Direct observation of glycogen synthesis in human muscle with 13C NMR.

Jue, Thomas; Rothman, Douglas L.; Shulman, Gerald I.; Tavitian, B. A.; DeFronzo, Ralph A.; Shulman, Robert G.

doi:10.1073/pnas.86.12.4489

Cited by 81 publications

(57 citation statements)

References 21 publications

(21 reference statements)

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“…The role of skeletal muscle as a primary site of insulindependent glucose disposal in humans is well established (5,21). In mice, its role is less clear.…”

Section: Discussionmentioning

confidence: 99%

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Glucose Metabolism in Mice Lacking Muscle Glycogen Synthase

et al. 2005

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Glycogen is an important component of whole-body glucose metabolism. MGSKO mice lack skeletal muscle glycogen due to disruption of the GYS1 gene, which encodes muscle glycogen synthase. MGSKO mice were 5-10% smaller than wild-type littermates with less body fat. They have more oxidative muscle fibers and, based on the activation state of AMP-activated protein kinase, more capacity to oxidize fatty acids. Blood glucose in fed and fasted MGSKO mice was comparable to wild-type littermates. Serum insulin was lower in fed but not in fasted MGSKO animals. In a glucose tolerance test, MGSKO mice disposed of glucose more effectively than wild-type animals and had a more sustained elevation of serum insulin. This result was not explained by increased conversion to serum lactate or by enhanced storage of glucose in the liver. However, glucose infusion rate in a euglycemic-hyperinsulinemic clamp was normal in MGSKO mice despite diminished muscle glucose uptake. During the clamp, MGSKO animals accumulated significantly higher levels of liver glycogen as compared with wild-type littermates. Although disruption of the GYS1 gene negatively affects muscle glucose uptake, overall glucose tolerance is actually improved, possibly because of a role for GYS1 in tissues other than muscle. Diabetes 54: 3466 -3473, 2005 A fter a meal, glucose is distributed into various tissues of the body where it can be utilized as an energy source or stored as glycogen (1). Glycogen is a branched polymer of glucose residues connected by ␣-1,4-glycosidic linkages formed by the enzyme glycogen synthase (EC 2.4.1.11) and branchpoints formed via ␣-1,6-glycosidic linkages, introduced by the branching enzyme (EC 2.4.1.18). There are two mammalian isoforms of glycogen synthase. One, encoded by the GYS2 gene, appears to be expressed only in liver (2) while a second gene, GYS1, is expressed in skeletal and cardiac muscle as well as adipose tissue, kidney, and brain (3).Estimates of the contribution of skeletal muscle glycogen to glucose disposal after ingestion of carbohydrate vary. In humans, reports of ingested glucose conversion to muscle glycogen range from ϳ40% (4) up to 90% (5). It is widely accepted that muscle is an important site for glucose disposal and one might hypothesize that, in the absence of muscle glycogen, glucose clearance would be impaired. Consistent with this hypothesis, mutations in the GYS1 gene in humans have been implicated in certain diabetic populations with, for example, the Pro442Ala mutation resulting in decreased muscle glycogen synthase activity (6).We recently described the MGSKO mouse, in which the GYS1 gene is disrupted (7). Analysis of MGSKO mice confirmed the long-held supposition that glycogen synthase is required for glycogen synthesis since these animals were devoid of glycogen in cardiac and skeletal muscle (7). In the present study, we analyzed a number of metabolic parameters in the MGSKO mouse, including whole-body glucose metabolism, with an initial hypothesis that mice lacking the ability to synthesize muscl...

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“…The role of skeletal muscle as a primary site of insulindependent glucose disposal in humans is well established (5,21). In mice, its role is less clear.…”

Section: Discussionmentioning

confidence: 99%

“…In humans, reports of ingested glucose conversion to muscle glycogen range from ϳ40% (4) up to 90% (5). It is widely accepted that muscle is an important site for glucose disposal and one might hypothesize that, in the absence of muscle glycogen, glucose clearance would be impaired.…”

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confidence: 99%

Glucose Metabolism in Mice Lacking Muscle Glycogen Synthase

et al. 2005

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“…Skeletal muscle is the major site of insulin-stimulated glucose uptake, and most of the glucose taken up by muscle in response to insulin is deposited as glycogen (1). This synthetic pathway begins with glucose transport, which is activated strongly by insulin (2).…”

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confidence: 99%

“…This synthetic pathway begins with glucose transport, which is activated strongly by insulin (2). Intracellular glucose is phosphorylated rapidly by hexokinase to form glucose 6-phosphate (Glu-6-P), 1 which is isomerized to glucose 1-phosphate (Glu-1-P) by phosphoglucomutase. Uridine diphosphoglucose (UDP-Glc) pyrophosphorylase (PPL) then utilizes UTP and Glu-1-P to form UDPGlc, the immediate precursor for glycogen synthesis.…”

