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PubMed1994

[Glycogen synthase gene-glycogen synthase gene in Japanese patients with NIDDM].

As glycogen synthase is a key enzyme of the non-oxidative pathway of glucose metabolism in the skeletal muscle, and reduced activity of this enzyme is related to insulin resistance, it seems likely that this enzyme is a candidate gene for contributing to the pathogenesis of NIDDM. In this paper, we review recent findings of polymorphism of the human glycogen synthase gene, XbaI restriction enzyme length polymorphism and simple tandem repeat DNA polymorphism, and discuss the possible association between the glycogen synthase gene and NIDDM.

Asian People↗
PubMed2004

The primary defect in glycogen synthase activity is not based on increased glycogen synthase kinase-3alpha activity in diabetic myotubes.

The mechanism responsible for the diminished activation of glycogen synthase (GS) in diabetic myotubes remains unclear, but may involve increased activity and/or expression of glycogen synthase kinase-3 (GSK-3). In myotubes established from type 2 diabetic and healthy control subjects we determined GS activity ratio, protein expression, and activity of GSK-3alpha and beta under basal and insulin-stimulated conditions when precultured in increasing insulin concentrations. In myotubes precultured at low insulin concentrations acute insulin stimulation increased GS activity more in control than in diabetic subjects, whereas the corresponding GSK-3alpha but not GSK-3beta activity was significantly reduced by acute insulin treatment in both groups. However, in myotubes precultured at high insulin concentrations the effect of insulin on GS and GSK-3alpha activity was blunted in both groups. The protein expression of GSK-3alpha or beta was unaffected. In conclusion, myotubes with a primary defect in GS activity express insulin responsive GSK-3alpha, suggesting that failure of insulin to decrease GS phosphorylation involves abnormal activity of another kinase or phosphatase.

Adult↗
PubMed2000

The effects of glucose and the hexosamine biosynthesis pathway on glycogen synthase kinase-3 and other protein kinases that regulate glycogen synthase activity.

BACKGROUND: Glycogen synthase (GS) activity is determined by its phosphorylation state. We have previously demonstrated that high glucose (HG) downregulates both basal and insulin-stimulated GS activity in rat-1 fibroblasts and that the hexosamine biosynthesis pathway (HBP) may be involved in mediating some of the effects of glucose. In this study we investigate the influence of high glucose and glucosamine (GlcN) on the activity of several kinases that phosphorylate and inactivate GS. METHODS: Glycogen synthase kinase (GSK) 3, cAMP-dependent protein kinase (PKA), protein kinase C (PKC), casein kinase (CK) 1, and phosphorylase kinase (PhK) activities were assayed in cellular extracts from control rat-1 fibroblasts and those that overexpress human cDNA for glutamine:fructose 6-phosphate amidotransferase (GFA), the rate-limiting enzyme in the HBP. RESULTS: Culturing rat-1 fibroblasts in HG (20 mmol/L) or GlcN (3-5 mmol/L) for 16-20 hours increases GSK-3 activity by 23.9 and 50%, respectively, when compared to activity at low glucose (LG, 1 mmol/L). The effects of HG on GSK-3 activity are greater in cells overexpressing GFA (38.8% increase). Insulin (1.7 nmol/L) treatment leads to a 20-25% decrease in GSK-3 activity that is not affected by HG, GlcN, or GFA overexpression. Culturing control cells in HG increases PKA and CK-1 activities by 56 and 95%, respectively, and HG diminishes insulin action on CK-1 activity. GlcN inhibits insulin action on both PKA and CK-1 activities. HG, GlcN, and GFA overexpression blunted insulin's ability to downregulate PhK activity in LG conditions. PKC activity is not significantly altered in either cell line in the above conditions. CONCLUSIONS: These results suggest that HG alters both basal and insulin-regulated activity of several kinases that phosphorylate GS, and some of the effects of glucose may be mediated by its metabolism via the HBP.

Amino Acid Sequence↗
PubMed1997

A nonsense mutation due to a single base insertion in the 3'-coding region of glycogen debranching enzyme gene associated with a severe phenotype in a patient with glycogen storage disease type IIIa.

