bims-glecem 2023-05-14 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2023–05–14
nine papers selected by
Dipsikha Biswas, Københavns Universitet

Glycogen storage disease in two sisters: A case report.
Current understanding on pathogenesis and effective treatment of glycogen storage disease type Ib with empagliflozin: new insights coming from diabetes for its potential implications in other metabolic disorders.
Patient-reported outcomes on empagliflozin treatment in glycogen storage disease type Ib: An international questionnaire study.
Standardization of Grocott's methenamine (hexamine) silver method for glycogen demonstration in liver tissue.
Generation of two induced pluripotent stem cell lines (CHOCi002-A and CHOCi003-A) from Pompe disease patients with compound heterozygous mutations in the GAA gene.
Effect of high temperature stress on glycogen metabolism in gills of Yesso scallop Patinopecten yessoensis.
The 15-hydroxyprostaglandin dehydrogenase inhibitor SW033291 ameliorates abnormal hepatic glucose metabolism through PGE2-EP4 receptor-AKT signaling in a type 2 diabetes mellitus mouse model.
In situ microwave fixation provides an instantaneous snapshot of the brain metabolome.
Exercise improves homeostasis of the intestinal epithelium by activation of APJ-AMPK signaling.

Clin Case Rep. 2023 May;11(5): e7318

Glycogen storage disease in two sisters: A case report.

Sajal Twanabasu, Prabin Duwadee, Sushan Homagain, Jeevan Ghimire, Ram Chandra Rijal.

  Glycogen storage diseases (GSDs) are rare autosomal disorders that result from defects in glycogen metabolism. There are more than 12 types, each with distinct clinical features. Clinical scenario, biochemical abnormalities are useful for suspicion whereas liver biopsy and enzyme assay provides definite diagnosis. We report a case of two sisters with similar clinical symptoms suggestive of the disease.

Keywords:  glycogen storage disease; hepatomegaly; hypoglycemia; metabolic

DOI:  https://doi.org/10.1002/ccr3.7318
Front Endocrinol (Lausanne). 2023 ;14 1145111

Current understanding on pathogenesis and effective treatment of glycogen storage disease type Ib with empagliflozin: new insights coming from diabetes for its potential implications in other metabolic disorders.

Arianna Maiorana, Francesco Tagliaferri, Carlo Dionisi-Vici.

  Glycogen storage type Ib (GSDIb) is a rare inborn error of metabolism caused by glucose-6-phosphate transporter (G6PT, SLC37A4) deficiency. G6PT defect results in excessive accumulation of glycogen and fat in the liver, kidney, and intestinal mucosa and into both glycogenolysis and gluconeogenesis impairment. Clinical features include hepatomegaly, hypoglycemia, lactic acidemia, hyperuricemia, hyperlipidemia, and growth retardation. Long-term complications are liver adenoma, hepatocarcinoma, nephropathy and osteoporosis. The hallmark of GSDIb is neutropenia, with impaired neutrophil function, recurrent infections and inflammatory bowel disease. Alongside classical nutritional therapy with carbohydrates supplementation and immunological therapy with granulocyte colony-stimulating factor, the emerging role of 1,5-anhydroglucitol in the pathogenesis of neutrophil dysfunction led to repurpose empagliflozin, an inhibitor of the renal glucose transporter SGLT2: the current literature of its off-label use in GSDIb patients reports beneficial effects on neutrophil dysfunction and its clinical consequences. Surprisingly, this glucose-lowering drug ameliorated the glycemic and metabolic control in GSDIb patients. Furthermore, numerous studies from big cohorts of type 2 diabetes patients showed the efficacy of empagliflozin in reducing the cardiovascular risk, the progression of kidney disease, the NAFLD and the metabolic syndrome. Beneficial effects have also been described on peripheral neuropathy in a prediabetic rat model. Increasing evidences highlight the role of empagliflozin in regulating the cellular energy sensors SIRT1/AMPK and Akt/mTOR, which leads to improvement of mitochondrial structure and function, stimulation of autophagy, decrease of oxidative stress and suppression of inflammation. Modulation of these pathways shift the oxidative metabolism from carbohydrates to lipids oxidation and results crucial in reducing insulin levels, insulin resistance, glucotoxicity and lipotoxicity. For its pleiotropic effects, empagliflozin appears to be a good candidate for drug repurposing also in other metabolic diseases presenting with hypoglycemia, organ damage, mitochondrial dysfunction and defective autophagy.

Keywords:  autophagy; empagliflozin; glycogen storage diseases; hypoglycemia; inflammatory bowel disease; neutropenia; neutrophil dysfunction

DOI:  https://doi.org/10.3389/fendo.2023.1145111
JIMD Rep. 2023 May;64(3): 252-258

Patient-reported outcomes on empagliflozin treatment in glycogen storage disease type Ib: An international questionnaire study.

