Defective Insulin-Induced GLUT4 Translocation in Skeletal Muscle of High Fat–Fed Rats Is Associated With Alterations in Both Akt/Protein Kinase B and Atypical Protein Kinase C (ζ/λ) Activities

Tremblay, François; Lavigne, Charles; Jacques, Hélène; Marette, André

doi:10.2337/diabetes.50.8.1901

Cited by 188 publications

(155 citation statements)

References 67 publications

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“…Here we show that insulin-stimulated PKC/ activation is impaired in skeletal muscle of lipid-infused rats compared with glycerolinfused rats. Consistent with our current results are data from several insulin-resistant models including Goto-Kakizaki diabetic rats (33), high fat fed rats (67), and obese Zucker rats.…”

Section: Fig 3 Pkc/ Activities (A) and Protein Levels (B) In Musclesupporting

confidence: 80%

Fatty Acid Infusion Selectively Impairs Insulin Action on Akt1 and Protein Kinase C λ/ζ but Not on Glycogen Synthase Kinase-3

Kim

Shulman

Kahn

2002

Journal of Biological Chemistry

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To determine the mechanism(s) for insulin resistance induced by fatty acids, we measured the ability of insulin to activate phosphoinositide 3-kinase (PI3K) and multiple distal pathways in rats. Following a 5-h infusion of lipid or glycerol (control), rats underwent a euglycemic hyperinsulinemic clamp. Insulin stimulated IRS-1-associated PI3K activity in muscle of glycerol-infused rats 2.4-fold but had no effect in lipid-infused rats. IRS-2-and phosphotyrosine-associated PI3K activity were increased 3.5-and 4.8-fold, respectively, by insulin in glycerol-infused rats but only 1.6-and 2.3-fold in lipidinfused rats. Insulin increased Akt1 activity 3.9-fold in glycerol-infused rats, and this was impaired 41% in lipid-infused rats. Insulin action on Akt2 and p70S6K were not impaired, whereas activation of protein kinase C / activity was reduced 47%. Insulin inhibited glycogen synthase kinase 3␣ (GSK-3␣) activity by 30% and GSK-3␤ activity by ϳ65% and increased protein phosphatase-1 activity by 40 -47% in both glycerol-and lipid-infused rats. Insulin stimulated glycogen synthase activity 2.0-fold in glycerol-infused rats but only 1.4-fold in lipidinfused rats. Thus, 1) elevation of fatty acids differentially affects insulin action on pathways distal to PI3K, impairing activation of Akt1 and protein kinase C / and 2) insulin action on glycogen synthase can be regulated independent of effects on GSK-3 and protein phosphatase-1 activity in vivo.

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Section: Fig 3 Pkc/ Activities (A) and Protein Levels (B) In Musclesupporting

confidence: 80%

Fatty Acid Infusion Selectively Impairs Insulin Action on Akt1 and Protein Kinase C λ/ζ but Not on Glycogen Synthase Kinase-3

Kim

Shulman

Kahn

2002

Journal of Biological Chemistry

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“…Concerning the possible involvement of atypical PKC in the state of insulin resistance, insulininduced PKC-/ activation and glucose transport have been found to be profoundly decreased in skeletal muscle and adipocyte of GK rats (23,24). Along this line, insulin completely failed to activate PKC-/, regardless of only a modest decrease in insulin-induced PI 3-kinase activity in the skeletal muscle of high fatϪfed rats (25).…”

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confidence: 72%

Association of SH2-Containing Inositol Phosphatase 2 With the Insulin Resistance of Diabetic db/db Mice

et al. 2002

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SH-2؊containing inositol 5-phosphatase 2 (SHIP-2) is a physiologically important lipid phosphatase that functions to hydrolyze phosphatidylinositol (PI) 3-kinase product PI(3,4,5)P3 to PI(3,4)P2 in the negative regulation of insulin signaling. We investigated whether SHIP-2 is associated with the insulin resistance of diabetic db/db mice. The amount of SHIP-2 protein was elevated in quadriceps muscle and epididymal fat tissue, but not in the liver, of db/db mice relative to that in control db/؉m mice. In accordance with the enhanced expression of SHIP-2, its localization at the membrane preparation was increased in the skeletal muscle and fat tissue of db/db mice. Insulin stimulation of PI 3-kinase activity was modestly decreased in skeletal muscle, fat tissue, and liver of db/db mice compared with that of db/؉m mice. In addition to the modest decrease at the level of PI 3-kinase, the activity of Akt and protein kinase C (PKC)-/, which are downstream molecules of PI 3-kinase, was more severely reduced in the skeletal muscle and fat tissue, but not in liver of db/db mice. Treatment with the insulin-sensitizing agent rosiglitazone decreased the elevated expression of SHIP-2 in the skeletal muscle and fat tissue of db/db mice. Insulininduced Akt activation and PKC-/ phosphorylation were restored to the control level, although insulinstimulated PI 3-kinase activation was minimally affected in the skeletal muscle and fat tissue of db/db mice. These results indicate that SHIP-2 is a novel molecule associated with insulin resistance in the skeletal muscle and fat tissue, and that insulin-induced activity of the downstream molecules of PI 3-kinase is decreased, at least in part, by the elevated expression of SHIP-2 in diabetic db/db mice. Diabetes 51:2387-2394, 2002

