Impaired Insulin Activation and Dephosphorylation of Glycogen Synthase in Skeletal Muscle of Women with Polycystic Ovary Syndrome Is Reversed by Pioglitazone Treatment

Glintborg, Dorte; Højlund, Kurt; Andersen, Nicoline R.; Hansen, Bo F.; Beck‐Nielsen, Henning; Wojtaszewski, Jørgen F. P.

doi:10.1210/jc.2008-0760

Cited by 35 publications

(39 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similar to the inconsistent finding of impaired insulin action on AKT phosphorylation (6,7,(11)(12)(13), this probably reflects the large heterogeneity in both type 2 diabetic and obese non-diabetic individuals combined with the relatively small sample sizes often used in such studies. However, the impaired insulin activation of GS and the lack of dephosphorylation of GS at sites 2+2a appear to be consistent findings in type 2 diabetic patients [3,7], as well as in other insulin-resistant conditions such as PCOS [9] and HIV lipodystrophy [37]. Consistently, we have demonstrated that insulin-mediated dephosphorylation of GS at sites 2 + 2a correlates significantly with insulinstimulated NOGM in a large cohort of twins [38].…”

Section: Discussionsupporting

confidence: 87%

“…Glycogen synthase activity Muscle GS activity in the presence of 8, 0.17 or 0.02 mmol/l G6P was measured in triplicate using a 96-well plate assay (Unifilter 350 Plates, Whatman, Cambridge, UK) [7,9]. GS activities are reported either as total GS activity (determined at 8 mmol/l G6P), the percentage of G6P-independent GS activity (%I-form) (100×activity in the presence of 0.02 mmol/l G6P divided by the activity at 8 mmol/l G6P [saturated]) or as the percentage of fractional velocity (%FV) (100×activity in the presence of 0.17 mmol/l G6P divided by the activity at 8 mmol/l G6P).…”

Section: Methodsmentioning

confidence: 99%

“…Skeletal muscle is the major site of glucose uptake during insulin stimulation, and correspondingly, the major site of insulin resistance in insulin-resistant conditions such as type 2 diabetes [1][2][3][4][5][6][7][8][9][10]. Reduced insulin-mediated glucose disposal is accounted for mainly by impaired stimulation of glycogen synthesis [1], but in obesity, polycystic ovary syndrome (PCOS) and type 2 diabetes also by reduced stimulation of glucose oxidation [3][4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 87%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

show abstract

“…This, together with differences in sex composition and a lower baseline V : O 2max , may explain these discordant findings. Mutational studies [18,19] as well as analysis on muscle biopsies from humans [15,21,22,29] have found phosphorylation of GS at sites 2+2a and 3a+3b to be the most important for GS activity. In accordance, we demonstrate an inverse correlation between both insulin-and exercise-induced measures of GS activity and GS phosphorylation at these sites.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of muscle glycogen synthase in recovery from exercise in type 2 diabetes

et al. 2015

Self Cite

View full text Add to dashboard Cite

Aims/hypothesis Insulin and exercise stimulate skeletal muscle glycogen synthase (GS) activity by dephosphorylation and changes in kinetic properties. The aim of this study was to investigate the effects of insulin, exercise and post-exercise insulin stimulation on GS phosphorylation, activity and substrate affinity in obesity and type 2 diabetes. Methods Obese men with type 2 diabetes (n=13) and weightmatched controls (n = 14) underwent euglycaemichyperinsulinaemic clamps in the rested state and 3 h after 60 min of cycling (70% maximal pulmonary oxygen uptake [V :O 2max ]) . Biopsies from vastus lateralis muscle were obtained before and after clamps, and before and immediately after exercise. Results Insulin-stimulated glucose uptake was lower in diabetic patients vs obese controls with or without prior exercise. Post exercise, glucose partitioning shifted away from oxidation and towards storage in both groups. Insulin and, more potently, exercise increased GS activity (fractional velocity [FV]) and substrate affinity in both groups. Both stimuli caused dephosphorylation of GS at sites 3a+3b, with exercise additionally decreasing phosphorylation at sites 2+2a. In both groups, changes in GS activity, substrate affinity and dephosphorylation at sites 3a+3b by exercise were sustained 3 h post exercise and further enhanced by insulin. Post exercise, reduced GS activity and substrate affinity as well as increased phosphorylation at sites 2+2a were found in diabetic patients vs obese controls. Conclusions/interpretation Exercise-induced activation of muscle GS in obesity and type 2 diabetes involves dephosphorylation of GS at sites 3a+3b and 2+2a and enhanced substrate affinity, which is likely to facilitate glucose partitioning towards storage. Lower GS activity and increased phosphorylation at sites 2+2a in type 2 diabetes in the recovery period imply an impaired response to exercise.

show abstract

“…2). It has been shown that insulin stimulation leads to GS dephosphorylation at sites 2ϩ2a and that such response is impaired in patients with T2DM and in women with polycystic ovary syndrome (5,45). Considering that subjects after the glycogen depletion protocol on day 1 went home and had a low carbohydrate dinner, dephosphorylation of GS at sites 2ϩ2a in pre-depleted muscle could respond to insulin stimulation during the postprandial state.…”

Section: Discussionmentioning

confidence: 99%

Dual Regulation of Muscle Glycogen Synthase during Exercise by Activation and Compartmentalization

Prats

Helge

Nordby

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

Glycogen synthase (GS) is considered the rate-limiting enzyme in glycogenesis but still today there is a lack of understanding on its regulation. We have previously shown phosphorylation-dependent GS intracellular redistribution at the start of glycogen re-synthesis in rabbit skeletal muscle (Prats, C., Cadefau, J. A., Cussó, R., Qvortrup, K., Nielsen, J. N., Wojtaszewki, J. F., Wojtaszewki, J. F., Hardie, D. G., Stewart, G., Hansen, B. F., and Ploug, T. (2005) J. Biol. Chem. 280, 23165-23172). In the present study we investigate the regulation of human muscle GS activity by glycogen, exercise, and insulin. Using immunocytochemistry we investigate the existence and relevance of GS intracellular compartmentalization during exercise and during glycogen re-synthesis. The results show that GS intrinsic activity is strongly dependent on glycogen levels and that such regulation involves associated dephosphorylation at sites 2؉2a, 3a, and 3a ؉ 3b. Furthermore, we report the existence of several glycogen metabolism regulatory mechanisms based on GS intracellular compartmentalization. After exhausting exercise, epinephrine-induced protein kinase A activation leads to GS site 1b phosphorylation targeting the enzyme to intramyofibrillar glycogen particles, which are preferentially used during muscle contraction. On the other hand, when phosphorylated at sites 2؉2a, GS is preferentially associated with subsarcolemmal and intermyofibrillar glycogen particles. Finally, we verify the existence in human vastus lateralis muscle of the previously reported mechanism of glycogen metabolism regulation in rabbit tibialis anterior muscle. After overnight low muscle glycogen level and/or in response to exhausting exercise-induced glycogenolysis, GS is associated with spherical structures at the I-band of sarcomeres.

show abstract

Impaired Insulin Activation and Dephosphorylation of Glycogen Synthase in Skeletal Muscle of Women with Polycystic Ovary Syndrome Is Reversed by Pioglitazone Treatment

Cited by 35 publications

References 42 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

Dysregulation of muscle glycogen synthase in recovery from exercise in type 2 diabetes

Dual Regulation of Muscle Glycogen Synthase during Exercise by Activation and Compartmentalization

Contact Info

Product

Resources

About