bims-glecem 2023-06-04 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2023–06–04
thirteen papers selected by
Dipsikha Biswas, Københavns Universitet

Mutant IDH regulates glycogen metabolism from early cartilage development to malignant chondrosarcoma formation.
Pathological modeling of glycogen storage disease type III with CRISPR/Cas9 edited human pluripotent stem cells.
Glycogen phosphorylase isoenzyme GPbb versus GPmm regulation of ventromedial hypothalamic nucleus glucoregulatory neurotransmitter and counter-regulatory hormone profiles during hypoglycemia: Role of L-lactate and octadecaneuropeptide.
Clinical and genetic spectrum of GSD type 6 in Korea.
[Splicing abnormalities caused by a novel mutation in the PHKA2 gene in children with glycogen storage disease type IX].
Nutritional management of glycogen storage disease type III: a case report and a critical appraisal of the literature.
In Vivo Imaging and Kinetic Modeling of Novel Glycogen Synthase Kinase-3 Radiotracers [11C]OCM-44 and [18F]OCM-50 in Non-Human Primates.
Euglycemia is affected by stress defense factor hepatocyte NRF1, but not NRF2.
Allantoic fluid metabolome reveals specific metabolic signatures in chicken lines different for their muscle glycogen content.
Underlying biochemical effects of intermittent fasting, exercise and honey on streptozotocin-induced liver damage in rats.
Effects of Starvation and Refeeding on Glucose Metabolism and Immune Responses in Macrobrachium rosenbergii.
Impact of particulate matter 2.5 on the liver function of mice.
Interleukin 6 acutely increases gluconeogenesis and decreases the suppressive effect of insulin on cAMP-stimulated glycogenolysis in rat liver.

Cell Rep. 2023 Jun 01. pii: S2211-1247(23)00589-2. [Epub ahead of print]42(6): 112578

Mutant IDH regulates glycogen metabolism from early cartilage development to malignant chondrosarcoma formation.

Sinthu Pathmanapan, Raymond Poon, Tomasa Barrientos De Renshaw, Puviindran Nadesan, Makoto Nakagawa, Gireesh A Seesankar, Adrian Kwan Ho Loe, Hongyuan H Zhang, Joan J Guinovart, Jordi Duran, Christopher B Newgard, Jay S Wunder, Benjamin A Alman.

  Chondrosarcomas are the most common malignancy of cartilage and are associated with somatic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 genes. Somatic IDH mutations are also found in its benign precursor lesion, enchondromas, suggesting that IDH mutations are early events in malignant transformation. Human mutant IDH chondrosarcomas and mutant Idh mice that develop enchondromas investigated in our studies display glycogen deposition exclusively in mutant cells from IDH mutant chondrosarcomas and Idh1 mutant murine growth plates. Pharmacologic blockade of glycogen utilization induces changes in tumor cell behavior, downstream energetic pathways, and tumor burden in vitro and in vivo. Mutant IDH1 interacts with hypoxia-inducible factor 1α (HIF1α) to regulate expression of key enzymes in glycogen metabolism. Here, we show a critical role for glycogen in enchondromas and chondrosarcomas, which is likely mediated through an interaction with mutant IDH1 and HIF1α.

Keywords:  CP: Cancer; CP: Metabolism; cancer; chondrosarcoma; development; genetic mutation; glycogen; metabolism; mutant IDH

DOI:  https://doi.org/10.1016/j.celrep.2023.112578
Front Cell Dev Biol. 2023 ;11 1163427

Pathological modeling of glycogen storage disease type III with CRISPR/Cas9 edited human pluripotent stem cells.

Lucille Rossiaud, Pascal Fragner, Elena Barbon, Antoine Gardin, Manon Benabides, Emilie Pellier, Jérémie Cosette, Lina El Kassar, Karine Giraud-Triboult, Xavier Nissan, Giuseppe Ronzitti, Lucile Hoch.

