Protein kinase C modulates insulin action in human skeletal muscle

2000 ◽  
Vol 278 (3) ◽  
pp. E553-E562 ◽  
Author(s):  
Ronald N. Cortright ◽  
John L. Azevedo ◽  
Qian Zhou ◽  
Madhur Sinha ◽  
Walter J. Pories ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Insulin Action ◽  
Human Skeletal Muscle ◽  
Kinase C ◽  
Pkc Activation

There is good evidence from cell lines and rodents that elevated protein kinase C (PKC) overexpression/activity causes insulin resistance. Therefore, the present study determined the effects of PKC activation/inhibition on insulin-mediated glucose transport in incubated human skeletal muscle and primary adipocytes to discern a potential role for PKC in insulin action. Rectus abdominus muscle strips or adipocytes from obese, insulin-resistant, and insulin-sensitive patients were incubated in vitro under basal and insulin (100 nM)-stimulated conditions in the presence of GF 109203X (GF), a PKC inhibitor, or 12-deoxyphorbol 13-phenylacetate 20-acetate (dPPA), a PKC activator. PKC inhibition had no effect on basal glucose transport. GF increased ( P < 0.05) insulin-stimulated 2-deoxyglucose (2-DOG) transport approximately twofold above basal. GF plus insulin also increased ( P < 0.05) insulin receptor tyrosine phosphorylation 48% and phosphatidylinositol 3-kinase (PI 3-kinase) activity ∼50% ( P< 0.05) vs. insulin treatment alone. Similar results for GF on glucose uptake were observed in human primary adipocytes. Further support for the hypothesis that elevated PKC activity is related to insulin resistance comes from the finding that PKC activation by dPPA was associated with a 40% decrease ( P < 0.05) in insulin-stimulated 2-DOG transport. Incubation of insulin-sensitive muscles with GF also resulted in enhanced insulin action (∼3-fold above basal). These data demonstrate that certain PKC inhibitors augment insulin-mediated glucose uptake and suggest that PKC may modulate insulin action in human skeletal muscle.

scholarly journals Involvement of protein kinase C in human skeletal muscle insulin resistance and obesity

Diabetes ◽  
2000 ◽  
Vol 49 (8) ◽  
pp. 1353-1358 ◽  
Author(s):  
S. I. Itani ◽  
Q. Zhou ◽  
W. J. Pories ◽  
K. G. MacDonald ◽  
G. L. Dohm
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Human Skeletal Muscle ◽  
Muscle Insulin Resistance ◽  
Skeletal Muscle Insulin Resistance ◽  
Kinase C

scholarly journals Interplay and Effects of Temporal Changes in the Phosphorylation State of Serine-302, -307, and -318 of Insulin Receptor Substrate-1 on Insulin Action in Skeletal Muscle Cells

2008 ◽  
Vol 22 (12) ◽  
pp. 2729-2740 ◽  
Author(s):  
Cora Weigert ◽  
Matthias Kron ◽  
Hubert Kalbacher ◽  
Ann Kathrin Pohl ◽  
Heike Runge ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Insulin Receptor ◽  
Insulin Action ◽  
Muscle Cells ◽  
Skeletal Muscle Cells ◽  
Insulin Signal ◽  
Kinase C ◽  
Phosphorylation Pattern

Abstract Transduction of the insulin signal is mediated by multisite Tyr and Ser/Thr phosphorylation of the insulin receptor substrates (IRSs). Previous studies on the function of single-site phosphorylation, particularly phosphorylation of Ser-302, -307, and -318 of IRS-1, showed attenuating as well as enhancing effects on insulin action. In this study we investigated a possible cross talk of these opposedly acting serine residues in insulin-stimulated skeletal muscle cells by monitoring phosphorylation kinetics, and applying loss of function, gain of function, and combination mutants of IRS-1. The phosphorylation at Ser-302 was rapid and transient, followed first by Ser-318 phosphorylation and later by phosphorylation of Ser-307, which remained elevated for 120 min. Mutation of Ser-302 to alanine clearly reduced the subsequent protein kinase C-ζ-mediated Ser-318 phosphorylation. The Ser-307 phosphorylation was independent of Ser-302 and/or Ser-318 phosphorylation status. The functional consequences of these phosphorylation patterns were studied by the expression of IRS-1 mutants. The E302A307E318 mutant simulating the early phosphorylation pattern resulted in a significant increase in Akt and glycogen synthase kinase 3 phosphorylation. Furthermore, glucose uptake was enhanced. Because the down-regulation of the insulin signal was not affected, this phosphorylation pattern seems to be involved in the enhancement but not in the termination of the insulin signal. This enhancing effect was completely absent when Ser-302 was unphosphorylated and Ser-307 was phosphorylated as simulated by the A302E307E318 mutant. Phospho-Ser-318, sequentially phosphorylated at least by protein kinase C-ζ and a mammalian target of rapamycin/raptor-dependent kinase, was part of the positive as well as of the subsequent negative phosphorylation pattern. Thus we conclude that insulin stimulation temporally generates different phosphorylation statuses of the same residues that exert different functions in insulin signaling.