Sarah C Grünert, Annieke Venema, Jamas LaFreniere, Blair Schneider, Enrique Contreras, Saskia B Wortmann, Terry G J Derks.

  In patients with glycogen storage disease type Ib (GSD Ib), quality of life is severely hampered by neutropenia and neutropenia-associated symptoms. SGLT2 inhibitors are a new treatment option and have shown improved medical outcomes in more than 120 patients so far. The aim of this international questionnaire study was to assess patient-reported outcomes of this new treatment in GSD Ib patients. Patients and caregivers of pediatric patients were invited to complete a web-based questionnaire. This was designed to evaluate treatment effects of the SGLT2 inhibitor empagliflozin on clinical symptoms and important aspects of daily life including physical performance, sleep, social and work life, traveling, socioeconomic aspects, and quality of life. The questionnaire was completed by 73 respondents from 17 different countries. The mean duration of treatment was 15 months, the cumulative treatment time was 94.8 years. More than 80% of patients reported an improved quality of life. The number of hospitalizations was reduced (66% of patients), as well as the number of days absent from school or work. Granulocyte colony-stimulating factor (G-CSF) treatment could be stopped in 49% of patients and reduced in another 42%. Clear improvement of neutropenia and all neutropenia-associated symptoms was reported by the majority of patients. Additionally, patients or caregivers reported positive effects on appetite (63%), level of activity (75%), overall well-being (96%), and sleep (63%). Empagliflozin positively impacts many aspects of daily life including work and social life and thereby significantly improves quality of life of patients and caregivers.

Keywords:  SGLT2 inhibitor; empagliflozin; glycogen storage disease type Ib; neutropenia; quality of life

DOI:  https://doi.org/10.1002/jmd2.12364
Histochem Cell Biol. 2023 May 12.

Standardization of Grocott's methenamine (hexamine) silver method for glycogen demonstration in liver tissue.

Atheelah Mohammed Idris, Hibatalla Elshazli Elgamri, Samah Abdelrahim Batran, Yosef Mohamed-Azzam Zakout.

  Demonstration of glycogen can be done in different lesions and is considered diagnostically significant, mainly in some tumors. Glycogen staining is affected by the type of fixative, the temperature of fixation, and the staining technique.Grocott's methenamine (hexamine) silver technique quality was assessed after four different types of fixatives at two different temperatures [Bouin's solution, 10% neutral buffered formalin (NBF), 80% alcohol, and Rossman's solution at room temperature (RT) and 4 °C, for 24 h]. These variables were studied to optimize this technique for glycogen demonstration. Archived paraffin blocks were used in this study. They were prepared from one rabbit's liver, and 32 paraffin sections were prepared and stained with Grocott's methenamine (hexamine) silver technique. Eighty percent alcohol provided the highest staining quality scores at both RT and 4 °C in comparison with the other fixatives. We concluded that 80% alcohol at 4 °C seems to be the fixative of choice for glycogen with the Grocott's methenamine (hexamine) silver technique at the level of this study.

Keywords:  Fixation; Fixative; Glycogen; Grocott’s methenamine (hexamine) silver; Liver

DOI:  https://doi.org/10.1007/s00418-023-02199-0
Stem Cell Res. 2023 May 06. pii: S1873-5061(23)00103-4. [Epub ahead of print]69 103117

Generation of two induced pluripotent stem cell lines (CHOCi002-A and CHOCi003-A) from Pompe disease patients with compound heterozygous mutations in the GAA gene.

Chloe Christensen, Perla Heckman, Allisandra Rha, Shih-Hsin Kan, Jerry Harb, Raymond Wang.

  Pompe disease is an autosomal recessive lysosomal storage disease caused by pathogenic variants in GAA, which encodes an enzyme integral to glycogen catabolism, acid α-glucosidase. Disease-relevant cell lines are necessary to evaluate the efficacy of genotype-specific therapies. Dermal fibroblasts from two patients presenting clinically with Pompe disease were reprogrammed to induced pluripotent stem cells using the Sendai viral method. One patient is compound heterozygous for the c.258dupC (p.N87QfsX9) frameshift mutation and the c.2227C>T (p.Q743X) nonsense mutation. The other patient harbors the c.-32-13T>G splice variant and the c.1826dupA (p.Y609X) frameshift mutation in compound heterozygosity.

Keywords:  Induced pluripotent stem cells; Lysosomal storage disorder; Pompe disease; Sendai virus

DOI:  https://doi.org/10.1016/j.scr.2023.103117
Fish Shellfish Immunol. 2023 May 09. pii: S1050-4648(23)00272-3. [Epub ahead of print] 108786

Effect of high temperature stress on glycogen metabolism in gills of Yesso scallop Patinopecten yessoensis.

