The Stimulation-Induced Increase in Skeletal Muscle Glycogen Synthase Content Is Impaired in Carriers of the Glycogen Synthase <i>XbaI</i> Gene Polymorphism

St-Onge, Josée; Joanisse, Denis R.; Simoneau, J. A.

doi:10.2337/diabetes.50.1.195

Cited by 20 publications

(12 citation statements)

References 19 publications

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“…When mutations corresponding to several of the alleles found in nature were introduced into enzyme expressed in COS cells, loss of activity was observed. Mutant alleles of GYS1, encoding muscle glycogen synthase, have also been reported and in some cases a correlation with type II diabetes has been suggested [105][106][107] but was not seen in others [108]. Insofar as muscle is an important site of glucose disposal, such a correlation would be reasonable but as yet not fully substantiated.…”

Section: Degradationmentioning

confidence: 89%

Glycogen and its Metabolism

Roach¹

2002

CMM

402

335

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Glycogen is a branched polymer of glucose which serves as a reservoir of glucose units. The two largest deposits in mammals are in the liver and skeletal muscle but many cells are capable synthesizing glycogen. Its accumulation and utilization are under elaborate controls involving primarily covalent phosphorylation and allosteric ligand binding. Both muscle and liver glycogen reserves are important for whole body glucose metabolism and their replenishment is linked hormonally to nutritional status. Control differs between muscle and liver in part due to the existence of different tissue-specific isoforms at key steps. Control of synthesis is shared between transport into the muscle and the step catalyzed by glycogen synthase. Breakdown of liver glycogen, as part of blood glucose homeostasis, is also in response to nutritional cues. Muscle glycogen serves only to fuel muscular activity and its utilization is controlled by muscle contraction and by catecholamines. Though the number of enzymes directly involved in the metabolism of glycogen is quite small, many more proteins act indirectly in a regulatory capacity. Defects in the basic metabolizing enzymes lead to severe consequences whereas, with some exceptions, mutations in the regulatory proteins appear to cause a more subtle phenotypic change.

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Section: Degradationmentioning

confidence: 89%

Glycogen and its Metabolism

Roach¹

2002

CMM

402

335

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“…However, it is possible that differences in the GS response could be identified in insulin-resistant subjects by testing the effect of a different exercise challenge. For example, St-Onge et al (41) demonstrated that GS protein content in muscle increases in response to 6 wk of electrical stimulation in subjects that do not carry the XbaI GS polymorphism, whereas muscle contraction does not increase GS content in carriers of this mutation. In the future, it will be interesting to investigate whether abnormalities in GS function can be detected by testing the response to other exercise/contraction protocols.…”

Section: E87 Glycogen Synthase Regulation and Phosphorylation In Diabmentioning

confidence: 99%

Effect of acute exercise on glycogen synthase in muscle from obese and diabetic subjects

Jensen

Tantiwong

Stuenæs

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Jensen J, Tantiwong P, Stuenaes JT, Molina-Carrion M, DeFronzo RA, Sakamoto K, Musi N. Effect of acute exercise on glycogen synthase in muscle from obese and diabetic subjects. Am J Physiol Endocrinol Metab 303: E82-E89, 2012. First published April 17, 2012; doi:10.1152/ajpendo.00658.2011.-Insulin stimulates glycogen synthase (GS) through dephosphorylation of serine residues, and this effect is impaired in skeletal muscle from insulin-resistant [obese and type 2 diabetic (T2DM)] subjects. Exercise also increases GS activity, yet it is not known whether the ability of exercise to affect GS is impaired in insulin-resistant subjects. The objective of this study was to examine the effect of acute exercise on GS phosphorylation and enzyme kinetic properties in muscle from insulin-resistant individuals. Lean normal glucose-tolerant (NGT), obese NGT, and obese T2DM subjects performed 40 min of moderate-intensity cycle exercise (70% of V O2max). GS kinetic properties and phosphorylation were measured in vastus lateralis muscle before exercise, immediately after exercise, and 3.5 h postexercise. In lean subjects, GS fractional activity increased twofold after 40 min of exercise, and it remained elevated after the 3.5-h rest period. Importantly, exercise also decreased GS K m for UDP-glucose from Ϸ0.5 to Ϸ0.2 mM. In lean subjects, exercise caused significant dephosphorylation of GS by 50 -70% (Ser 641 , Ser 645 , and Ser 645,649,653,657 ), and phosphorylation of these sites remained decreased after 3.5 h; Ser 7 phosphorylation was not regulated by exercise. In obese NGT and T2DM subjects, exercise increased GS fractional activity, decreased K m for UDPglucose, and decreased GS phosphorylation as effectively as in lean NGT subjects. We conclude that the molecular regulatory process by which exercise promotes glycogen synthesis in muscle is preserved in insulin-resistant subjects.

