Two phases of palmitate-induced insulin resistance in skeletal muscle: impaired GLUT4 translocation is followed by a reduced GLUT4 intrinsic activity

Alkhateeb, Hakam; Chabowski, Adrian; Glatz, Jan F. C.; Luiken, Joost F. P.; Bonen, Arend

doi:10.1152/ajpendo.00685.2006

Cited by 75 publications

(109 citation statements)

References 68 publications

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“…However, the decreased ability of insulin to phosphorylate Akt on T308 and induce GLUT4 translocation did not result in reduced glucose uptake, which suspected the exclusive role of GLUT4 translocation in glucose uptake (Tajmir et al, 2003). In particular, a reduction of intrinsic GLUT4 activity has been suggested to be a contributor to insulin resistance in obese diabetic subjects (Alkhateeb et al, 2007). In L6 muscle cells, insulin-stimulated glucose transport was reduced by altering the intrinsic activity of cell surface GLUT4 without change of GLUT4 translocation and Akt phosphorylation (Moon et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Insulin-stimulated glucose uptake was achieved by activating only 10-20% of insulin receptor substrate-1 (IRS-1) and Akt in one study (Whitehead et al, 2001), and insulinstimulated Akt activation was not severely impaired in obese individuals with insulin resistance in another study (Storgaard et al, 2004), indicating that factors other than an impaired insulin signaling pathway may be involved in the induction of insulin resistance. Additionally, a report that palmitate induces insulin resistance without a defect in insulin-stimulated Akt phosphorylation in the soleus muscle (Alkhateeb et al, 2007) suspects a role for impairment of the insulin signaling pathway in PIIR. In particular, Cleasby et al reported that reduced IRS-1 levels in muscle did not severely impair insulin action (Cleasby et al, 2007) and Hoehn et al revealed that upstream elements of the insulin signaling cascade are not a central feature of the origin of insulin resistance (Hoehn et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to impaired translocation of GLUT4, intrinsic inactivity of GLUT4 or reduced expression of GLUT4 is presumably responsible for inducing insulin resistance (Alkhateeb et al, 2007;Garvey et al, 1992;Klip, 2009;Shepherd and Kahn, 1999). The current paradigm is that decreased GLUT4 expression in adipose tissues, but not in muscle, is a common feature of many insulin-resistant states (Armoni et al, 2005a,b;Graham and Kahn, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Supplementation of pyruvate prevents palmitate-induced impairment of glucose uptake in C2 myotubes

Jung

Choi

Hwang

et al. 2011

Molecular and Cellular Endocrinology

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Supplementation of pyruvate prevents palmitate-induced impairment of glucose uptake in C2 myotubes

Jung

Choi

Hwang

et al. 2011

Molecular and Cellular Endocrinology

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“…Intramuscular lipids Control and transfected muscles were analysed for triacylglycerol, diacylglycerol and ceramide content as reported previously [22,23]. Briefly, lipids were extracted with a modified Folch procedure and thin-layer chromatography was used to separate lipids.…”

Section: Intramuscular Lipids and Mitochondrial Fatty Acid Oxidationmentioning

confidence: 99%

Increased levels of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α) improve lipid utilisation, insulin signalling and glucose transport in skeletal muscle of lean and insulin-resistant obese Zucker rats

