Allosteric Regulation of Glycogen Synthase Controls Glycogen Synthesis in Muscle

Bouskila, Michale; Hunter, Roger W.; Ibrahim, Adel; Delattre, Lucie; Peggie, Mark; Diepen, Janna A. van; Voshol, Peter J.; Jensen, Jørgen; Sakamoto, Kei

doi:10.1016/j.cmet.2010.10.006

Cited by 171 publications

(171 citation statements)

References 30 publications

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“…We were not able to demonstrate any differences between the diabetic and control groups, or between the isoglycaemic and euglycaemic clamp in type 2 diabetic patients either in the basal or the insulin-stimulated steady-state periods ( Table 3). As reported in rodent muscle [35], insulin significantly reduced intracellular levels of UDP-glucose (p<0.001, main effect) in the present study with no significant difference between the groups. In both control groups, insulin significantly increased glycogen levels (p<0.05), whereas no such effect was seen in the diabetic groups clamped at either euglycaemia or hyperglycaemia.…”

Section: Resultssupporting

confidence: 69%

“…We therefore measured muscle levels of UDPglucose. As reported in mouse muscle [35], we observed that insulin caused a significant reduction in muscle UDPglucose. However, there was no difference between diabetic and non-diabetic groups, and, most importantly, no effect of hyperglycaemia on UDP-glucose that could explain improved insulin-mediated glycogen synthesis.…”

Section: Discussionsupporting

confidence: 68%

“…Muscle specimens were extracted with perchloric acid, neutralised and analysed for glucose, G6P and uridine diphosphate (UDP)-glucose [35] using standard enzymatic methods [34].…”

Section: Methodsmentioning

confidence: 99%

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Hyperglycaemia normalises insulin action on glucose metabolism but not the impaired activation of AKT and glycogen synthase in the skeletal muscle of patients with type 2 diabetes

Vind

Birk

Vienberg³

et al. 2012

Diabetologia

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Aims/hypothesis In type 2 diabetes, reduced insulinstimulated glucose disposal, primarily glycogen synthesis, is associated with defective insulin activation of glycogen synthase (GS) in skeletal muscle. Hyperglycaemia may compensate for these defects, but to what extent it involves improved insulin signalling to glycogen synthesis remains to be clarified. Methods Whole-body glucose metabolism was studied in 12 patients with type 2 diabetes, and 10 lean and 10 obese non-diabetic controls by means of indirect calorimetry and tracers during a euglycaemic-hyperinsulinaemic clamp. The diabetic patients underwent a second isoglycaemichyperinsulinaemic clamp maintaining fasting hyperglycaemia. Muscle biopsies from m. vastus lateralis were obtained before and after the clamp for examination of GS and relevant insulin signalling components. Results During euglycaemia, insulin-stimulated glucose disposal, glucose oxidation and non-oxidative glucose metabolism were reduced in the diabetic group compared with both control groups (p<0.05). This was associated with impaired insulin-stimulated GS and AKT2 activity, deficient dephosphorylation at GS sites 2+2a, and reduced Thr308 and Ser473 phosphorylation of AKT. When studied under hyperglycaemia, all variables of insulin-stimulated glucose metabolism were normalised compared with the weightmatched controls. However, insulin activation and dephosphorylation (site 2+2a) of GS as well as activation of AKT2 and phosphorylation at Thr308 and Ser473 remained impaired (p<0.05). Conclusions/interpretations These data confirm that hyperglycaemia compensates for decreased whole-body glucose disposal in type 2 diabetes. In contrast to previous less wellcontrolled studies, we provide evidence that the compensatory effect of hyperglycaemia in patients with type 2 diabetes does not involve normalisation of insulin action on GS or upstream signalling in skeletal muscle.

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Section: Resultssupporting

confidence: 69%

Section: Discussionsupporting

confidence: 68%

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Hyperglycaemia normalises insulin action on glucose metabolism but not the impaired activation of AKT and glycogen synthase in the skeletal muscle of patients with type 2 diabetes

Vind

Birk

Vienberg³

et al. 2012

Diabetologia

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“…However, in the Ob sensitive group there is a discordance between Akt phosphorylation (as high as the lean sensitive group) and GSK3 phosphorylation (as low as the type 2 diabetes group), making it difficult to draw conclusions on the role of defective GSK3 phosphorylation in the development of insulin resistance. This may be because glycogen synthase activity may be regulated by non-insulin mediated mechanisms such as exercise [45] or allosteric changes independent of GSK3 [46]. FOXO phosphorylation is apparently preserved despite the clear defect in Akt phosphorylation, perhaps because FOXO phosphorylation occurs at submaximal levels of Akt phosphorylation [47,48], and particularly if FOXO phosphorylation remains more sensitive to insulin stimulation than other Akt pathways.…”

