Protein kinase C modulates insulin action in human skeletal muscle

Cortright, Ronald N.; Azevedo, J. L.; Zhou, Qian; Sinha, Madhur K.; Pories, Walter J.; Itani, Samar I.; Dohm, G. Lynis

doi:10.1152/ajpendo.2000.278.3.e553

Cited by 91 publications

(64 citation statements)

References 45 publications

(46 reference statements)

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“…PKC activity is increased in tissues from obese Zucker rats. In liver this increase appears to be the result of an increase in the membrane content of PKC isoforms , ,´and , (Considine et al 1995, Qu et al 1999, while in skeletal muscle this increase has been ascribed to an elevation in the membrane content of PKC isoforms (Cortright et al 2000) and´ (Avignon et al 1996). In the current study, we have demonstrated that IR Ser 994 is an in vitro phosphorylation target for PKC.…”

Section: Discussionmentioning

confidence: 95%

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Increased in vivo phosphorylation of insulin receptor at serine 994 in the liver of obese insulin-resistant Zucker rats

Muñoz¹,

Dominici²,

Toblli³

et al. 2004

Journal of Endocrinology

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Serine phosphorylation of the insulin receptor (IR) has been proposed to exert an inhibitory influence on its tyrosine kinase activity. Previous works using site-directed mutagenesis suggested that serine 994 of the IR (IR Ser 994) might be part of an inhibitory domain of the receptor. In this study we examined whether this residue is subjected to phosphorylation in vivo. We used a sitephosphospecific antibody to determine the extent of phosphorylation of IR Ser 994 in insulin target tissues from two animal models of insulin resistance with different IR kinase (IRK) activity: obese (fa/fa) Zucker rats and transgenic mice overexpressing bovine growth hormone (PEPCK-bGH mice).Phosphorylation at IR Ser 994 was markedly increased in liver of obese rats. This alteration appeared to be tissue-selective since no phosphorylation on Ser 994 was detected in IRs isolated from skeletal muscle of these animals. On the other hand, the phosphorylation level of IR Ser 994 was very low in liver of PEPCK-bGH mice and did not differ from that of the control group. We have also demonstrated that protein kinase (PK) C isoforms , I and are able to promote the in vitro phosphorylation of the IR on Ser 994. Differential findings in these two models of insulin resistance might thus reflect increased PKC activity resulting from increased lipid availability in obese Zucker rats. Our results suggest that Ser 994 is a novel in vivo IR phosphorylation site that might be involved in the regulation of the IRK in some states of insulin resistance.

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Section: Discussionmentioning

confidence: 95%

“…In PKC-mediated insulin-resistant states such as obesity or conditions of elevated lipid availability, both a tissue and isoform-selective PKC activation has been detected (Avignon et al 1996, Griffin et al 1999, Cortright et al 2000. PKC activity is increased in tissues from obese Zucker rats.…”

Section: Discussionmentioning

confidence: 99%

Increased in vivo phosphorylation of insulin receptor at serine 994 in the liver of obese insulin-resistant Zucker rats

Muñoz¹,

Dominici²,

Toblli³

et al. 2004

Journal of Endocrinology

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“…In muscle, a short-term infusion of Intralipid (a fatty acid emulsion comprised of a mixture of fatty acids, including linoleic, oleic, and palmitic acid) impairs insulin-stimulated glucose disposal, and this is thought to be due to increased activation of PKC-θ, the most abundant of the novel class of PKC isoforms in skeletal muscle (23)(24)(25)(26)(27), with a consequent decrease in insulin-stimulated IRS-1 tyrosine phosphorylation and PI3K activity (5)(6)(7)28). Based on these data from peripheral tissues, we hypothesize that PKC-θ is a critical mediator of fatty acid-induced central insulin and leptin resistance.…”

Section: Introductionmentioning

confidence: 99%

Palmitic acid mediates hypothalamic insulin resistance by altering PKC-θ subcellular localization in rodents

