Isoform-specific defects of insulin stimulation of Akt/protein kinase B (PKB) in skeletal muscle cells from type 2 diabetic patients

Cozzone, D.; Fröjdö, Sara; Disse, Emmanuel; Debard, Cyrille; Laville, Martine; Pirola, Luciano; Vidal, Hubert

doi:10.1007/s00125-007-0913-8

Cited by 80 publications

(86 citation statements)

References 39 publications

(73 reference statements)

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“…The defect in insulin-dependent Akt phosphorylation in muscle of insulin-resistant or type 2 diabetic humans is consistent with previous studies [9][10][11][12][13][14][15][16][17]. Some studies have failed to report defective Akt phosphorylation [12,13,40], perhaps due to differences in experimental design.…”

Section: Discussionsupporting

confidence: 90%

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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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Section: Discussionsupporting

confidence: 90%

“…Disruptions in this pathway have been demonstrated in human insulin resistance and type 2 diabetes [9][10][11][12][13][14][15][16][17][18]. Akt phosphorylates numerous regulatory molecules pivotal to metabolic regulation [19].…”

Section: Introductionmentioning

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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“…Among the three highly homologous Akt isoforms, increasing evidence suggests that Akt2 plays a major role in glucose metabolism [30,31]. Although conflicting results have been obtained on whether Akt activation in adipose tissue and skeletal muscle is impaired in conditions of insulin resistance [21][22][23][24][25][26][27], defects in Ser473 phosphorylation and activation of Akt2, but not of Akt1 have been observed in skeletal muscle of insulin-resistant morbidly obese and type 2 diabetic participants [33][34][35]. Mechanisms by which Akt is inactivated have, until recently, been poorly documented.…”

Section: Discussionmentioning

confidence: 99%

“…Akt2 is produced in insulin-responsive tissues and plays a pivotal role in glucose metabolism [30,31], whereas Akt3 is essential for brain growth, but not glucose homeostasis [32]. Accordingly, defects in Ser473 phosphorylation and activation of Akt2, but not Akt1 have been reported in skeletal muscle from insulin-resistant morbidly obese and type 2 diabetic participants [33][34][35], and have been shown to be associated with impaired glucose transport.…”

Section: Introductionmentioning

confidence: 99%

Increased levels of the Akt-specific phosphatase PH domain leucine-rich repeat protein phosphatase (PHLPP)-1 in obese participants are associated with insulin resistance

et al. 2011

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Aims/hypothesis We determined the contribution to insulin resistance of the PH domain leucine-rich repeat protein phosphatase (PHLPP), which dephosphorylates Akt at Ser473, inhibiting its activity. We measured the abundance of PHLPP in fat and skeletal muscle from obese participants. To study the effect of PHLPP on insulin signalling, PHLPP (also known as PHLPP1) was overexpressed in HepG2 and L6 cells. Methods Subcutaneous fat samples were obtained from 82 morbidly obese and ten non-obese participants. Skeletal muscle samples were obtained from 12 obese and eight non-obese participants. Quantification of PHLPP-1 in human tissues was performed by immunoblotting. The functional consequences of recombinant PHLPP1 overexpression in hepatoma HepG2 cells and L6 myoblasts were investigated. Results Of the 82 obese participants, 31 had normal fasting glucose, 33 impaired fasting glucose and 18 type 2 diabetes. PHLPP-1 abundance was twofold higher in the three obese groups than in non-obese participants (p=0.004). No differences were observed between obese participants with normal fasting glucose, impaired fasting glucose or type 2 diabetes. PHLPP-1 abundance was correlated with basal Akt Ser473 phosphorylation (r=−0.48; p=0.001), BMI (r=0.44; p< 0.0001), insulin (r=0.35; p<0.0001) and HOMA (r=0.38; p<0.0001). PHLPP-1 abundance was twofold higher in the skeletal muscle of 12 obese participants than in that of eight non-obese participants (p<0.0001). Insulin treatment of HepG2 cells resulted in a dose-and time-dependent upregulation of PHLPP-1. Overexpression of PHLPP1 in HepG2 cells and L6 myoblasts resulted in impaired insulin signalling involving Akt/glycogen synthase kinase 3, glycogen synthesis and glucose transport. Conclusions/interpretation Increased abundance of PHLPP-1, production of which is regulated by insulin, may represent a new molecular defect in insulin-resistant states such as obesity.

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“…This defect seems to be maintained in cultures as well (Cozzone, et al, 2008). However, insulin-stimulated phosphorylation of Akt is not reduced in muscles from 72 h fasted subjects although severe insulin resistance occurs (Vendelbo, et al, 2012).…”

Section: Retention Of Metabolic Characteristics Of the Muscle Cell Donormentioning

confidence: 92%

Are cultured human myotubes far from home?

et al. 2013

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IntroductionSatellite cells can be isolated from skeletal muscle biopsies, activated to proliferating myoblast and differentiated into multinuclear myotubes in culture. These cell cultures represent an essential model system to intact human skeletal muscle, which can be modulated ex vivo. Advantages of this system include; having the most relevant genetic background to study human disease (as opposed to rodent cell cultures), the extracellular environment can be precisely controlled and the cells are not immortalized, thereby offering the possibility of studying innate characteristics of the donor. This review will focus on how human myotubes can be used as a tool to study metabolism in skeletal muscles, with a special attention to changes in muscle energy metabolism in obesity and type 2 diabetes.Limitations of this cell system and possible approaches to improve the current model will also be discussed.

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Isoform-specific defects of insulin stimulation of Akt/protein kinase B (PKB) in skeletal muscle cells from type 2 diabetic patients

Abstract: Aims/hypothesis The serine/threonine kinase Akt/protein kinase B (PKB) is required for the metabolic actions of insulin.

Cited by 80 publications

References 39 publications

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

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

Increased levels of the Akt-specific phosphatase PH domain leucine-rich repeat protein phosphatase (PHLPP)-1 in obese participants are associated with insulin resistance

Are cultured human myotubes far from home?

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