et al. 2010

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Aims/hypothesis Reductions in peroxisome proliferatoractivated receptor gamma, coactivator 1 alpha (PGC-1α) levels have been associated with the skeletal muscle insulin resistance. However, in vivo, the therapeutic potential of PGC-1α has met with failure, as supra-physiological overexpression of PGC-1α induced insulin resistance, due to fatty acid translocase (FAT)-mediated lipid accumulation. Based on physiological and metabolic considerations, we hypothesised that a modest increase in PGC-1α levels would limit FAT upregulation and improve lipid metabolism and insulin sensitivity, although these effects may differ in lean and insulin-resistant muscle. Methods Pgc-1α was transfected into lean and obese Zucker rat muscles. Two weeks later we examined mitochondrial biogenesis, intramuscular lipids (triacylglycerol, diacylglycerol, ceramide), GLUT4 and FAT levels, insulin-stimulated glucose transport and signalling protein phosphorylation (thymoma viral proto-oncogene 2 [Akt2], Akt substrate of 160 kDa [AS160]), and fatty acid oxidation in subsarcolemmal and intermyofibrillar mitochondria. Results Electrotransfection yielded physiologically relevant increases in Pgc-1α (also known as Ppargc1a) mRNA and protein (∼25%) in lean and obese muscle. This induced mitochondrial biogenesis, and increased FAT and GLUT4 levels, insulin-stimulated glucose transport, and Akt2 and AS160 phosphorylation in lean and obese animals, while bioactive intramuscular lipids were only reduced in obese muscle. Concurrently, PGC-1α increased palmitate oxidation in subsarcolemmal, but not in intermyofibrillar mitochondria, in both groups. In obese compared with lean animals, the PGC-1α-induced improvement in insulin-stimulated glucose transport was smaller, but intramuscular lipid reduction was greater. Conclusions/interpretations Increases in PGC-1α levels, similar to those that can be induced by physiological stimuli, altered intramuscular lipids and improved fatty acid oxidation, insulin signalling and insulin-stimulated glucose transport, albeit to different extents in lean and insulinresistant muscle. These positive effects are probably attributable to limiting the PGC-1α-induced increase in FAT, thereby preventing bioactive lipid accumulation as has occurred in transgenic PGC-1α animals.

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“…Intramuscular levels of triacylglycerol, diacylglycerol and ceramide were measured as described previously [21].…”

Section: Biochemical Determination Of Intramuscular Lipid Contentmentioning

confidence: 99%

Subcellular lipid droplet distribution in red and white muscles in the obese Zucker rat

et al. 2011

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Aims/hypothesis Little is known about the subcellular distribution of lipids in insulin-resistant skeletal muscle. However, it has recently been suggested that lipid accumulation in the subsarcolemmal region directly contributes to insulin resistance. Therefore we hypothesised that regional differences in lipid distribution in insulin-resistant muscle may be mediated by: (1) a reduction in fatty acid trafficking into mitochondria; and/or (2) a regional increase in the enzymes regulating lipid synthesis. Methods Transmission electron microscopy was used to quantify lipid droplet and mitochondrial abundance in the subsarcolemmal and intermyofibrillar compartments in red and white muscles from lean and obese Zucker rats. To estimate rates of lipid trafficking into mitochondria, the metabolic fate of radiolabelled palmitate was determined. Key enzymes of triacylglycerol synthesis were also determined in each subcellular region. Results Subsarcolemmal-compartmentalised lipids represented a small absolute fraction of the overall lipid content in muscle, as regardless of fibre composition (red/white) or phenotype (lean/obese), lipid droplets were more prevalent in the intermyofibrillar region, whereas insulin-resistant white muscles were devoid of subsarcolemmal-compartmentalised lipid droplets. While, in obese animals, lipid droplets accumulated in both subcellular regions, in red muscle of these animals lipids only appeared to be trafficked away from intermyofibrillar mitochondria, a process that cannot be explained by regional differences in the abundance of triacylglycerol esterification enzymes. Conclusions/interpretation Lipid accumulation in the subsarcolemmal region is not necessary for insulin resistance. In the intermyofibrillar compartment, the diversion of lipids away from mitochondria in insulin-resistant animals probably contributes to lipid accumulation in this subcellular area.

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Two phases of palmitate-induced insulin resistance in skeletal muscle: impaired GLUT4 translocation is followed by a reduced GLUT4 intrinsic activity

Abstract: Alkhateeb H, Chabowski A, Glatz JF, Luiken JF, Bonen A. Two phases of palmitate-induced insulin resistance in skeletal muscle: impaired GLUT4 translocation is followed by a reduced GLUT4 intrinsic activity.

Cited by 75 publications

References 68 publications

Supplementation of pyruvate prevents palmitate-induced impairment of glucose uptake in C2 myotubes

Supplementation of pyruvate prevents palmitate-induced impairment of glucose uptake in C2 myotubes

Increased levels of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α) improve lipid utilisation, insulin signalling and glucose transport in skeletal muscle of lean and insulin-resistant obese Zucker rats

Subcellular lipid droplet distribution in red and white muscles in the obese Zucker rat

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