  Introduction: Glycogen storage disease type III (GSDIII) is a rare genetic disease caused by mutations in the AGL gene encoding the glycogen debranching enzyme (GDE). The deficiency of this enzyme, involved in cytosolic glycogen degradation, leads to pathological glycogen accumulation in liver, skeletal muscles and heart. Although the disease manifests with hypoglycemia and liver metabolism impairment, the progressive myopathy is the major disease burden in adult GSDIII patients, without any curative treatment currently available. Methods: Here, we combined the self-renewal and differentiation capabilities of human induced pluripotent stem cells (hiPSCs) with cutting edge CRISPR/Cas9 gene editing technology to establish a stable AGL knockout cell line and to explore glycogen metabolism in GSDIII. Results: Following skeletal muscle cells differentiation of the edited and control hiPSC lines, our study reports that the insertion of a frameshift mutation in AGL gene results in the loss of GDE expression and persistent glycogen accumulation under glucose starvation conditions. Phenotypically, we demonstrated that the edited skeletal muscle cells faithfully recapitulate the phenotype of differentiated skeletal muscle cells of hiPSCs derived from a GSDIII patient. We also demonstrated that treatment with recombinant AAV vectors expressing the human GDE cleared the accumulated glycogen. Discussion: This study describes the first skeletal muscle cell model of GSDIII derived from hiPSCs and establishes a platform to study the mechanisms that contribute to muscle impairments in GSDIII and to assess the therapeutic potential of pharmacological inducers of glycogen degradation or gene therapy approaches.

Keywords:  CRISPR/Cas9; glycogen storage disease; induced pluripotent stem cell; muscular disorders; skeletal muscle cell

DOI:  https://doi.org/10.3389/fcell.2023.1163427
Mol Cell Neurosci. 2023 May 31. pii: S1044-7431(23)00057-X. [Epub ahead of print] 103863

Glycogen phosphorylase isoenzyme GPbb versus GPmm regulation of ventromedial hypothalamic nucleus glucoregulatory neurotransmitter and counter-regulatory hormone profiles during hypoglycemia: Role of L-lactate and octadecaneuropeptide.

Md Main Uddin, Md Haider Ali, A S M H Mahmood, Khaggeswar Bheemanapally, Jérôme Leprince, Karen P Briski.

  Glucose accesses the brain primarily via the astrocyte cell compartment, where it passes through the glycogen shunt before catabolism to the oxidizable fuel L-lactate. Glycogen phosphorylase (GP) isoenzymes GPbb and GPmm impose distinctive control of ventromedial hypothalamic nucleus (VMN) glucose-regulatory neurotransmission during hypoglycemia, but lactate and/or gliotransmitter involvement in those actions is unknown. Lactate or the octadecaneuropeptide receptor antagonist cyclo(1-8)[DLeu5] OP (LV-1075) did not affect gene product down-regulation caused by GPbb or GPmm siRNA, but suppressed non-targeted GP variant expression in a VMN region-specific manner. Hypoglycemic up-regulation of neuronal nitric oxide synthase was enhanced in rostral and caudal VMN by GPbb knockdown, yet attenuated by GPMM siRNA in the middle VMN; lactate or LV-1075 reversed these silencing effects. Hypoglycemic inhibition of glutamate decarboxylase65/67 was magnified by GPbb (middle and caudal VMN) or GPmm (middle VMN) knockdown, responses that were negated by lactate or LV-1075. GPbb or GPmm siRNA enlarged hypoglycemic VMN glycogen profiles in rostral and middle VMN. Lactate and LV-1075 elicited progressive rostral VMN glycogen augmentation in GPbb knockdown rats, but stepwise-diminution of rostral and middle VMN glycogen after GPmm silencing. GPbb, not GPmm, knockdown caused lactate or LV-1075 - reversible amplification of hypoglycemic hyperglucagonemia and hypercorticosteronemia. Results show that lactate and octadecaneuropeptide exert opposing control of GPbb protein in distinct VMN regions, while the latter stimulates GPmm. During hypoglycemia, GPbb and GPmm may respectively diminish (rostral, caudal VMN) or enhance (middle VMN) nitrergic transmission and each oppose GABAergic signaling (middle VMN) by lactate- and octadecaneuropeptide-dependent mechanisms.

