Correlations of glycogen synthase and phosphorylase activities with glycogen concentration in human muscle biopsies. Evidence for a double-feedback mechanism regulating glycogen synthesis and breakdown

Munger, R.; Temler, E; Jallut, D; Haesler, Erik; Felber, J. P.

doi:10.1016/0026-0495(93)90169-o

Cited by 39 publications

(30 citation statements)

References 36 publications

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“…In skeletal muscle, a negative feedback mechanism between tissue glycogen concentration and the rate of glycogen synthesis has been described [23,24,36]. In this study, the 24-h period of fasting before the study was performed resulted, however, in low muscle glycogen concentrations in both unmated and late-pregnant 24-h starved rats.…”

Section: Discussionmentioning

confidence: 51%

In late pregnancy insulin-dependent glucose transport/phosphorylation is selectively impaired and activation of glycogen synthase by insulin facilitated in skeletal muscles of 24-h starved rats

Holness

Sugden

1999

Diabetologia

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Glucose sparing during pregnancy is achieved through suppression of glucose utilisation by the skeletal muscle mass [1±4]. This adaptation spares glucose for use by the feto-placental unit by limiting maternal glucose utilisation [2,3,5] and is also an important adaptation for safeguarding fetal nutrient supply during periods of nutrient (e. g. glucose) scarcity. Individual skeletal muscle types respond selectively to the requirement for glucose sparing during pregnancy [1]. Although suppression of glucose utilisation is more pronounced in slow-twitch (oxidative) skeletal Diabetologia (1999) Abstract Aims/hypothesis. We investigated the relation between glucose transport/phosphorylation and glycogen synthase activation in individual rat skeletal muscles in response to moderate hyperinsulinaemia in the absence or presence of hyperglycaemia during pregnancy. Methods. Rats were studied on day 20 of pregnancy after 24-h starvation, with unmated rats as controls. Insulin and glucose were infused into conscious rats through an indwelling cannula as specified. Glucose transport/phosphorylation was assessed in vivo using 2-deoxy-[1-3

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Section: Discussionmentioning

confidence: 51%

In late pregnancy insulin-dependent glucose transport/phosphorylation is selectively impaired and activation of glycogen synthase by insulin facilitated in skeletal muscles of 24-h starved rats

Holness

Sugden

1999

Diabetologia

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“…Conversely, in McArdle patients with a high muscle glycogen content, we found that glycogen synthase activity induced by euglycemic hyperinsulinemia was impaired and correlated tightly negatively with glycogen levels in skeletal muscle. A negative correlation between muscle glycogen content and insulin-stimulated glycogen synthase activity has also been reported in healthy subjects (7,28). In some studies, insulininduced whole body glucose utilization is independent of the prevailing glycogen concentration in human skeletal muscle (7,21), whereas in other studies examining leg glucose uptake, glycogen does play a role in insulin-induced muscle glucose utilization (31).…”

Section: Discussionmentioning

confidence: 96%

“…One of the aims of this study was to elucidate whether differences in basal and insulin-induced glycogen synthase activity between McArdle patients and control subjects could be attributed to insulin-signaling intermediates known to affect glycogen synthase. Glycogen synthase activity is regulated by activating phosphatases and deactivating kinases but is also strongly correlated with the cellular glycogen level (7,28,42) by a yet unknown mechanism. Activity of GSK3␣ is reduced by insulin stimulation (41), but as a novel finding in the present study, the basal level of GSK3␣ and -␤ as well as the deactivation by insulin of GSK3␣ were unaffected by glycogen level per se in human skeletal muscle (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Studies investigating the function of different insulin-signaling molecules as possible sites of dysfunction have so far been inconclusive (34,43). It has, however, been shown that, in humans, glycogen exerts a negative effect on the ability of insulin to increase muscle glycogen synthase activity (7,21,28), but the effect of glycogen levels on insulin-stimulated muscle glucose uptake has not been studied. In rodent skeletal muscle studied in vitro, glycogen synthase activity and glucose transport are decreased by glycogen loading and increased by glycogen depletion.…”

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confidence: 99%

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Decreased insulin action in skeletal muscle from patients with McArdle's disease

