay and a cell assay using human neuroblastoma SH-SY5Y cells expressing Tau repeat domain (TauRD) with pro-aggregant mutation ΔK280. In the kinase assay for these 7 compounds, residual GSK-3β activities ranged from 36.1% to 90.0% were detected at the IC50 of SB-216763. In the cell assay, only compounds VB-030 and VB-037 reduced Tau aggregation in SH-SY5Y cells expressing ΔK280 TauRD-DsRed folding reporter. In SH-SY5Y cells expressing ΔK280 TauRD, neither VB-030 nor VB-037 increased expression of GSK-3α Ser21 or GSK-3β Ser9. Among extracellular signal-regulated kinase (ERK), AKT serine/threonine kinase 1 (AKT), mitogen-activated protein kinase 14 (P38) and mitogenactivated protein kinase 8 (JNK) which modulate Tau phosphorylation, VB-037 attenuated active phosphorylation of P38 Thr180/ Tyr182, whereas VB-030 had no effect on the phosphorylation status of ERK, AKT, P38 or JNK. However, both VB-030 and VB-037 reduced endogenous Tau phosphorylation at Ser202, Thr231, Ser396 and Ser404 in neuronally differentiated SH-SY5Y expressing ΔK280 TauRD. In addition, VB-030 and VB-037 further improved neuronal survival and/or neurite length and branch in mouse hippocampal primary culture under Tau cytotoxicity. Overall, through inhibiting GSK-3β kinase activity and/or p-P38 (Thr180/Tyr182), both compounds may serve as promising candidates to reduce Tau aggregation/cytotoxicity for AD treatment.
    Keywords:  Alzheimer's disease; Cell assay; Enzyme assay; GSK-3β kinase inhibitor; Mouse hippocampal primary culture; Virtual screening
    DOI:  https://doi.org/10.4062/biomolther.2022.035
  15. Int J Mol Sci. 2022 Jun 24. pii: 7014. [Epub ahead of print]23(13):
      To investigate the role of the transient receptor potential channel vanilloid type 1 (TRPV1) in hepatic glucose metabolism, we analyzed genes related to the clock system and glucose/lipid metabolism and performed glycogen measurements at ZT8 and ZT20 in the liver of C57Bl/6J (WT) and Trpv1 KO mice. To identify molecular clues associated with metabolic changes, we performed proteomics analysis at ZT8. Liver from Trpv1 KO mice exhibited reduced Per1 expression and increased Pparα, Pparγ, Glut2, G6pc1 (G6pase), Pck1 (Pepck), Akt, and Gsk3b expression at ZT8. Liver from Trpv1 KO mice also showed reduced glycogen storage at ZT8 but not at ZT20 and significant proteomics changes consistent with enhanced glycogenolysis, as well as increased gluconeogenesis and inflammatory features. The network propagation approach evidenced that the TRPV1 channel is an intrinsic component of the glucagon signaling pathway, and its loss seems to be associated with increased gluconeogenesis through PKA signaling. In this sense, the differentially identified kinases and phosphatases in WT and Trpv1 KO liver proteomes show that the PP2A phosphatase complex and PKA may be major players in glycogenolysis in Trpv1 KO mice.
    Keywords:  gluconeogenesis; glycogenolysis; liver clock and glucose metabolism genes; proteomics
    DOI:  https://doi.org/10.3390/ijms23137014
  16. Int J Mol Sci. 2022 Jul 04. pii: 7418. [Epub ahead of print]23(13):
      Glycosylphosphatidylinositol-anchored proteins (GPI-APs), which are anchored at the outer leaflet of plasma membranes (PM) only by a carboxy-terminal GPI glycolipid, are known to fulfill multiple enzymic and receptor functions at the cell surface. Previous studies revealed that full-length GPI-APs with the complete GPI anchor attached can be released from and inserted into PMs in vitro. Moreover, full-length GPI-APs were recovered from serum, dependent on the age and metabolic state of rats and humans. Here, the possibility of intercellular control of metabolism by the intercellular transfer of GPI-APs was studied. Mutant K562 erythroleukemia (EL) cells, mannosamine-treated human adipocytes and methyl-ß-cyclodextrin-treated rat adipocytes as acceptor cells for GPI-APs, based on their impaired PM expression of GPI-APs, were incubated with full-length GPI-APs, prepared from rat adipocytes and embedded in micelle-like complexes, or with EL cells and human adipocytes with normal expression of GPI-APs as donor cells in transwell co-cultures. Increases in the amounts of full-length GPI-APs at the PM of acceptor cells as a measure of their transfer was assayed by chip-based sensing. Both experimental setups supported both the transfer and upregulation of glycogen (EL cells) and lipid (adipocytes) synthesis. These were all diminished by serum, serum GPI-specific phospholipase D, albumin, active bacterial PI-specific phospholipase C or depletion of total GPI-APs from the culture medium. Serum inhibition of both transfer and glycogen/lipid synthesis was counteracted by synthetic phosphoinositolglycans (PIGs), which closely resemble the structure of the GPI glycan core and caused dissociation of GPI-APs from serum proteins. Finally, large, heavily lipid-loaded donor and small, slightly lipid-loaded acceptor adipocytes were most effective in stimulating transfer and lipid synthesis. In conclusion, full-length GPI-APs can be transferred between adipocytes or between blood cells as well as between these cell types. Transfer and the resulting stimulation of lipid and glycogen synthesis, respectively, are downregulated by serum proteins and upregulated by PIGs. These findings argue for the (patho)physiological relevance of the intercellular transfer of GPI-APs in general and its role in the paracrine vs. endocrine (dys)regulation of metabolism, in particular. Moreover, they raise the possibility of the use of full-length GPI-APs as therapeutics for metabolic diseases.