Keywords:  Corticosterone; Glycogen phosphorylase-brain type: Insulin-induced hypoglycemia; Glycogen phosphorylase-muscle type; Neuronal nitric oxide synthase; Octadecaneuropeptide

DOI:  https://doi.org/10.1016/j.mcn.2023.103863
Orphanet J Rare Dis. 2023 Jun 01. 18(1): 132

Clinical and genetic spectrum of GSD type 6 in Korea.

Jong Woo Hahn, Heerah Lee, Moon Woo Seong, Gyeong Hoon Kang, Jin Soo Moon, Jae Sung Ko.

   BACKGROUND: Glycogen storage disease type VI (GSD VI) is a rare disease in which liver glycogen metabolism is impaired by mutations in the glycogen phosphorylase L (PYGL). This study aimed to examine the clinical features, genetic analyses, and long-term outcomes of patients with GSD VI in Korea.
METHODS: From January 2002 to November 2022, we retrospectively reviewed patients diagnosed with GSD VI using a gene panel at Seoul National University Hospital. We investigated the clinical profile, liver histology, molecular diagnosis, and long-term outcomes of patients with GSD VI.
RESULTS: Five patients were included in the study. The age at onset was 18-30 months (median, 21 months), and current age was 3.7-17 years (median, 11 years). All patients showed hepatomegaly, elevated liver transaminase activity, and hypertriglyceridaemia. Hypercholesterolaemia and fasting hypoglycaemia occurred in 60% and 40% of patients, respectively. Ten variants of PYGL were identified, of which six were novel: five missense (p.[Gly607Val], p.[Leu445Pro], p.[Gly695Glu], p.[Val828Gly], p.[Tyr158His]), and one frameshift (p.[Arg67AlafsTer34]). All patients were treated with a high-protein diet, and four also received corn starch. All patients showed improved liver function tests, hypertriglyceridaemia, hepatomegaly, and height z score.
CONCLUSIONS: The GSD gene panel is a useful diagnostic tool for confirming the presence of GSD VI. Genetic heterogeneity was observed in all patients with GSD VI. Increased liver enzyme levels, hypertriglyceridaemia, and height z score in patients with GSD VI improved during long-term follow-up.

Keywords:  Glycogen storage disease; Molecular diagnosis; Next-generation sequencing; PYGL

DOI:  https://doi.org/10.1186/s13023-023-02750-1
Zhonghua Gan Zang Bing Za Zhi. 2023 Apr 20. 31(4): 428-432

[Splicing abnormalities caused by a novel mutation in the PHKA2 gene in children with glycogen storage disease type IX].

Z H Zhang, B X Zheng, Y J Zhuo, Y Jin, Z F Liu, Y C Zheng.

  Objective: Glycogen storage disease type IX (GSD-IX) is a rare primary glucose metabolism abnormality caused by phosphorylase kinase deficiency and a series of pathogenic gene mutations. The clinical characteristics, gene analysis, and functional verification of a mutation in a child with hepatomegaly are summarized here to clarify the pathogenic cause of the disease. Methods: The clinical data of a child with GSD-IX was collected. Peripheral blood from the child and his parents was collected for genomic DNA extraction. The patient's gene diagnosis was performed by second-generation sequencing. The suspected mutations were verified by Sanger sequencing and bioinformatics analysis. The suspected splicing mutations were verified in vivo by RT-PCR and first-generation sequencing. Results: Hepatomegaly, transaminitis, and hypertriglyceridemia were present in children. Liver biopsy pathological examination results indicated glycogen storage disease. Gene sequencing revealed that the child had a c.285 + 2_285 + 5delTAGG hemizygous mutation in the PHKA2 gene. Sanger sequencing verification showed that the mother of the child was heterozygous and the father of the child was of the wild type. Software such as HSF3.1 and ESEfinder predicted that the gene mutation affected splicing. RT-PCR of peripheral blood from children and his mother confirmed that the mutation had caused the skipping of exon 3 during the constitutive splicing of the PHKA2 gene. Conclusion: The hemizygous mutation in the PHKA2 gene (c.285 + 2_285 + 5delTAGG) is the pathogenic cause of the patient's disease. The detection of the novel mutation site enriches the mutation spectrum of the PHKA2 gene and serves as a basis for the family's genetic counseling.