Glycogen storage disease type III (GSD-III) is an autosomal recessive disease resulting from deficient glycogen debranching enzyme (GDE) activity. A child with GDE deficient in both liver and muscle (GSD-IIIa) had recurrent hypoglycemia, seizures, severe cardiomegaly, and hepatomegaly and died at 4 years of age. Analysis of the GDE gene in this child by single-strand conformation polymorphism, followed by direct DNA sequencing and restriction analysis, revealed an insertion of a nucleotide A into position 4529 of the GDE cDNA (4529insA). This insertion resulted in substitution of a tyrosine to a stop codon at amino acid 1510 (Y1510X). The 4529insA mutation appeared to be homozygous in this patient and was not found in 20 unrelated controls or 18 other GSD-III patients (14 GSD-IIIa and 4 GSD-IIIb). This is the first identification of a disease mutation in this gene, and the data suggest that homozygous 4529insA may be associated with a severe phenotype in GSD-IIIa.

Glycogen Debranching Enzyme System↗
PubMed1996

A novel donor splice site mutation in the glycogen debranching enzyme gene is associated with glycogen storage disease type III.

Analysis of glycogen debranching enzyme (debrancher) cDNA from a patient with glycogen storage disease type III revealed a deletion of 124 base pairs. A donor splice site mutation (IVS G+1 to T) was identified in the patient's debrancher gene, which caused exon skipping of the upstream exon and resulted in a truncated enzyme due to premature termination. Mutational analysis of the patient's family showed that this point mutation was inherited from the father. Southern blot analysis of the patient's genomic DNA showed an additional, unique EcoRI fragment of 5.8 kb, which was inherited from the mother. These results suggested that the patient was a compound heterozygote for the donor splice site mutation, which is the first identified in the debrancher gene, and had a genetic defect relating to an aberrant 5.8-kb EcoRI fragment.

Adult↗
PubMed2003

Muscle- and fibre type-specific expression of glucose transporter 4, glycogen synthase and glycogen phosphorylase proteins in human skeletal muscle.

The muscle- and fibre type-specific expression of skeletal muscle glucose transporter 4 (GLUT4), glycogen synthase (GS) and glycogen phosphorylase (GP) was investigated in six young male subjects. Single muscle fibres were dissected from vastus lateralis (VL), soleus (SO) and triceps brachii (TB) muscle biopsy samples. On the basis of myosin heavy chain (MHC) expression, fibres were pooled into three groups (MHC I, MHC IIA and MHC IIX) and the GLUT4, GS and GP content of 15-40 pooled fibres determined using SDS-PAGE and immunological detection. In VL, the GLUT4 content in the pooled muscle fibres expressing MHC I was approximately 33% higher ( P<0.05) than in fibres expressing MHC IIA or IIX. There was no difference in GLUT4 content between fibres expressing MHC IIA or IIX, nor were there any differences in GS and GP content between any of the fibre types. In SO, there was no difference in GLUT4, GS and GP between fibres expressing MHC I or IIA. No fibres expressing type IIX were detected. In TB, fibres expressing MHC IIA and IIX had significantly ( P<0.05) more GP (66% and 55 % in MHC IIA and MHCIIX, respectively) than those expressing MHC I, whilst there was no difference in GP between MHC IIA and MHC IIX fibres. The GLUT4 and the GS content was similar in fibres expressing MHC I, IIA and IIX in the TB. Our data directly demonstrate that some proteins, like GLUT4 and GP, are expressed in a fibre type-specific manner in some, but not all, muscles, whilst other proteins, like GS, are not. In human skeletal muscle the GLUT4, GS and GP content thus seems to be related primarily to factors other than the fibre type as defined by the expression of contractile protein. These findings imply that it is not possible to generalize fibre type-dependent protein expression on the basis of biopsies from only one muscle.

Adult↗
PubMed1984

Phosphorylation and inactivation of rabbit skeletal muscle glycogen synthase: distinction between kinase Fa-, phosphorylase kinase-, and glycogen synthase (casein) kinase-1-catalyzed reactions.

Rabbit skeletal muscle glycogen synthase was phosphorylated by kinase Fa, phosphorylase kinase, and cAMP-independent synthase (casein) kinase-1 to determine the differences among these kinase-catalyzed reactions. The stoichiometry of phosphate incorporation, the extent of inactivation, and the sites of phosphorylation were compared. Synthase (casein) kinase-1 catalyzes the highest level of synthase phosphorylation (4 mol/subunit) and inactivation (reduction of the activity ratio to below 0.05). The sites, defined by characteristic tryptic peptides, phosphorylated by synthase (casein) kinase-1 are distinguishable from those by kinase Fa and phosphorylase kinase. In addition, synthase (casein) kinase-1, unlike kinase Fa, does not activate ATP X Mg2+-dependent protein phosphatase. These results demonstrate that synthase (casein) kinase-1 is a distinct glycogen synthase kinase.