    Keywords:  (G)PI-specific phospholipases; diabetes; glycogen and lipid synthesis; glycosylphosphatidylinositol (GPI)-anchored proteins (GPI-APs); phosphoinositolglycans; protein transfer
    DOI:  https://doi.org/10.3390/ijms23137418
  17. Cureus. 2022 Jun;14(6): e25570
      Background Chronic liver disease (CLD) is one of the most significant causes of morbidity and mortality among the pediatric age group. The identification of the etiology of the disease is of utmost importance for the effective management of the disease. Objective To determine the various causes of CLD in pediatric patients attending a large public sector pediatric hospital. Patients and methods A prospective cross-sectional study was conducted at the National Institute of Child Health, Karachi, Pakistan from August 1, 2021, to February 28, 2022. All patients below 16 years of age of either gender with more than three months of symptoms duration on admission were enrolled. The diagnosis was labeled after the standard reference ranges for the pediatric age group. Results Of 136 patients, the mean age was 4.42 ± 3.92 years. More than half of the patients were males (76, 55.9%). Hepatitis B (31, 22.8%), idiopathic (23, 16.9%), glycogen storage disorder (GSD) (21, 15.4%), and Wilson disease (14, 10.3%) were the most common cause of CLD. A significant association of hepatitis was observed with age (p-value < 0.001), residence (p-value = 0.048), symptomatic (p-value < 0.001), total bilirubin level (p-value = 0.003), direct bilirubin level (p-value = 0.002), and albumin level (p-value = 0.003). Whereas a significant association of GSD was observed with age (p-value = 0.001), residence (p-value < 0.001), and serum glutamic pyruvic transaminase (SGPT) level (p-value = 0.033). Conclusion In our cohort, hepatitis B, idiopathic, GSD, and Wilson disease were the most common causes of CLD in pediatric patients. Moreover, age, residence, symptomatic, total bilirubin level, direct bilirubin level, SGPT, and albumin level were the important predictor variables.
    Keywords:  chronic liver disease (cld); glycogen storage disorder; hepatitis b (hbv); idiopathic; wilson disease
    DOI:  https://doi.org/10.7759/cureus.25570
  18. Curr Drug Deliv. 2022 Jun 23.
      BACKGROUND: Type II diabetes mellitus is significant public health issues globally-type II diabetes inadequacies and serious adverse effects are associated with conventional medicines, herbal medicine as a path Setaria italica often known as foxtail millet, is a popular crop. Rice put into practice in many ways, and this crop seven has utilized in both sweet and savory meals. It is suitable as a meal for diabetes people in India due to its low gluten level.OBJECTIVE: To evaluate antidiabetic, antihyperglycemic activity, histopathological change of type II diabetic rat, simultaneous determination of kaempferol and quercetin in foxtail millet (Setaria italica (L.) Beauv.) by validated high -performance thin layer chromatography.
    METHODS: Five best-selected genotypes of FM K-1, K-4, K-5, K-6, K-7, K-10 was put to work out of 10 genotypes for the study that forced to endure to initial antidiabetic activity involving D.P.P.H. investigation, glycogen content, and histological investigation done with the rat organs liver, mussels & blood. Furthermore, experiments of seed aqueous extract performed via oral administration of Setaria italica seed aqueous extract (SISAE) in streptozotocin-induced diabetic rats and further compared using glibenclamide, a standard oral hypoglycemic agent. The effect of long-term treatment with 300 mg of S.I.S.A.E./kg body weight/day on blood glucose & glycemic control evaluated in normal and diabetic rats.
    RESULTS: There was a significant decrease in fasting blood glucose associated with a significant improvement in glycemic control as evidenced by lower levels of HbA1c in diabetic treated rats when compared to those in untreated diabetic rats. The differences in the glycemic index determined among all the five genotypes of Setaria italica no significant alterations in liver gross found. However, minor cholesterol hemorrhage and lymphocytic infiltrations spotted in the liver of rats.
    CONCLUSION: Experimental finding refers that the aqueous extract of Setaria italica seeds have excellent antihyperglycemic and has excellent potential as a source for natural health products.
    Keywords:  H.P.T.L.C.; NIDDM; antidiabetic activity; glycogen; histopathology; kaempferol; phytochemicals; quercetin.; streptozotocin
    DOI:  https://doi.org/10.2174/1567201819666220623153204