Lipid and insulin infusion-induced skeletal muscle insulin resistance is likely due to metabolic feedback and not changes in IRS-1, Akt, or AS160 phosphorylation

Hoy, Andrew J.; Brandon, Amanda E.; Turner, Nigel; Watt, Matthew J.; Bruce, Clinton R.; Cooney, Gregory J.; Kraegen, Edward W.

doi:10.1152/ajpendo.90945.2008

Cited by 78 publications

(82 citation statements)

References 59 publications

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“…These data strongly suggest that sortilin restoration, rather than signaling competency involving Akt phosphorylation, is crucial for maintaining the insulin-responsive GLUT4 recycling in skeletal muscle cells at least under the present culture conditions. In excellent agreement with this idea, it has become increasingly apparent that the most deleterious defects of skeletal muscle insulin resistance including those evoked by palmitate/high fat occur independently of the IRS signaling cascades (53,(55)(56)(57). Moreover, several lines of evidence have also demonstrated that despite its therapeutic benefits, rosiglitazone, a PPAR␥ agonist, failed to ameliorate the IRS signaling cascade defects in the skeletal muscles of FFA-induced insulin resistant rodents (58) as well as that in human patients with type 2 diabetes (59).…”

Section: Discussionmentioning

confidence: 90%

Palmitate-induced Down-regulation of Sortilin and Impaired GLUT4 Trafficking in C2C12 Myotubes

Tsuchiya

Hatakeyama

Emoto

et al. 2010

Journal of Biological Chemistry

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Elevated saturated FFAs including palmitate (C16:0) are a primary trigger for peripheral insulin resistance characterized by impaired glucose uptake/disposal in skeletal muscle, resulting from impaired GLUT4 translocation in response to insulin. We herein demonstrate that palmitate induces down-regulation of sortilin, a sorting receptor implicated in the formation of insulin-responsive GLUT4 vesicles, via mechanisms involving PKC and TNF-␣-converting enzyme, but not p38, JNK, or mitochondrial reactive oxygen species generation, leading to impaired GLUT4 trafficking in C2C12 myotubes. Intriguingly, unsaturated FFAs such as palmitoleate (C16:1) and oleate (C18:1) had no such detrimental effects, appearing instead to effectively reverse palmitate-induced impairment of insulin-responsive GLUT4 recycling along with restoration of sortilin abundance by preventing aberrant PKC activation. On the other hand, shRNA-mediated reduction of sortilin in intact C2C12 myotubes inhibited insulin-induced GLUT4 recycling without dampening Akt phosphorylation. We found that the peroxisome proliferator-activated receptor ␥ agonist troglitazone prevented the palmitate-induced sortilin reduction and also ameliorated insulin-responsive GLUT4 recycling without altering the palmitate-evoked insults on signaling cascades; neither highly phosphorylated PKC states nor impaired insulin-responsive Akt phosphorylation was affected. Taken together, our data provide novel insights into the pathogenesis of PKC-dependent insulin resistance with respect to insulin-responsive GLUT4 translocation, which could occur not only through defects of insulin signaling but also via a reduction of sortilin, which directly controls trafficking/sorting of GLUT4 in skeletal muscle cells. In addition, our data suggest the insulin-sensitizing action of peroxisome proliferator-activated receptor ␥ agonists to be at least partially mediated through the restoration of proper GLUT4 trafficking/sorting events governed by sortilin.Skeletal muscle cells as well as adipocytes exhibit the highest levels of insulin-stimulated glucose uptake, which is achieved by translocation of the insulin-responsive glucose transporter (GLUT4) from intracellular storage compartment(s) to the plasma membrane (1). It has become increasingly apparent that sortilin, a type I transmembrane protein originally identified as a major component of GLUT4-containing vesicles from rat adipocytes (2, 3), plays crucial roles in the development of the insulin-responsive GLUT4 translocation system not only in adipocytes (4, 5) but also in skeletal muscle cells (6). Evidence available thus far indicates sortilin to be directly involved in the biogenesis of insulin-responsive GLUT4 storage vesicles by regulating sorting events of GLUT4 protein between the transGolgi network and endosomes (4, 5, 7), and experimental suppression of sortilin in adipocytes has been shown to inhibit insulin-responsive GLUT4 translocation (4).Intriguingly, a recent report demonstrated sortilin expression to be significantly reduce...