Animals↗
PubMed1988

Binding of glycogen, oligosaccharides, and glucose to glycogen debranching enzyme.

The binding of glucose and a series of oligosaccharides to glycogen debranching enzyme was determined by the ability of the saccharides to decrease the rate of reaction of sulfhydryl groups with 5,5'-dithiobis(2-nitrobenzoate) (DTNB). At pH 7.2, the strength of binding increases with chain length from glucose to maltotriose to maltopentaose but not to maltohexaose, and the free energies for binding of the oligosaccharides suggest subsites of equivalent affinities for the four glucose units following the initial reducing moiety. The rate of reaction of DTNB with enzyme saturated with saccharide is the same for all compounds, suggesting that all the saccharides, including glucose, induce the same conformational state. The site of binding may be that which binds the alpha-1,6-linked side chain of the natural limit dextrin substrate. At pH 8.0, this site exhibits similar characteristics, but an additional site, which may bind the four terminal glucose units of the main chain of the natural substrate, is manifested and exhibits different characteristics, including a very low affinity for glucose itself. The binding of glycogen to the debranching enzyme was monitored by centrifugal separation from the protein and exhibits a much lower dissociation constant than that for the oligomers, suggesting that branched polymers have more than one set of subsites.

Animals↗
PubMed2004

Activation of glycogen phosphorylase with 5-aminoimidazole-4-carboxamide riboside (AICAR). Assessment of glycogen as a precursor of mannosyl residues in glycoconjugates.

The experimental evaluation of the contribution of glycogen phosphorylase (GP) to biochemical pathways is limited to methods that raise cAMP, activating the cAMP-dependent protein kinase/phosphorylase kinase/GP cascade. Such methods convert the unphosphorylated form, "GPb," which catalyzes glycogenolysis only in the presence of appropriate allosteric activators such as AMP, to the phosphorylated, constitutively activated form, "GPa." However, activation of GP in this way is indirect, requires a functional cAMP kinase cascade, and is complicated by other actions of cAMP. Here, we demonstrate a strategy for the experimental manipulation of GP in intact dermal fibroblasts, involving activation by the membrane-permeable adenosine analog 5-aminoimidazole-4-carboxamide riboside (AICAR) and inhibition by caffeine and Pfizer compound CP-91149, which bind to GP at distinct sites. Potential complications because of activation of AMP-activated protein kinase by AICAR were assessed with metformin, which activates this kinase but does not activate GP. Using this strategy, we show that glycogen can be a significant and regulatable precursor of mannosyl units in lipid-linked oligosaccharides and glycoproteins.

Amides↗
PubMed1998

Identification of a mutation in liver glycogen phosphorylase in glycogen storage disease type VI.

Glycogen storage disease type VI (GSD6) defines a group of disorders that cause hepatomegaly and hypoglycemia with reduced liver phosphorylase activity. The course of these disorders is generally mild, but definitive diagnosis requires invasive procedures. We analyzed a Mennonite kindred with an autosomal recessive form of GSD6 to determine the molecular defect and develop a non-invasive diagnostic test. Linkage analysis was performed using genetic markers flanking the liver glycogen phosphorylase gene ( PYGL ), which was suspected to be the cause of the disorder on biochemical grounds. Mennonite GSD6 was linked to the PYGL locus with a multipoint LOD score of 4.7. The PYGL gene was analyzed for mutations by sequencing genomic DNA. Sequencing of genomic DNA revealed a splice site abnormality of the intron 13 splice donor. Confirmation of the genomic mutation was performed by sequencing RT-PCR products, which showed heterogeneous PYGL mRNA lacking all or part of exon 13 in affected persons. This study is the first to demonstrate that a mutation in the PYGL gene can cause GSD6. This mutation is estimated to be present on 3% of Mennonite chromosomes and the disease affects 0.1% of that population. Determination of this mutation provides a basis for the development of a simple and non-invasive diagnostic test for the disease and the carrier state in this population and confirms biochemical data showing the importance of this gene in glucose homeostasis.