Keywords:  Aberrant RNA splicing; Glycogen storage disease type IX; Next-generation panel sequencing; PHKA2 gene

DOI:  https://doi.org/10.3760/cma.j.cn501113-20220120-00034
Front Nutr. 2023 ;10 1178348

Nutritional management of glycogen storage disease type III: a case report and a critical appraisal of the literature.

Elena Massimino, Anna Paola Amoroso, Roberta Lupoli, Alessandro Rossi, Brunella Capaldo.

  Glycogen storage disease Type III (GSD III) is an autosomal recessive disease due to the deficiency of the debranching enzyme, which has two main consequences: a reduced availability of glucose due to the incomplete degradation of glycogen, and the accumulation of abnormal glycogen in liver and cardiac/skeletal muscle. The role of dietary lipid manipulations in the nutritional management of GSD III is still debated. A literature overview shows that low-carbohydrate (CHO) / high-fat diets may be beneficial in reducing muscle damage. We present a 24-year GSD IIIa patient with severe myopathy and cardiomyopathy in whom a gradual shift from a high-CHO diet (61% total energy intake), low-fat (18%), high-protein (21%) to a low-CHO (32 %) high-fat (45%) / high-protein (23%) diet was performed. CHO was mainly represented by high-fiber, low glycemic index food, and fat consisted prevalently of mono and polyunsaturated fatty acids. After a 2-year follow-up, all biomarkers of muscle and heart damage markedly decreased (by 50-75%), glucose levels remained within the normal range and lipid profile was unchanged. At echocardiography, there was an improvement in geometry and left ventricular function. A low -CHO, high-fat, high-protein diet seems to be safe, sustainable and effective in reducing muscle damage without worsening cardiometabolic profile in GSDIIIa. This dietary approach could be started as early as possible in GSD III displaying skeletal/cardiac muscle disease in order to prevent/minimize organ damage.

Keywords:  cardiomyopathy; continuous glucose monitoring (CGM); dietary intervention; glycogen storage disease; high-fat diet; myopathy

DOI:  https://doi.org/10.3389/fnut.2023.1178348
Pharmaceuticals (Basel). 2023 Jan 28. pii: 194. [Epub ahead of print]16(2):

In Vivo Imaging and Kinetic Modeling of Novel Glycogen Synthase Kinase-3 Radiotracers [11C]OCM-44 and [18F]OCM-50 in Non-Human Primates.

Kelly Smart, Ming-Qiang Zheng, Daniel Holden, Zachary Felchner, Li Zhang, Yanjiang Han, Jim Ropchan, Richard E Carson, Neil Vasdev, Yiyun Huang.

  Glycogen synthase kinase 3 (GSK-3) is a potential therapeutic target for a range of neurodegenerative and psychiatric disorders. The goal of this work was to evaluate two leading GSK-3 positron emission tomography (PET) radioligands, [11C]OCM-44 and [18F]OCM-50, in non-human primates to assess their potential for clinical translation. A total of nine PET scans were performed with the two radiotracers using arterial blood sampling in adult rhesus macaques. Brain regional time-activity curves were extracted and fitted with one- and two-tissue compartment models using metabolite-corrected arterial input functions. Target selectivity was assessed after pre-administration of the GSK-3 inhibitor PF-04802367 (PF-367, 0.03-0.25 mg/kg). Both radiotracers showed good brain uptake and distribution throughout grey matter. [11C]OCM-44 had a free fraction in the plasma of 3% at baseline and was metabolized quickly. The [11C]OCM-44 volume of distribution (VT) values in the brain increased with time; VT values from models fitted to truncated 60-min scan data were 1.4-2.9 mL/cm3 across brain regions. The plasma free fraction was 0.6% for [18F]OCM-50 and VT values (120-min) were 0.39-0.87 mL/cm3 in grey matter regions. After correcting for plasma free fraction increases during blocking scans, reductions in regional VT indicated >80% target occupancy by 0.1 mg/kg of PF-367 for both radiotracers, supporting target selectivity in vivo. [11C]OCM-44 and [18F]OCM-50 warrant further evaluation as radioligands for imaging GSK-3 in the brain, though radio-metabolite accumulation may confound image analysis.