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“…7). Previous biochemical studies have found either normal (4,5) or reduced (6,37,39) overall GLUT4 content in muscle from high fat-fed animals, while GLUT4 translocation was reduced (4,5,7). One study using subcellular fractionation found completely abrogated insulin-stimulated GLUT4 translocation to both sarcolemma and T-tubules (38).…”

Section: Discussionmentioning

confidence: 99%

Denervation and High-Fat Diet Reduce Insulin Signaling in T-Tubules in Skeletal Muscle of Living Mice

Lauritzen

Ploug

et al. 2008

Diabetes

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OBJECTIVE-Insulin stimulates muscle glucose transport by translocation of GLUT4 to sarcolemma and T-tubules. Despite muscle glucose uptake playing a major role in insulin resistance and type 2 diabetes, the temporal and spatial changes in insulin signaling and GLUT4 translocation during these conditions are not well described.RESEARCH DESIGN AND METHODS-We used time-lapse confocal imaging of green fluorescent protein (GFP) ADP-ribosylation factor nucleotide-binding site opener (ARNO) (evaluation of phosphatidylinositide 3-kinase activation) and GLUT4-GFP-transfected quadriceps muscle in living, anesthetized mice either muscle denervated or high-fat fed. T-tubules were visualized with sulforhodamine B dye. In incubated muscle, glucose transport was measured by 2-deoxy-D-[3 H]-glucose uptake, and functional detubulation was carried out by osmotic shock. Muscle fibers were immunostained for insulin receptors.RESULTS-Denervation and high-fat diet reduced insulin-mediated glucose transport. In denervated muscle, insulin-stimulated phosphatidylinositol 3,4,5 P 3 (PIP3) production was abolished in T-tubules, while PIP3 production at sarcolemma was increased 2.6-fold. Correspondingly, GLUT4-GFP translocation to T-tubules was abolished, while translocation to sarcolemma was increased 2.3-fold. In high fat-fed mice, a ϳ65% reduction in both insulininduced T-tubular PIP3 production and GLUT4-GFP translocation was seen. Sarcolemma was less affected, with reductions of ϳ40% in PIP3 production and ϳ15% in GLUT4-GFP translocation. Access to T-tubules was not compromised, and insulin receptor distribution in sarcolemma and T-tubules was unaffected by denervation or high-fat feeding. Detubulation of normal muscle reduced basal and abolished insulin-induced glucose transport.CONCLUSIONS-Our findings demonstrate, for the first time, that impaired insulin signaling and GLUT4 translocation is compartmentalized in muscle and primarily localized to T-tubules and not sarcolemma during insulin resistance. Diabetes 57: 13-23, 2008 S keletal muscle plays an important role in glucose homeostasis, and defects in glucose uptake in muscle are involved in states of insulin resistance (e.g., type 2 diabetes). Upon stimulation with insulin, the GLUT4 glucose transporters in skeletal muscle fibers are translocated from intracellular compartments to the plasma membrane and T-tubules, and, in turn, glucose uptake is increased (1,2). In type 2 diabetes, the number of GLUT4 transporters in muscle is normal (3,4), and in other states of insulin resistance as well, reductions in GLUT4 content cannot fully explain the diminished glucose transport in muscle (5-7). Accordingly, the insulin signaling and/or the trafficking of GLUT4 must be impaired (4). However, the nature of these cellular defects is poorly understood. By imaging the dynamic changes in localization of green fluorescent protein (GFP)-tagged proteins in skeletal muscle fibers in situ in normal living mice (8), we have revealed previously unnoticed signaling functions of the T-tubule system ...

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Defective Insulin-Induced GLUT4 Translocation in Skeletal Muscle of High Fat–Fed Rats Is Associated With Alterations in Both Akt/Protein Kinase B and Atypical Protein Kinase C (ζ/λ) Activities

Cited by 188 publications

References 67 publications

Fatty Acid Infusion Selectively Impairs Insulin Action on Akt1 and Protein Kinase C λ/ζ but Not on Glycogen Synthase Kinase-3

Fatty Acid Infusion Selectively Impairs Insulin Action on Akt1 and Protein Kinase C λ/ζ but Not on Glycogen Synthase Kinase-3

Association of SH2-Containing Inositol Phosphatase 2 With the Insulin Resistance of Diabetic db/db Mice

Denervation and High-Fat Diet Reduce Insulin Signaling in T-Tubules in Skeletal Muscle of Living Mice

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