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“…Interestingly, electrical stimulation of skeletal muscle to mimic physical exercise increased the amount of glycogen synthase in carriers of wild-type C-allele but not in carriers of the T-allele. As a consequence, carriers of the T-allele may benefit less from physical exercise than carriers of the normal allele [11]. GYS1 is located on chromosome 19q13.3, a region that has in several linkage studies been linked to MetS and T2D associated phenotypes [12]–[17].…”

Section: Introductionmentioning

confidence: 99%

Variation in GYS1 Interacts with Exercise and Gender to Predict Cardiovascular Mortality

et al. 2007

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BackgroundThe muscle glycogen synthase gene (GYS1) has been associated with type 2 diabetes (T2D), the metabolic syndrome (MetS), male myocardial infarction and a defective increase in muscle glycogen synthase protein in response to exercise. We addressed the questions whether polymorphism in GYS1 can predict cardiovascular (CV) mortality in a high-risk population, if this risk is influenced by gender or physical activity, and if the association is independent of genetic variation in nearby apolipoprotein E gene (APOE).Methodology/Principal FindingsPolymorphisms in GYS1 (XbaIC>T) and APOE (-219G>T, ε2/ε3/ε4) were genotyped in 4,654 subjects participating in the Botnia T2D-family study and followed for a median of eight years. Mortality analyses were performed using Cox proportional-hazards regression. During the follow-up period, 749 individuals died, 409 due to CV causes. In males the GYS1 XbaI T-allele (hazard ratio (HR) 1.9 [1.2–2.9]), T2D (2.5 [1.7–3.8]), earlier CV events (1.7 [1.2–2.5]), physical inactivity (1.9 [1.2–2.9]) and smoking (1.5 [1.0–2.3]) predicted CV mortality. The GYS1 XbaI T-allele predicted CV mortality particularly in physically active males (HR 1.7 [1.3–2.0]). Association of GYS1 with CV mortality was independent of APOE (219TT/ε4), which by its own exerted an effect on CV mortality risk in females (2.9 [1.9–4.4]). Other independent predictors of CV mortality in females were fasting plasma glucose (1.2 [1.1–1.2]), high body mass index (BMI) (1.0 [1.0–1.1]), hypertension (1.9 [1.2–3.1]), earlier CV events (1.9 [1.3–2.8]) and physical inactivity (1.9 [1.2–2.8]).Conclusions/SignificancePolymorphisms in GYS1 and APOE predict CV mortality in T2D families in a gender-specific fashion and independently of each other. Physical exercise seems to unmask the effect associated with the GYS1 polymorphism, rendering carriers of the variant allele less susceptible to the protective effect of exercise on the risk of CV death, which finding could be compatible with a previous demonstration of defective increase in the glycogen synthase protein in carriers of this polymorphism.

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The Stimulation-Induced Increase in Skeletal Muscle Glycogen Synthase Content Is Impaired in Carriers of the Glycogen Synthase XbaI Gene Polymorphism

Cited by 20 publications

References 19 publications

Glycogen and its Metabolism

Glycogen and its Metabolism

Effect of acute exercise on glycogen synthase in muscle from obese and diabetic subjects

Variation in GYS1 Interacts with Exercise and Gender to Predict Cardiovascular Mortality

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