Chuanyan Yang, Xiangbo Wang, Kai Zhou, Dongli Jiang, Ying Shan, Lingling Wang, Linsheng Song.

  Glycogen was the main energy storage material in mollusc, and the regulation of its metabolism is essential for the response against high temperature stress. In the present study, the alternation of lactic acid (LD) content, glycogen reserves, mRNA expression level of genes encoding glycogen metabolism enzymes and activities of glycogen metabolism enzymes in gills of Yesso scallop Patinopecten yessoensis after an acute high temperature treatment at 25 °C were examined to understand the effect of high temperature on glycogen metabolism. The activity of T-ATPase in gills of scallops presented a gradual increase trend especially at 6 h after an acute high temperature treatment (p < 0.05). The glycogen reserves did not change significantly even there was a downward trend at 24 h after the acute high temperature treatment (p > 0.05). The mRNA transcripts of glycogen synthase (PyGCS) in gills of scallops decreased significantly at 1, 3, 6 and 12 h (p < 0.05), and recovered to normal level at 24 h (p > 0.05) after the acute high temperature treatment, while that of glycogen phosphorylase a (PyGPa) and phosphoenol pyruvate carboxy kinase (PyPEPCK) were both significantly down-regulated from 1 h to 24 h (p < 0.05) after the acute high temperature treatment. The activity of PyGPa at 1, 12 and 24 h and the content of LD at 3 and 24 h in gills of scallops after the acute high temperature treatment both increased significantly (p < 0.05). Furthermore, the mRNA transcripts of hexokinase (PyHK) and pyruvate kinase (PyPK) in gills of scallops increased significantly (p < 0.05) after the acute high temperature treatment, and the response of PyHK was stronger. However, there was no significant difference on the activity of PyPK in gills of scallops between the experimental samples and the blank samples (p > 0.05). In addition, the mRNA transcripts of citrate synthase (PyCS) in gills of scallops were significantly down-regulated at 6 h and 12 h (p < 0.05), and finally returned to normal level at 24 h (p > 0.05) after the acute high temperature treatment. These results collectively indicated acute high temperature stress leaded the alternation of glycogen metabolism in the gills of Yesso scallop, glycogenesis, gluconeogenesis and TCA cycle were inhibited, and the glycolysis pathway of glycogen was enhanced to produce more energy for coping with environmental pressure.

Keywords:  Glycogen metabolism; Glycolysis; High temperature stress; Patinopecten yessoensis

DOI:  https://doi.org/10.1016/j.fsi.2023.108786
Cell Signal. 2023 May 08. pii: S0898-6568(23)00121-3. [Epub ahead of print] 110707

The 15-hydroxyprostaglandin dehydrogenase inhibitor SW033291 ameliorates abnormal hepatic glucose metabolism through PGE2-EP4 receptor-AKT signaling in a type 2 diabetes mellitus mouse model.

Mingjie Liang, Lexun Wang, Weixuan Wang.

  Type 2 diabetes mellitus (T2DM) is associated with high rates of morbidity and mortality worldwide. Prostaglandin E2 (PGE2) is a lipid signaling molecule that can ameliorate the symptoms of some metabolic diseases, including T2DM, and improve tissue repair and regeneration. Although SW033291 can increase PGE2 levels through its action as a small molecule inhibitor of the PGE2-degrading enzyme 15-hydroxyprostaglandin dehydrogenase, its effects on T2DM remain unclear. In the present study, we evaluated whether SW033291 treatment exerts a protective effect against T2DM and explored the underlying mechanisms. A T2DM mouse model was established using a high-fat diet combined with streptozotocin treatment. Palmitic acid-treated LO2 cells were used as an insulin-resistant cell model. SW033291 treatment reduced body weight and fasting blood glucose levels as well as serum triglyceride, total cholesterol, and low-density lipoprotein cholesterol levels in vivo. In addition to ameliorating glucose and insulin tolerance, SW033291 treatment reversed the T2DM-induced decrease in glycogen synthesis and increase in gluconeogenesis in the liver. Furthermore, SW033291 administration increased hepatic glycogen synthase kinase 3 beta (GSK3β) phosphorylation levels to promote glycogen synthesis. SW033291 treatment also inhibited gluconeogenesis by upregulating AKT serine/threonine kinase (AKT) and forkhead box O1 (FOXO1) phosphorylation and reducing glucose-6-phosphatase and phosphoenolpyruvate carboxykinase 1 expression in the livers of T2DM model mice. Additionally, SW033291 treatment improved abnormal hepatic glucose metabolism through the PGE2-EP4 receptor-AKT-GSK3β/FOXO1 signaling pathway in vitro. These results suggest a novel role of SW033291 in improving T2DM and support its potential as a novel therapeutic agent.