Keywords:  glycogen synthase kinase 3; non-human primates; positron emission tomography; radiopharmaceutical

DOI:  https://doi.org/10.3390/ph16020194
Biochem Biophys Res Commun. 2023 May 22. pii: S0006-291X(23)00660-5. [Epub ahead of print]668 96-103

Euglycemia is affected by stress defense factor hepatocyte NRF1, but not NRF2.

May G Akl, Raquel Baccetto, Brynne M Stebbings, Lei Li, Scott B Widenmaier.

  Hepatocyte stress signaling has been established to alter glucose metabolism and impair systemic glucose homeostasis. In contrast, the role of stress defenses in the control of glucose homeostasis is less understood. Nuclear factor erythroid 2 related factor-1 (NRF1) and -2 (NRF2) are transcription factors that promote stress defense and can exert hepatocyte stress defense programming via complementary gene regulation. To identify whether there are independent or complementary roles of these factors in hepatocytes on glucose homeostasis, we investigated the effect of adult-onset, hepatocyte-specific deletion of NRF1, NRF2, or both on glycemia in mice fed 1-3 weeks with a mildly stressful diet enriched with fat, fructose, and cholesterol. Compared to respective control, NRF1 deficiency and combined deficiency reduced glycemia, in some cases resulting in hypoglycemia, whereas there was no effect of NRF2 deficiency. However, reduced glycemia in NRF1 deficiency did not occur in the leptin-deficient mouse model of obesity and diabetes, suggesting hepatocyte NRF1 support defenses that counteract hypoglycemia but does not promote hyperglycemia. Consistent with this, NRF1 deficiency was associated with reduced liver glycogen and glycogen synthase expression as well as marked alteration to circulating level of glycemia-influencing hormones, growth hormone and insulin-like growth factor-1 (IGF1). Overall, we identify a role for hepatocyte NRF1 in modulating glucose homeostasis, which may be linked to liver glycogen storage and the growth hormone/IGF1 axis.

Keywords:  Glycemia; Immunometabolism; Liver stress defense; Transcription factor

DOI:  https://doi.org/10.1016/j.bbrc.2023.05.082
Sci Rep. 2023 May 31. 13(1): 8867

Allantoic fluid metabolome reveals specific metabolic signatures in chicken lines different for their muscle glycogen content.

Angélique Petit, Sophie Tesseraud, Stéphane Beauclercq, Lydie Nadal-Desbarats, Estelle Cailleau-Audouin, Sophie Réhault-Godbert, Cécile Berri, Elisabeth Le Bihan-Duval, Sonia Métayer-Coustard.

Nutrient availability in eggs can affect early metabolic orientation in birds. In chickens divergently selected on the Pectoralis major ultimate pH, a proxy for muscle glycogen stores, characterization of the yolk and amniotic fluid revealed a different nutritional environment. The present study aimed to assess indicators of embryo metabolism in pHu lines (pHu+ and pHu-) using allantoic fluids (compartment storing nitrogenous waste products and metabolites), collected at days 10, 14 and 17 of embryogenesis and characterized by 1H-NMR spectroscopy. Analysis of metabolic profiles revealed a significant stage effect, with an enrichment in metabolites at the end of incubation, and an increase in interindividual variability during development. OPLS-DA analysis discriminated the two lines. The allantoic fluid of pHu- was richer in carbohydrates, intermediates of purine metabolism and derivatives of tryptophan-histidine metabolism, while formate, branched-chain amino acids, Krebs cycle intermediates and metabolites from different catabolic pathways were more abundant in pHu+. In conclusion, the characterization of the main nutrient sources for embryos and now allantoic fluids provided an overview of the in ovo nutritional environment of pHu lines. Moreover, this study revealed the establishment, as early as day 10 of embryo development, of specific metabolic signatures in the allantoic fluid of pHu+ and pHu- lines.

DOI: https://doi.org/10.1038/s41598-023-35652-0
J Diabetes Metab Disord. 2023 Jun;22(1): 515-527

Underlying biochemical effects of intermittent fasting, exercise and honey on streptozotocin-induced liver damage in rats.