Reversal of chronic alterations of skeletal muscle protein kinase C from fat-fed rats by BRL-49653

1997 ◽  
Vol 273 (5) ◽  
pp. E915-E921 ◽  
Author(s):  
Carsten Schmitz-Peiffer ◽  
Nicholas D. Oakes ◽  
Carol L. Browne ◽  
Edward W. Kraegen ◽  
Trevor J. Biden
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Muscle Protein ◽  
Skeletal Muscle Protein ◽  
Insulin Sensitizer ◽  
Muscle Insulin Resistance ◽  
Skeletal Muscle Insulin Resistance ◽  
Kinase C

We have recently shown that the reduction in insulin sensitivity of rats fed a high-fat diet is associated with the translocation of the novel protein kinase Cε(nPKCε) from cytosolic to particulate fractions in red skeletal muscle and also the downregulation of cytosolic nPKCθ. Here we have further investigated the link between insulin resistance and PKC by assessing the effects of the thiazolidinedione insulin-sensitizer BRL-49653 on PKC isoenzymes in muscle. BRL-49653 increased the recovery of nPKC isoenzymes in cytosolic fractions of red muscle from fat-fed rats, reducing their apparent activation and/or downregulation, whereas PKC in control rats was unaffected. Because BRL-49653 also improves insulin-stimulated glucose uptake in fat-fed rats and reduces muscle lipid storage, especially diglyceride content, these results strengthen the association between lipid availability, nPKC activation, and skeletal muscle insulin resistance and support the hypothesis that chronic activation of nPKC isoenzymes is involved in the generation of muscle insulin resistance in fat-fed rats.

Inhibitors such as staurosporine, H-7 or polymyxin B cannot be used in skeletal muscle to prove the role of protein kinase C on insulin action

1992 ◽  
Vol 12 (5) ◽  
pp. 413-424 ◽  
Author(s):  
Anna Gumà ◽  
Purificación Muñoz ◽  
Marta Camps ◽  
Xavier Testar ◽  
Manuel Palacín ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Insulin Action ◽  
Lactate Production ◽  
Polymyxin B ◽  
Transport Activity ◽  
System A ◽  
Kinase C

The precise role of protein kinase C in insulin action in skeletal muscle is not well defined. Based on the fact that inhibitors of protein kinase C block some insulin effects, it has been concluded that some of the biological actions of insulin are mediated via protein kinase C. In this study, we present evidence that inhibitors of protein kinase C such as staurosporine, H-7 or polymyxin B cannot be used to ascertain the role of protein kinase C in skeletal muscle. This is based on the following experimental evidences: a) staurosporine, H-7 and polymyxin B markedly block in muscle the effect of insulin on System A transport activity; however, this effect of insulin is not mimicked in muscle by TPA-induced stimulation of protein kinase C, b) H-7 and polymyxin B block insulin action on System A transport activity in an additive manner to the inhibitory effect of phorbol esters, c) staurosporine, H-7 and polymyxin B block the effect of insulin on lactate production, a process that is activated by insulin and TPA in an additive fashion, and d) staurosporine completely blocks the tyrosine kinase activity of insulin receptors partially purified from rat skeletal muscle.

Localization of protein kinase C in human skeletal muscle

1992 ◽  
Vol 15 (4) ◽  
pp. 496-499 ◽  
Author(s):  
Satoshi Nakano ◽  
Shun Shimohama ◽  
Tsunao Saitoh ◽  
Ichiro Akiguchi ◽  
Jun Kimura
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Human Skeletal Muscle ◽  
Kinase C
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