Nielsen

Vissing

Wojtaszewski

et al. 2002

American Journal of Physiology-Endocrinology and Metabolism

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Insulin action is decreased by high muscle glycogen concentrations in skeletal muscle. Patients with McArdle's disease have chronic high muscle glycogen levels and might therefore be at risk of developing insulin resistance. In this study, six patients with McArdle's disease and six matched control subjects were subjected to an oral glucose tolerance test and a euglycemic-hyperinsulinemic clamp. The muscle glycogen concentration was 103 Ϯ 45% higher in McArdle patients than in controls. Four of six McArdle patients, but none of the controls, had impaired glucose tolerance. The insulin-stimulated glucose utilization and the insulin-stimulated increase in glycogen synthase activity during the clamp were significantly lower in the patients than in controls (51.3 Ϯ 6.0 vs. 72.6 Ϯ 13.1 mol ⅐ min Ϫ1 ⅐ kg lean body mass Ϫ1 , P Ͻ 0.05, and 53 Ϯ 15 vs. 79 Ϯ 9%, P Ͻ 0.05, n ϭ 6, respectively). The difference in insulin-stimulated glycogen synthase activity between the pairs was significantly correlated (r ϭ 0.96, P Ͻ 0.002) with the difference in muscle glycogen level. The insulinstimulated increase in Akt phosphorylation was smaller in the McArdle patients than in controls (45 Ϯ 13 vs. 76 Ϯ 13%, P Ͻ 0.05, respectively), whereas basal and insulinstimulated glycogen synthase kinase 3␣ and protein phosphatase-1 activities were similar in the two groups. Furthermore, the ability of insulin to decrease and increase fat and carbohydrate oxidation, respectively, was blunted in the patients. In conclusion, these data show that patients with McArdle's glycogen storage disease are insulin resistant in terms of glucose uptake, glycogen synthase activation, and alterations in fuel oxidation. The data further suggest that skeletal muscle glycogen levels play an important role in the regulation of insulin-stimulated glycogen synthase activity. glycogen synthase; protein phosphatase; glycogen synthase kinase 3; glucose clamp technique; glycogen storage disease type V SKELETAL MUSCLE serves as the major site of whole body insulin-mediated glucose disposal (10). The two main metabolic end points for insulin action are glucose uptake across the plasma membrane and glycogen synthesis, both of which can be dysfunctional in different pathophysiological conditions of insulin resistance (9). However, the cellular and molecular mechanisms responsible for impaired muscular insulin are not fully elucidated. Studies investigating the function of different insulin-signaling molecules as possible sites of dysfunction have so far been inconclusive (34,43). It has, however, been shown that, in humans, glycogen exerts a negative effect on the ability of insulin to increase muscle glycogen synthase activity (7,21,28), but the effect of glycogen levels on insulin-stimulated muscle glucose uptake has not been studied. In rodent skeletal muscle studied in vitro, glycogen synthase activity and glucose transport are decreased by glycogen loading and increased by glycogen depletion. There is evidence that protein kinase B/Akt plays a role in this regulation (...

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“…This feedback mechanism invokes the inhibition of protein phosphatase 1 when bound to glycogen, and the removal of the inhibition as glycogen is depleted by exercise and the phosphatase is released (35)(36)(37). This mechanism has been widely accepted but has been questioned by some authors (38, …”

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confidence: 99%

In vivo regulation of muscle glycogen synthase and the control of glycogen synthesis.

Shulman

Bloch²,

Rothman³

1995

Proc. Natl. Acad. Sci. U.S.A.

136

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The activity of glycogen synthase (GSase; EC 2.4.1.11) is regulated by covalent phosphorylation. Because of this regulation, GSase has generally been considered to control the rate of glycogen synthesis. This hypothesis is examined in light of recent in vivo NMR experiments on rat and human muscle and is found to be quantitatively inconsistent with the data under conditions of glycogen synthesis. Our first experiments showed that muscle glycogen synthesis was slower in non-insulin-dependent diabetics compared to normals and that their defect was in the glucose transporter/hexokinase (GT/HK) part of the pathway. From

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Correlations of glycogen synthase and phosphorylase activities with glycogen concentration in human muscle biopsies. Evidence for a double-feedback mechanism regulating glycogen synthesis and breakdown

Cited by 39 publications

References 36 publications

In late pregnancy insulin-dependent glucose transport/phosphorylation is selectively impaired and activation of glycogen synthase by insulin facilitated in skeletal muscles of 24-h starved rats

In late pregnancy insulin-dependent glucose transport/phosphorylation is selectively impaired and activation of glycogen synthase by insulin facilitated in skeletal muscles of 24-h starved rats

Decreased insulin action in skeletal muscle from patients with McArdle's disease

In vivo regulation of muscle glycogen synthase and the control of glycogen synthesis.

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