Ejime Agbonifo-Chijiokwu, Kingsley E Nwangwa, Mega O Oyovwi, Benneth Ben-Azu, Alexander O Naiho, Victor Emojevwe, Ejiro Peggy Ohwin, Azuka Prosper Ehiwarior, Evelyn Tarela Ojugbeli, Shalom Udoka Nwabuoku, Emuesiri Goodies Moke, Bright O Oghenetega.

   Purpose: Derangements of liver transcriptional factors and enzymes have important implications in diabetes-induced related complications. Hence, this study which consists of two experimental phases was aimed at evaluating the possible underlying molecular mechanisms of intermittent fasting (IF), exercise starvation and honey in streptozotocin (STZ)-mediated liver damage in diabetic rats.
Methods: The diabetic rats were treated orally with distilled water (0.5 ml/kg), IF, starvation and honey at 1 g/kg body weight in the non-diabetic phase for four (4) weeks. After STZ injections, four (4) weeks of IF, exercise, starvation, and honey therapy were used as interventions prior to a biochemical evaluation of the liver.
Results: IF and exercise greatly decreased liver transcription factor (resistin, SREBP-1c), inflammatory cytokines/enzyme (TNF-α, IL-6, IL-1ß, MPO) as well as oxidative and nitrergic stress with correspondence increased liver PPAR-γ, IL-10, SOD, CAT and GSH in diabetic rats unlike starvation and honey regimen relative to diabetic controls. Furthermore, IF and exercise significantly improved hepatic glycogen synthase and decreased glycogen phosphorylase in diabetic rats compared to the diabetic control group, but starvation and honey therapy had no such influence. IF and exercise strategically reduces STZ-induced liver metabolic disorder via through modulation of liver transcriptional factors and inhibition of pro-inflammatory cytokines, oxido-nitrergic and adipokine signaling pathway.

Keywords:  Diabetes mellitus; Exercise; Fasting; Honey; Liver cirrhosis; Oxidative stress

DOI:  https://doi.org/10.1007/s40200-022-01173-2
Mar Biotechnol (NY). 2023 May 30.

Effects of Starvation and Refeeding on Glucose Metabolism and Immune Responses in Macrobrachium rosenbergii.

Qun Jiang, Peng Ji, Shiqi Ao, Xiaojian Gao, Xiaojun Zhang.

  Starvation is a common challenge for aquatic animals in both natural and cultured environments. To investigate the effects of starvation and refeeding on glucose metabolism and immunity in Macrobrachium rosenbergii, prawns were starved for 14 days and then refed for 7 days. Results showed that both glucose and trehalose levels decreased significantly at the beginning of starvation, followed by a significant decrease in glycogen content in the hepatopancreas and muscle. Triglyceride and total protein reserves were also mobilized under starvation, with a slightly quicker response from triglycerides. The mRNA levels of glycolysis (glucokinase) and anabolism-related enzymes (glycogen branching enzyme, diacylglycerol acyltransferase, and transpeptidase) decreased during starvation, while gluconeogenic potential was induced, as indicated by up-regulated transcriptional levels of gluconeogenic enzymes (phosphoenolpyruvate carboxykinase) and catabolism-related enzymes (glycogen debranching enzyme, adipose triglyceride lipase, and cathepsin B). Starvation also stimulated the expression of the crustacean hyperglycemic hormone and inhibited insulin-like peptide expression, indicating their potential role in glucose metabolism regulation. In addition, starvation increased the mRNA levels of superoxide dismutase and prophenoloxidase, indicating an influence on the immune system. After bacterial infection, starved prawns showed enhanced activity of non-specific immunological parameters and reduced mortality. Refeeding for 7 days led to a recovery of physiological and biochemical indices and transcriptional levels of metabolism/immune-related genes. Our findings provide a better understanding of the mechanisms underlying energy utilization, metabolic adaptation, and immune response to starvation in M. rosenbergii.

Keywords:  Glucose metabolism; Macrobrachium rosenbergii; Non-specific immunity; Starvation stress

DOI:  https://doi.org/10.1007/s10126-023-10218-3
Eur Rev Med Pharmacol Sci. 2023 May;pii: 32440. [Epub ahead of print]27(10): 4357-4368

Impact of particulate matter 2.5 on the liver function of mice.