Base Sequence↗
PubMed1997

Polymorphic markers of the glycogen debranching enzyme gene allowing linkage analysis in families with glycogen storage disease type III.

Glycogen storage disease type III (GSD-III), an autosomal recessive disease, is caused by deficient glycogen debranching enzyme (GDE) activity. We identified three polymorphic markers in the GDE gene using single strand conformation polymorphism (SSCP) analysis and DNA sequencing. They were -10G/A in the 5' non-translated region of exon 3,2001 + 8C/T in intron 16, and 3199C/T (P1067S) in exon 25. Two polymorphic markers (-10G/A and 2001 + 8C/T) were highly informative in both controls and GSD-III patients with heterozygosity values of 0.50 and 0.46, respectively. The third marker (3199C/T) had a heterozygosity value of 0.26. Restriction analysis of the PCR amplified genomic DNA products in two GSD-III families showed for the first time the potential use of these markers for carrier detection and prenatal diagnosis in this disease.

Base Sequence↗
PubMed1996

Mutations in exon 3 of the glycogen debranching enzyme gene are associated with glycogen storage disease type III that is differentially expressed in liver and muscle.

Glycogen storage disease type HI (GSD-III), an autosomal recessive disease, is caused by deficient glycogen debranching enzyme (GDE) activity. Most GSD-III patients are GDE deficient in both liver and muscle (type IIIa), and some GSD-III patients have GDE absent in liver but retained in muscle (type IIIb). The molecular basis for this enzymatic variability is largely unknown. In the present study, the analysis of the GDE gene in three GSD-IIIb patients by single-strand conformation polymorphism (SSCP), DNA sequencing, restriction analysis, and family studies, revealed each of them as being a compound heterozygote for two different mutations. The first mutant alleles in all three patients involved mutations in exon 3 at amino acid codon 6 of the GDE protein. Two had an AG deletion at nucleotides 17 and 18 of the GDE cDNA (17delAG) which resulted in change of subsequent amino acid sequence and a truncated protein (25X); the other had a C to T transition at nucleotide 16 of the cDNA which changed a Glutamine codon to a stop codon (Q6X). The 17delAG mutation was also found in 8 of the 10 additional GSD-IIIb patients. The Q6X mutation was found in one of the remaining two GSD-IIIb patients. These two mutations were not found in any of the 31 GSD-IIIa patients, 2 GSD-IIId patients, nor 28 unrelated normal controls. The second mutant alleles in each of the three GSD-IIIb patients were R864X, R1228X, and W68OX. The R864X and R1228X were not unique for GSD-IIIb as they were also found in GSD-IIIa patients (frequency of 10.3% and 5.2% in Caucasian patients, respectively). Our data demonstrated that both IIIa and IIIb had mutations in the same GDE gene and established for the first time the molecular basis of GSD-III that differentially expressed in liver and muscle. The striking and specific association of exon 3 mutations with GSD-IIIb may provide insight into mechanisms controlling tissue-specific expression of the GDE gene. The identification of exon 3 mutations has clinical significance as well because it distinguished GSD-IIIb from IIIa hence permitting diagnosis from a blood sample rather than a more invasive muscle biopsy.

Base Sequence↗
PubMedDate not supplied

A single-base deletion in the 3'-coding region of glycogen-debranching enzyme is prevalent in glycogen storage disease type IIIA in a population of North African Jewish patients.

Glycogen storage disease type III (GSD III) is an autosomal recessive disease caused by the deficiency of glycogen-debranching enzyme (AGL). The overall incidence of the disease is about 1:100,000 life births in the USA; however, it is unusually frequent among North African Jews in Israel (prevalence 1:5,400, carrier prevalence 1:35). All North African Jewish GSD III patients examined have both liver and muscle involvement. While all patients showed the characteristic features related to the liver enzyme deficiency, the peripheral muscular impairment varied from minimal to severe, with neuromuscular involvement. A single mutation in the AGL gene, the deletion of T at position 4,455 (4,455delT) in homozygous form, was found in this patient population. The mutation 4,455delT results in the change of 17 amino acids at the carboxy terminus of the AGL protein (1,486-1,502) and truncation of the last 30 amino acids of the normal AGL 1,532 amino acids. The mutation appears to be ethnic specific as it was not seen in 18 patients of different ethnic origins. This is the first report of a mutation in the AGL gene affecting a considerable number of GSD III patients in a defined population.