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Section: Discussionmentioning

confidence: 90%

Palmitate-induced Down-regulation of Sortilin and Impaired GLUT4 Trafficking in C2C12 Myotubes

Tsuchiya

Hatakeyama

Emoto

et al. 2010

Journal of Biological Chemistry

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“…Numerous studies have demonstrated that insulin resistance is linked with increased amounts of various deleterious lipid intermediates within skeletal muscle [1,2]. Accumulation of LCACoA in muscle has been observed in association with insulin resistance in high-fat fed rats [46] and in rats and humans infused with lipid [47,48]. LCACoA have been shown to inhibit hexokinase activity, thereby impairing glucose phosphorylation and reducing glucose uptake [49].…”

Section: Discussionmentioning

confidence: 99%

Amelioration of lipid-induced insulin resistance in rat skeletal muscle by overexpression of Pgc-1β involves reductions in long-chain acyl-CoA levels and oxidative stress

et al. 2011

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Aims/Hypothesis To determine if acute overexpression of peroxisome proliferator-activated receptor, gamma, coactivator 1 beta (Pgc-1β [also known as Ppargc1b]) in skeletal muscle improves insulin action in a rodent model of dietinduced insulin resistance. Methods Rats were fed either a low-fat or high-fat diet (HFD) for 4 weeks. In vivo electroporation was used to overexpress Pgc-1β in the tibialis cranialis (TC) and extensor digitorum longus (EDL) muscles. Downstream effects of Pgc-1β on markers of mitochondrial oxidative capacity, oxidative stress and muscle lipid levels were characterised. Insulin action was examined ex vivo using intact muscle strips and in vivo via a hyperinsulinaemic-euglycaemic clamp. Results Pgc-1β gene expression was increased >100% over basal levels. The levels of proteins involved in mitochondrial function, lipid metabolism and antioxidant defences, the activity of oxidative enzymes, and substrate oxidative capacity were all increased in muscles overexpressing Pgc-1β. In rats fed a HFD, increasing the levels of Pgc-1β partially ameliorated muscle insulin resistance, in association with decreased levels of long-chain acyl-CoAs (LCACoAs) and increased antioxidant defences. Conclusions Our data show that an increase in Pgc-1β expression in vivo activates a coordinated subset of genes that increase mitochondrial substrate oxidation, defend against oxidative stress and improve lipid-induced insulin resistance in skeletal muscle.

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“…A relative shortage of insulin causes a delay in glucose uptake within the cells, despite a normal glucose level. Insulin resistance is also associated with the accumulation of lipid intermediates such as long chain acyl-coA, which are presumed to be toxic and responsible for metabolic derangement (Morris and Turnbull 1998;Hoy et al 2009). Thus, in case of an increase in CK, additional glucose needs to be administered.…”

Section: Glucose Infusion and Laboratory Measurementsmentioning

confidence: 99%

Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency and Perioperative Management in Adult Patients

et al. 2016

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Surgery and anesthesia pose a threat to patients with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD), because prolonged fasting, stress, and pain are known risk factors for the induction of metabolic derangement. The optimal perioperative management in these patients is unknown and the use of volatile agents and agents dissolved in fatty acids has been related to postoperative metabolic complications. However, the occurrence of metabolic derangement is multifactorial and depends, amongst others, on the severity of the mutation and residual enzyme activity. Current guidelines suggest avoiding both volatile anesthetics as well as propofol, which seriously limits the options for providing safe anesthesia. Therefore, we reviewed the available literature on the perioperative management of patients with VLCADD. We concluded that the use of some medications, such as volatile anesthetics, in patients with VLCADD might be wrongfully avoided and could in fact prevent metabolic derangement by the adequate suppression of pain and stress during surgery. We will illustrate this with a case report of an adult VLCADD patient undergoing minor surgery. Besides the use of remifentanil, anesthesia was uneventfully maintained with the use of sevoflurane, a volatile agent, and continuous glucose infusion. The patient was monitored with a continuous glucose meter and creatinine kinase measurements.

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Lipid and insulin infusion-induced skeletal muscle insulin resistance is likely due to metabolic feedback and not changes in IRS-1, Akt, or AS160 phosphorylation

Cited by 78 publications

References 59 publications

Palmitate-induced Down-regulation of Sortilin and Impaired GLUT4 Trafficking in C2C12 Myotubes

Palmitate-induced Down-regulation of Sortilin and Impaired GLUT4 Trafficking in C2C12 Myotubes

Amelioration of lipid-induced insulin resistance in rat skeletal muscle by overexpression of Pgc-1β involves reductions in long-chain acyl-CoA levels and oxidative stress

Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency and Perioperative Management in Adult Patients

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