Keywords:  EP4 receptor; Gluconeogenesis; Glycogen synthesis; Prostaglandin E(2); SW033291; Type 2 diabetes mellitus

DOI:  https://doi.org/10.1016/j.cellsig.2023.110707
Cell Rep Methods. 2023 04 24. 3(4): 100455

In situ microwave fixation provides an instantaneous snapshot of the brain metabolome.

Jelena A Juras, Madison B Webb, Lyndsay E A Young, Kia H Markussen, Tara R Hawkinson, Michael D Buoncristiani, Kayli E Bolton, Peyton T Coburn, Meredith I Williams, Lisa P Y Sun, William C Sanders, Ronald C Bruntz, Lindsey R Conroy, Chi Wang, Matthew S Gentry, Bret N Smith, Ramon C Sun.

  Brain glucose metabolism is highly heterogeneous among brain regions and continues postmortem. In particular, we demonstrate exhaustion of glycogen and glucose and an increase in lactate production during conventional rapid brain resection and preservation by liquid nitrogen. In contrast, we show that these postmortem changes are not observed with simultaneous animal sacrifice and in situ fixation with focused, high-power microwave. We further employ microwave fixation to define brain glucose metabolism in the mouse model of streptozotocin-induced type 1 diabetes. Using both total pool and isotope tracing analyses, we identified global glucose hypometabolism in multiple brain regions, evidenced by reduced 13C enrichment into glycogen, glycolysis, and the tricarboxylic acid (TCA) cycle. Reduced glucose metabolism correlated with a marked decrease in GLUT2 expression and several metabolic enzymes in unique brain regions. In conclusion, our study supports the incorporation of microwave fixation for more accurate studies of brain metabolism in rodent models.

Keywords:  brain metabolism; isotope tracing; microwave fixation; regional metabolism; type 1 diabetes

DOI:  https://doi.org/10.1016/j.crmeth.2023.100455
J Physiol. 2023 May 08.

Exercise improves homeostasis of the intestinal epithelium by activation of APJ-AMPK signaling.

Song Ah Chae, Min Du, Jun Seok Son, Mei-Jun Zhu.

  Intestinal remodeling is dynamically regulated by energy metabolism. Exercise is beneficial for gut health, but the specific mechanisms remain poorly understood. Both intestine-specific apelin receptor (APJ) knockdown (KD) and wild-type male mice were randomly divided into two subgroups with/without exercise to obtain four groups: WT, WT with exercise, APJ KD, and APJ KD with exercise. Animals in exercise groups were subjected to daily treadmill exercise for 3 weeks. Duodenum was collected at 48h after the last bout of exercise. AMP-activated protein kinase (AMPK) α1 KD and wild-type mice were also utilized for investigating the mediatory role of AMPK on exercise-induced duodenal epithelial development. AMPK and peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1 α) were upregulated by exercise via APJ activation in the intestinal duodenum. Correspondingly, exercise induced permissive histone modifications in the PR domain containing 16 (PRDM16) promoter to activate its expression, which was dependent on APJ activation. In agreement, exercise elevated the expression of mitochondrial oxidative markers. The expression of intestinal epithelial markers was downregulated due to AMPK deficiency, and AMPK signaling facilitated epithelial renewal. These data demonstrate that exercise-induced activation of APJ-AMPK axis facilitates the homeostasis of the intestinal duodenal epithelium. ONE-SENTENCE SUMMARY: Exercise-induced APJ-AMPK axis upregulated the expression of PGC-1α and PRDM16 to improve homeostasis of intestinal epithelium. KEY POINTS: APJ signaling is required for improved epithelial homeostasis of the small intestine in response to exercise. Exercise intervention activates PRDM16 through inducing histone modifications, improving mitochondrial biogenesis and fatty acid metabolism in duodenum. Structure of intestinal epithelium is improved by muscle-derived exerkine apelin through APJ-AMPK axis. Abstract figure legend. Exercise training increases expression of apelin in muscle and the circulating apelin level. Exercise-induced apelin-APJ signaling enhances villus and crypt structure of the small intestine (duodenum) through the activation of AMPK and stimulation of mitochondrial biogenesis. Of note, exercise program induces histone modifications for PRDM16 expression, which enhances mitochondrial oxidative metabolism, thereby improving intestinal epithelial homeostasis. This article is protected by copyright. All rights reserved.

Keywords:  AMPK, APJ, duodenum, exercise; mitochondrial oxidation, PRDM16

DOI:  https://doi.org/10.1113/JP284552