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confidence: 99%

Effects of Insulin and Transgenic Overexpression of UDP-glucose Pyrophosphorylase on UDP-glucose and Glycogen Accumulation in Skeletal Muscle Fibers

Reynolds

Pak

Harris

et al. 2005

Journal of Biological Chemistry

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UDP-glucose (UDP-Glc) and glycogen levels in skeletal muscle fibers of defined fiber type were measured using microanalytical methods. Infusing rats with insulin increased glycogen in both Type I and Type II fibers. Insulin was without effect on UDP-Glc in Type I fibers but decreased UDP-Glc by 35-40% in Type IIA/D and Type IIB fibers. The reduction in UDP-Glc suggested that UDP-Glc pyrophosphorylase (PPL) activity might limit glycogen synthesis in response to insulin. To explore this possibility, we generated mice overexpressing a UDP-Glc PPL transgene in skeletal muscle. The transgene increased both UDP-Glc PPL activity and levels of UDP-Glc in skeletal muscles by ϳ3-fold. However, overexpression of UDP-Glc PPL was without effect on either the levels of skeletal muscle glycogen or glucose tolerance in vivo. The transgene was also without effect on either control or insulin-stimulated rates of 14 C-glucose incorporation into glycogen in muscles incubated in vitro. The results indicate that UDP-Glc PPL activity is not limiting for glycogen synthesis.

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“…The large majority of postprandial glucose uptake occurs in skeletal muscle (1,2), and most of the glucose that enters muscle fibers in response to insulin is converted to glycogen (3). This hormonal effect involves activation of glycogen synthase, the enzyme that catalyzes the rate-limiting step in the conversion of intracellular glucose to glycogen (4,5).…”

mentioning

confidence: 99%

Regulation of Both Glycogen Synthase and PHAS-I by Insulin in Rat Skeletal Muscle Involves Mitogen-activated Protein Kinase-independent and Rapamycin-sensitive Pathways

Azpiazu

Saltiel²,

DePaoli‐Roach

et al. 1996

Journal of Biological Chemistry

148

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Incubating rat diaphragm muscles with insulin increased the glycogen synthase activity ratio (minus glucose 6-phosphate/plus glucose 6-phosphate) by approximately 2-fold. Insulin increased the activities of mitogen-activated protein (MAP) kinase and the M r ‫؍‬ 90,000 isoform of ribosomal protein S6 kinase (Rsk) by approximately 1.5-2.0-fold. Epidermal growth factor (EGF) was more effective than insulin in increasing MAP kinase and Rsk activity, but in contrast to insulin, EGF did not affect glycogen synthase activity. The activation of both MAP kinase and Rsk by insulin was abolished by incubating muscles with the MAP kinase kinase (MEK) inhibitor, PD 098059; however, the MEK inhibitor did not significantly reduce the effect of insulin on activating glycogen synthase. Incubating muscles with concentrations of rapamycin that inhibited activation of p70 S6K abolished the activation of glycogen synthase. Insulin also increased the phosphorylation of PHAS-I (phosphorylated heat-and acid-stable protein) and promoted the dissociation of the PHAS-I⅐eIF-4E complex. Increasing MAP kinase activity with EGF did not mimic the effect of insulin on PHAS-I phosphorylation, and the effect of insulin on increasing MAP kinase could be abolished with the MEK inhibitor without decreasing the effect of insulin on PHAS-I. The effects of insulin on PHAS-I were attenuated by rapamycin. Thus, activation of the MAP kinase/Rsk signaling pathway appears to be neither necessary nor sufficient for insulin action on glycogen synthase and PHAS-I in rat skeletal muscle. The results indicate that the effects of insulin on increasing the synthesis of glycogen and protein in skeletal muscle, two of the most important actions of the hormone, involve a rapamycin-sensitive mechanism that may include elements of the p70 S6K signaling pathway.

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Direct observation of glycogen synthesis in human muscle with 13C NMR.

Cited by 81 publications

References 21 publications

Glucose Metabolism in Mice Lacking Muscle Glycogen Synthase

Glucose Metabolism in Mice Lacking Muscle Glycogen Synthase

Effects of Insulin and Transgenic Overexpression of UDP-glucose Pyrophosphorylase on UDP-glucose and Glycogen Accumulation in Skeletal Muscle Fibers

Regulation of Both Glycogen Synthase and PHAS-I by Insulin in Rat Skeletal Muscle Involves Mitogen-activated Protein Kinase-independent and Rapamycin-sensitive Pathways

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