Section: Discussionmentioning

confidence: 99%

Impaired Akt phosphorylation in insulin-resistant human muscle is accompanied by selective and heterogeneous downstream defects

Tonks

Miller

et al. 2013

Diabetologia

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Aims/hypothesis Muscle insulin resistance, one of the earliest defects associated with type 2 diabetes, involves changes in the phosphoinositide 3-kinase/Akt network. The relative contribution of obesity vs insulin resistance to perturbations in this pathway is poorly understood. Methods We used phosphospecific antibodies against targets in the Akt signalling network to study insulin action in muscle from lean, overweight/obese and type 2 diabetic individuals before and during a hyperinsulinaemic-euglycaemic clamp. Results Insulin-stimulated Akt phosphorylation at Thr309 and Ser474 was highly correlated with whole-body insulin sensitivity. In contrast, impaired phosphorylation of Akt substrate of 160 kDa (AS160; also known as TBC1D4) was associated with adiposity, but not insulin sensitivity. Neither insulin sensitivity nor obesity was associated with defective insulin-dependent phosphorylation of forkhead box O (FOXO) transcription factor. In view of the resultant basal hyperinsulinaemia, we predicted that this selective response within the Akt pathway might lead to hyperactivation of those processes that were spared. Indeed, the expression of genes targeted by FOXO was downregulated in insulin-resistant individuals. Conclusions/interpretation These results highlight nonlinearity in Akt signalling and suggest that: (1) the pathway from Akt to glucose transport is complex; and (2) pathways, particularly FOXO, that are not insulin-resistant, are likely Electronic supplementary material The online version of this article (doi:10.1007/s00125-012-2811-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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“…In addition to glucose uptake, virtually all of insulin's metabolic effects are regulated by AKT. For example, AKT-dependent phosphorylation of glycogen synthase kinase 3 (GSK-3β) leads to the activation of glycogen synthase and enhances glucose storage as glycogen (Rowland et al 2011, Bouskila et al 2010. The activation of AKT's kinase activity requires three steps, however, the order of these phosphorylation events is not clear yet (Rowland Figure 1 -The insulin activates a number of intracellular signaling proteins that are involved in the insulin-dependent glucose uptake mechanism [e.g., insulin receptor substrate (IRS), phosphatidylinositol-3-kinase (PI3K), regulatory subunit of PI3K (P85), catalytic subunit of PI3K (P110), phosphoinositide-dependent protein kinase 1(PDK1), protein kinase C (PKC), protein kinase B (PKB or AKT), and glucose transporters 4 (GLUT4)].…”

Section: Insulin-dependent Pathwaymentioning

confidence: 99%

General aspects of muscle glucose uptake

Alvim

Cheuhen

Machado

et al. 2015

An. Acad. Bras. Ciênc.

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Glucose uptake in peripheral tissues is dependent on the translocation of GLUT4 glucose transporters to the plasma membrane. Studies have shown the existence of two major signaling pathways that lead to the translocation of GLUT4. The first, and widely investigated, is the insulin activated signaling pathway through insulin receptor substrate-1 and phosphatidylinositol 3-kinase. The second is the insulin-independent signaling pathway, which is activated by contractions. Individuals with type 2 diabetes mellitus have reduced insulin-stimulated glucose uptake in skeletal muscle due to the phenomenon of insulin resistance. However, those individuals have normal glucose uptake during exercise. In this context, physical exercise is one of the most important interventions that stimulates glucose uptake by insulin-independent pathways, and the main molecules involved are adenosine monophosphate-activated protein kinase, nitric oxide, bradykinin, AKT, reactive oxygen species and calcium. In this review, our main aims were to highlight the different glucose uptake pathways and to report the effects of physical exercise, diet and drugs on their functioning. Lastly, with the better understanding of these pathways, it would be possible to assess, exactly and molecularly, the importance of physical exercise and diet on glucose homeostasis. Furthermore, it would be possible to assess the action of drugs that might optimize glucose uptake and consequently be an important step in controlling the blood glucose levels in diabetic patients, in addition to being important to clarify some pathways that justify the development of drugs capable of mimicking the contraction pathway.

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Allosteric Regulation of Glycogen Synthase Controls Glycogen Synthesis in Muscle

Cited by 171 publications

References 30 publications

Hyperglycaemia normalises insulin action on glucose metabolism but not the impaired activation of AKT and glycogen synthase in the skeletal muscle of patients with type 2 diabetes

Hyperglycaemia normalises insulin action on glucose metabolism but not the impaired activation of AKT and glycogen synthase in the skeletal muscle of patients with type 2 diabetes

Impaired Akt phosphorylation in insulin-resistant human muscle is accompanied by selective and heterogeneous downstream defects

General aspects of muscle glucose uptake

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