Q Zhang, H-Y Zhang, X-Q Yu, Z-J Cui, Z-W Lv.

OBJECTIVE: The aim of this study was to evaluate the impact of particulate matter 2.5 (PM2.5) on liver function at the animal level and to study its impact targets.
MATERIALS AND METHODS: 60 male and female BALB/c mice of SPF grade, aged 6-8 weeks, were randomly divided into four groups, with 15 mice in each, including the normal saline control group, the PM2.5 low dose group [2 μg/(100 g/d)], the PM2.5 medium dose group [8 μg/(100 g/d)] and the PM2.5 high dose group [16 μg/(100 g/d)]. Each day, 0.9% saline or PM2.5 particles were administered through the nasal route, and samples were taken after 3 weeks of continuous exposure. Hematoxylin-eosin staining (HE) was used to observe the liver damage caused by PM2.5. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were detected by using an automatic biochemical analyzer to detect the content of liver glycogen and blood glucose. Multiple indicators were observed, including plasma tumor necrosis factor (TNF-α) and interleukin-6 (IL-6) levels, oxidative stress response indicators reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD) detection, RT-PCR and Western blot detection of glycogen synthase (GS), glucokinase (GK), nuclear factor erythroid 2-related factor 2 (Nrf2) expression and phosphorylation level of phospho-c-Jun N-terminal kinases (p-JNK).
RESULTS: PM2.5 can cause damage to the liver by increasing PM2.5 concentrations, raising the metabolic rate of liver cells, resulting in a substantial amount of inflammatory infiltration and vacuolar degeneration of cells, and increasing the liver/body weight. TNF-α and IL-6 inflammatory factor expression increased (p<0.05). An increase in the serum ALT and AST levels were also observed. The blood glucose of mice increased, whereas the content of liver glycogen declined (p<0.05). ROS, MDA, and SOD levels all increased considerably. PM2.5 can drastically lower the expression of GS and GK, increase the expression of Nrf2, and raise the phosphorylation level of p-JNK (p<0.05).
CONCLUSIONS: PM2.5 can induce oxidative stress in mouse liver through the Nrf2/JNK pathway, induce liver inflammation in mice, and inhibit glycogen synthesis.

DOI: https://doi.org/10.26355/eurrev_202305_32440
Cell Biochem Funct. 2023 May 31.

Interleukin 6 acutely increases gluconeogenesis and decreases the suppressive effect of insulin on cAMP-stimulated glycogenolysis in rat liver.

Giuliana R Biazi, Isabele G F Uemura, Daniele R Miksza, Laura S Ferraz, Brenda F Diaz, Gisele L Bertolini, Helenir M de Souza.

  Interleukin 6 (IL6) is an multifunctional cytokine that modulates several biological responses, including glucose metabolism. However, its acute effects on hepatic glucose release are still uncertain. The main purpose of this study was to investigate the effects of IL6 on gluconeogenesis from several glucose precursors (alanine, pyruvate and glutamine) and on the suppressive action of insulin on cAMP-stimulated glycogen catabolism in rat liver. IL6 effect on insulin peripheral sensitivity was also evaluated. IL6 was injected intravenously into rats and, 1 h later, gluconeogenesis and glycogenolysis were assessed in liver perfusion and peripheral insulin sensitivity by insulin tolerance test (ITT). IL6 intravenous injection increased hepatic glucose production from alanine, without changing pyruvate, lactate and urea production. IL6 injection also increased hepatic glucose production from pyruvate and glutamine. In addition, IL6 decreased the suppressive effect of insulin on cAMP-stimulated glucose and lactate production and glycogenolysis, without affecting pyruvate production. Furthermore, IL6 reduced the plasma glucose disappearance constant (kITT), an indicator of insulin resistance. In conclusion, IL6 acutely increased hepatic glucose release (gluconeogenesis and glycogenolysis) by a mechanism that likely involved the induction of insulin resistance in the liver, as evidenced by the reduced suppressive effect of insulin on cAMP-stimulated glycogen catabolism. In consistency, IL6 acutely induced peripheral insulin resistance.

Keywords:  cAMP; cytokine; glycogenolysis; insulin resistance; liver perfusion

DOI:  https://doi.org/10.1002/cbf.3817