Benoit¹,

Kemp²,

Elias³

et al. 2009

J. Clin. Invest.

292

134

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Insulin signaling can be modulated by several isoforms of PKC in peripheral tissues. Here, we assessed whether one specific isoform, PKC-θ, was expressed in critical CNS regions that regulate energy balance and whether it mediated the deleterious effects of diets high in fat, specifically palmitic acid, on hypothalamic insulin activity in rats and mice. Using a combination of in situ hybridization and immunohistochemistry, we found that PKC-θ was expressed in discrete neuronal populations of the arcuate nucleus, specifically the neuropeptide Y/agouti-related protein neurons and the dorsal medial nucleus in the hypothalamus. CNS exposure to palmitic acid via direct infusion or by oral gavage increased the localization of PKC-θ to cell membranes in the hypothalamus, which was associated with impaired hypothalamic insulin and leptin signaling. This finding was specific for palmitic acid, as the monounsaturated fatty acid, oleic acid, neither increased membrane localization of PKC-θ nor induced insulin resistance. Finally, arcuate-specific knockdown of PKC-θ attenuated diet-induced obesity and improved insulin signaling. These results suggest that many of the deleterious effects of high-fat diets, specifically those enriched with palmitic acid, are CNS mediated via PKC-θ activation, resulting in reduced insulin activity.

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“…The increase in IMCL-TG occurred several hours after the elevation of plasma FFA levels and coincided with the development of insulin resistance (10), suggesting that an insulin resistance-causing signal was generated during the synthesis (or the breakdown) of IMCL-TG. We hypothesize that diacylglycerol (DAG) may be such a signal because an increase in its synthesis would coincide with that of triglycerides (11) and because it is a well-known allosteric activator of protein kinase C (PKC) (12)(13)(14), an enzyme that has been linked to insulin resistance in muscle in a wide variety of rodent models (11,15,16), including rats infused with lipid (17) and massively obese humans (18,19). To evaluate this possibility, DAG mass and PKC activity and distribution were assayed in skeletal muscle biopsies obtained from normal human volunteers in whom insulin resistance was produced by raising plasma FFA levels during a euglycemic-hyperinsulinemic clamp.…”

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confidence: 99%

Lipid-Induced Insulin Resistance in Human Muscle Is Associated With Changes in Diacylglycerol, Protein Kinase C, and IκB-α

Itani

Ruderman²,

Schmieder³

et al. 2002

Diabetes

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1,216

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The possibility that lipid-induced insulin resistance in human muscle is related to alterations in diacylglycerol (DAG)/protein kinase C (PKC) signaling was investigated in normal volunteers during euglycemic-hyperinsulinemic clamping in which plasma free fatty acid (FFA) levels were increased by a lipid/heparin infusion. In keeping with previous reports, rates of insulin-stimulated glucose disappearance (G Rd ) were normal after 2 h but were reduced by 43% (from 52.7 ؎ 8.2 to 30.0 ؎ 5.3 mol ⅐ kg -1 ⅐ min -1 , P < 0.05) after 6 h of lipid infusion. No changes in PKC activity or DAG mass were seen in muscle biopsy samples after 2 h of lipid infusion; however, at ϳ6 h, PKC activity and DAG mass were increased approximately fourfold, as were the abundance of membrane-associated PKC-␤II and -␦. A threefold increase in membrane-associated PKC-␤II was also observed at ϳ2 h but was not statistically significant (P ‫؍‬ 0.058). Ceramide mass was not changed at either time point. To evaluate whether the fatty acidinduced insulin activation of PKC was associated with a change in the IkB kinase (IKK)/nuclear factor (NF)-B pathway, we determined the abundance in muscle of IB-␣, an inhibitor of NF-B that is degraded after its phosphorylation by IKK. In parallel with the changes in DAG/PKC, no change in IB-␣ mass was observed after 2 h of lipid infusion, but at ϳ6 h, IB-␣ was diminished by 70%. In summary, the results indicated that the insulin resistance observed in human muscle when plasma FFA levels were elevated during euglycemic-hyperinsulinemic clamping was associated with increases in DAG mass and membrane-associated PKC-␤II and -␦ and a decrease in IB-␣. Whether acute FFA-induced insulin resistance in human skeletal muscle is caused by the activation of these specific PKC isoforms and the IKK-␤/IB/NFB pathway remains to be established. Diabetes

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Protein kinase C modulates insulin action in human skeletal muscle

Cited by 91 publications

References 45 publications

Increased in vivo phosphorylation of insulin receptor at serine 994 in the liver of obese insulin-resistant Zucker rats

Increased in vivo phosphorylation of insulin receptor at serine 994 in the liver of obese insulin-resistant Zucker rats

Palmitic acid mediates hypothalamic insulin resistance by altering PKC-θ subcellular localization in rodents

Lipid-Induced Insulin Resistance in Human Muscle Is Associated With Changes in Diacylglycerol, Protein Kinase C, and IκB-α

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