Rapid impairment of skeletal muscle glucose transport/phosphorylation by free fatty acids in humans

Rat muscle studies suggest competition between free fatty acids (FFA) and glucose for oxidation, resulting in glucose-6-phosphate accumulation. However, FFA decrease glucose-6-phosphate in human skeletal muscle, indicating direct inhibition of glucose transport/phosphorylation. This mechanism could redirect glucose from muscle to brain during fasting and explain the insulin resistance associated with high-lipid diets and obesity.

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The effects of free fatty acids on glucose transport and phosphorylation in human skeletal muscle

Current Opinion in Endocrinology & Diabetes ◽

10.1097/00060793-200008000-00006 ◽

2000 ◽

Vol 7 (4) ◽

pp. 211-216 ◽

Cited By ~ 11

Author(s):

Werner K. Waldhäusl ◽

Michael Roden

Keyword(s):

Skeletal Muscle ◽

Fatty Acids ◽

Free Fatty Acids ◽

Glucose Transport ◽

Human Skeletal Muscle

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Nitric oxide stimulates skeletal muscle glucose transport through a calcium/contraction- and phosphatidylinositol-3-kinase-independent pathway

Diabetes ◽

10.2337/diabetes.46.11.1915 ◽

1997 ◽

Vol 46 (11) ◽

pp. 1915-1919 ◽

Cited By ~ 35

Author(s):

G. J. Etgen ◽

D. A. Fryburg ◽

E. M. Gibbs

Keyword(s):

Nitric Oxide ◽

Skeletal Muscle ◽

Glucose Transport ◽

Phosphatidylinositol 3 Kinase ◽

Muscle Glucose Transport ◽

Phosphatidylinositol 3

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Faculty Opinions recommendation of Direct renin inhibition improves systemic insulin resistance and skeletal muscle glucose transport in a transgenic rodent model of tissue renin overexpression.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1157635.617835 ◽

2009 ◽

Author(s):

Sharma Prabhakar

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Glucose Transport ◽

Rodent Model ◽

Systemic Insulin Resistance ◽

Renin Inhibition ◽

Muscle Glucose Transport

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Skeletal Muscle Glucose Transport and Metabolism Are Enhanced in Transgenic Mice Overexpressing the Glut4 Glucose Transporter.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)85410-2 ◽

1995 ◽

Vol 270 (4) ◽

pp. 1679-1684

Author(s):

Polly A. Hansen ◽

Eric A. Gulve ◽

Bess Adkins Marshall ◽

Jiaping Gao ◽

Jeffrey E. Pessin ◽

...

Keyword(s):

Skeletal Muscle ◽

Transgenic Mice ◽

Glucose Transport ◽

Glucose Transporter ◽

Muscle Glucose Transport

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Isomer-specific actions of conjugated linoleic acid on muscle glucose transport in the obese Zucker rat

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00013.2003 ◽

2003 ◽

Vol 285 (1) ◽

pp. E98-E105 ◽

Cited By ~ 52

Author(s):

Erik J. Henriksen ◽

Mary K. Teachey ◽

Zachary C. Taylor ◽

Stephan Jacob ◽

Arne Ptock ◽

...

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Glucose Tolerance ◽

Glucose Transport ◽

Zucker Rat ◽

Transport Activity ◽

Insulin Resistant ◽

Obese Zucker Rat ◽

Cla Isomers ◽

Muscle Glucose Transport

The fatty acid-conjugated linoleic acid (CLA) enhances glucose tolerance and insulin action on skeletal muscle glucose transport in rodent models of insulin resistance. However, no study has directly compared the metabolic effects of the two primary CLA isomers, cis-9, trans-11-CLA (c9,t11-CLA) and trans-10, cis-12-CLA (t10,c12-CLA). Therefore, we assessed the effects of a 50:50 mixture of these two CLA isomers (M-CLA) and of preparations enriched in either c9,t11-CLA (76% enriched) or t10,c12-CLA (90% enriched) on glucose tolerance and insulin-stimulated glucose transport in skeletal muscle of the insulin-resistant obese Zucker ( fa/ fa) rat. Animals were treated daily by gavage with either vehicle (corn oil), M-CLA, c9,t11-CLA, or t10,c12-CLA (all CLA treatments at 1.5 g total CLA/kg body wt) for 21 consecutive days. During an oral glucose tolerance test, glucose responses were reduced ( P < 0.05) by 10 and 16%, respectively, in the M-CLA and t10,c12-CLA animals, respectively, whereas insulin responses were diminished by 21 and 19% in these same groups. There were no significant alterations in these responses in the c9,t11-CLA group. Insulin-mediated glucose transport activity was enhanced by M-CLA treatment in both type I soleus (32%) and type IIb epitrochlearis (58%) muscles and by 36 and 48%, respectively, with t10,c12-CLA. In the soleus, these increases were associated with decreases in protein carbonyls (index of oxidative stress, r = -0.616, P = 0.0038) and intramuscular triglycerides ( r = -0.631, P = 0.0028). Treatment with c9,t11-CLA was without effect on these variables. These results suggest that the ability of CLA treatment to improve glucose tolerance and insulin-stimulated glucose transport activity in insulin-resistant skeletal muscle of the obese Zucker rat are associated with a reduction in oxidative stress and muscle lipid levels and can be specifically ascribed to the actions of the t10,c12 isomer. In the obese Zucker rat, the c9,t11 isomer of CLA is metabolically neutral.

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Elevated plasma free fatty acids decrease basal protein synthesis, but not the anabolic effect of leucine, in skeletal muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00065.2006 ◽

2006 ◽

Vol 291 (3) ◽

pp. E666-E674 ◽

Cited By ~ 24

Author(s):

Charles H. Lang

Keyword(s):

Skeletal Muscle ◽

Fatty Acids ◽

Protein Synthesis ◽

Free Fatty Acids ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Short Term ◽

Lipid Infusion ◽

Igf I ◽

Plasma Ffas

Elevations in free fatty acids (FFAs) impair glucose uptake in skeletal muscle. However, there is no information pertaining to the effect of elevated circulating lipids on either basal protein synthesis or the anabolic effects of leucine and insulin-like growth factor I (IGF-I). In chronically catheterized conscious rats, the short-term elevation of plasma FFAs by the 5-h infusion of heparin plus Intralipid decreased muscle protein synthesis by ∼25% under basal conditions. Lipid infusion was associated with a redistribution of eukaryotic initiation factor (eIF)4E from the active eIF4E·eIF4G complex to the inactive eIF4E·4E-BP1 complex. This shift was associated with a decreased phosphorylation of eIF4G but not 4E-BP1. Lipid infusion did not significantly alter either the total amount or phosphorylation state of mTOR, TSC2, S6K1, or the ribosomal protein S6 under basal conditions. In control rats, oral leucine increased muscle protein synthesis. This anabolic response was not impaired by lipid infusion, and no defects in signal transduction pathways regulating translation initiation were detected. In separate rats that received a bolus injection of IGF-I, lipid infusion attenuated the normal redistribution of eIF4E from the active to inactive complex and largely prevented the increased phosphorylation of 4E-BP1, eIF4G, S6K1, and S6. This IGF-I resistance was associated with enhanced Ser307 phosphorylation of insulin receptor substrate-1 (IRS-1). These data indicate that the short-term elevation of plasma FFAs impairs basal protein synthesis in muscle by altering eIF4E availability, and this defect may be related to impaired phosphorylation of eIF4G, not 4E-BP1. Moreover, hyperlipidemia impairs IGF-I action but does not produce leucine resistance in skeletal muscle.

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