Adult↗
PubMed1988

Periodic acid Schiff--p phenylenediamine staining of glycogen in chondrocytes. A new combination which improves both cellular detail and glycogen identification.

This study reports a method whereby glycogen is identified in the chondrocytes of the secondary center of ossification prior to mineralization. The use of new fuchsin rather than basic fuchsin on one micron Spurr sections of femoral head cartilage fixed with potassium ferrocyanide-reduced osmium produced excellent identification of glycogen and when followed by p phenylenediamine, intensified cellular detail.

Animals↗
PubMed2002

Glycogen storage disease type I: diagnosis, management, clinical course and outcome. Results of the European Study on Glycogen Storage Disease Type I (ESGSD I).

UNLABELLED: Glycogen storage disease type I (GSD I) is a relatively rare metabolic disease and therefore, no metabolic centre has experience of large numbers of patients. To document outcome, to develop guidelines about (long-term) management and follow-up, and to develop therapeutic strategies, the collaborative European Study on GSD I (ESGSD I) was initiated. This paper is a descriptive analysis of data obtained from the retrospective part of the ESGSD I. Included were 231 GSD Ia and 57 GSD Ib patients. Median age of data collection was 10.4 years (range 0.4-45.4 years) for Ia and 7.1 years (0.4-30.6 years) for Ib patients. Data on dietary treatment, pharmacological treatment, and outcome including mental development, hyperlipidaemia and its complications, hyperuricaemia and its complications, bleeding tendency, anaemia, osteopenia, hepatomegaly, liver adenomas and carcinomas, progressive renal disease, height and adult height, pubertal development and bone maturation, school type, employment, and pregnancies are presented. Data on neutropenia, neutrophil dysfunction, infections, inflammatory bowel disease, and the use of granulocyte colony-stimulating factor are presented elsewhere (Visser et al. 2000, J Pediatr 137:187-191; Visser et al. 2002, Eur J Pediatr DOI 10.1007/s00431-002-1010-0). CONCLUSION: there is still wide variation in methods of dietary and pharmacological treatment of glycogen storage disease type I. Intensive dietary treatment will improve, but not correct completely, clinical and biochemical status and fewer patients will die as a direct consequence of acute metabolic derangement. With ageing, more and more complications will develop of which progressive renal disease and the complications related to liver adenomas are likely to be two major causes of morbidity and mortality.

Adenoma↗
PubMed1983

Glycogen metabolism in the capillary endothelium. Electron histochemical study of glycogen synthetase and phosphorylase in the pecten capillary of the chick.

Glycogen synthetase and phosphorylase activities in the pecten capillary of the chick were studied electron histochemically. Polyglucose particles synthesized by glycogen synthetase or phosphorylase in the pecten capillary were demonstrated to be amorphous. They were located in the cytoplasmic matrix of the endothelium and expanded it widely. The endothelial cell of the pecten capillary plays a role in glycogenesis as well as glycogenolysis and may require substantial energy to its important transport functions.

Animals↗
PubMed2000

Novel mutations in two Japanese cases of glycogen storage disease type IIIa and a review of the literature of the molecular basis of glycogen storage disease type III.

We report two novel mutations in two Japanese patients with glycogen storage disease type IIIa (GSD IIIa). In addition, we review the literature on mutations in GSD III to understand better the molecular basis of GSD III. In our first case, the homozygous A-to-C mutation at the acceptor site of intron 5 (IVS5-2A > C) was identified. This leads to the skipping of exon 6 and the predicted mutant protein was found to be 68 amino acids shorter than normal. This is the first report of skipping exon 6, which encodes one of the putative active sites, resulting in a profoundly deleterious effect on debrancher activity. In our second case, the homozygous deletion of an A at position 4234 (4234delA) was identified; this induces a frameshift resulting in the appearance of a stop codon at amino acid position 1276 (1276X). In patients with GSD IIIa, several mutations of the debrancher gene located in the C-terminal region containing putative glycogen binding domains have been identified as well as 4234delA in our second case. On the other hand, specific localization of the mutations within exon 3 was proposed in patients with GSD IIIb.

Adult↗