Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2012 Nov;61(11):2743-52.
doi: 10.2337/db11-1572. Epub 2012 Jul 30.

Exercise alleviates lipid-induced insulin resistance in human skeletal muscle-signaling interaction at the level of TBC1 domain family member 4

Christian Pehmøller  1 , Nina Brandt, Jesper B Birk, Louise D Høeg, Kim A Sjøberg, Laurie J Goodyear, Bente Kiens, Erik A Richter, Jørgen F P Wojtaszewski
Affiliations
Randomized Controlled Trial

Exercise alleviates lipid-induced insulin resistance in human skeletal muscle-signaling interaction at the level of TBC1 domain family member 4

Christian Pehmøller et al. Diabetes. 2012 Nov.

Abstract

Excess lipid availability causes insulin resistance. We examined the effect of acute exercise on lipid-induced insulin resistance and TBC1 domain family member 1/4 (TBCD1/4)-related signaling in skeletal muscle. In eight healthy young male subjects, 1 h of one-legged knee-extensor exercise was followed by 7 h of saline or intralipid infusion. During the last 2 h, a hyperinsulinemic-euglycemic clamp was performed. Femoral catheterization and analysis of biopsy specimens enabled measurements of leg substrate balance and muscle signaling. Each subject underwent two experimental trials, differing only by saline or intralipid infusion. Glucose infusion rate and leg glucose uptake was decreased by intralipid. Insulin-stimulated glucose uptake was higher in the prior exercised leg in the saline and the lipid trials. In the lipid trial, prior exercise normalized insulin-stimulated glucose uptake to the level observed in the resting control leg in the saline trial. Insulin increased phosphorylation of TBC1D1/4. Whereas prior exercise enhanced TBC1D4 phosphorylation on all investigated sites compared with the rested leg, intralipid impaired TBC1D4 S341 phosphorylation compared with the control trial. Intralipid enhanced pyruvate dehydrogenase (PDH) phosphorylation and lactate release. Prior exercise led to higher PDH phosphorylation and activation of glycogen synthase compared with resting control. In conclusion, lipid-induced insulin resistance in skeletal muscle was associated with impaired TBC1D4 S341 and elevated PDH phosphorylation. The prophylactic effect of exercise on lipid-induced insulin resistance may involve augmented TBC1D4 signaling and glycogen synthase activation.

PubMed Disclaimer

Figures

FIG. 1.
FIG. 1.
A: Glucose infusion rate/arterial insulin concentration the last 40 min of the clamp. B: Insulin-stimulated leg glucose uptake during the last 40 min of the clamp (LLM, lean leg mass). Insulin-stimulated leg glucose uptake in the rested and previously exercised (Ex’d) leg during the 120 min of the clamp in the saline trial (C) and intralipid trial (D). Data are expressed as means ± SEM (n = 8). #P < 0.05, ##P < 0.01 vs. saline trial; ††P < 0.01 vs. rested leg; *P < 0.05, **P < 0.01, ***P < 0.001 vs. basal (0 min) in respective trial.
FIG. 2.
FIG. 2.
Akt T308 phosphorylation (A), Akt S473 phosphorylation (B), and AMPK T172 phosphorylation/AMPK-α2 expression (C) in rested or exercised (Ex’d) vastus lateralis muscle in the saline and lipid trials. D: Representative Western blots of Akt protein expression and site-specific phosphorylation and AMPK-α2 protein expression and phosphorylation. Blots show the quality and signal obtained with the corresponding antibody and represent one subject; thus, they do not necessarily represent an exact mean of all subjects. Data are expressed as means ± SEM (n = 8). ***P < 0.001 vs. basal (0 min.) in respective trial. AU, arbitrary units.
FIG. 3.
FIG. 3.
Site-specific phosphorylation in rested or exercised (Ex’d) vastus lateralis muscle in the saline and lipid trials. A: TBC1D1 pS237 phosphorylation/TBC1D1 protein expression. B: TBC1D1 pT596 phosphorylation/TBC1D1 protein expression. C: Representative Western blots of TBC1D1 protein expression and phosphorylation show the quality and signal obtained with the corresponding antibody and represent one subject; thus, they do not necessarily represent an exact mean of all subjects. Data are expressed as means ± SEM (n = 8). **P < 0.01 vs. basal (0 min) in respective trial. AU, arbitrary units.
FIG. 4.
FIG. 4.
14-3-3 binding to TBC1D4 and site-specific phosphorylation in rested or exercised (Ex’d) vastus lateralis muscle in the saline and lipid trials. A: 14-3-3 binding to TBC1D4/TBC1D4 protein expression. B: TBC1D4 S318 phosphorylation/TBC1D4 protein expression. C: TBC1D4 S341 phosphorylation/TBC1D4 protein expression. D: TBC1D4 S588 phosphorylation/TBC1D4 protein expression. E: TBC1D4 T642 phosphorylation/TBC1D4 protein expression. F: TBC1D4 S704 phosphorylation/TBC1D4 protein expression. G: TBC1D4 S751 phosphorylation/TBC1D4 protein expression. H: Representative Western blots of TBC1D4 phosphorylation and 14-3-3 binding to TBC1D4 show the quality and signal obtained with the corresponding antibody and represent one subject; thus, they do not necessarily represent an exact mean of all subjects. Data are expressed as means ± SEM (n = 8). #P < 0.05 vs. saline trial; *P < 0.05, **P < 0.01, ***P < 0.001 vs. basal (0 min.) in respective trial; †P < 0.05, ††P < 0.01, †††P < 0.001 vs. rested leg. AU, arbitrary units.
FIG. 5.
FIG. 5.
PDH site 1 and site 2 phosphorylation in rested or exercised (Ex’d) vastus lateralis muscle in the saline and lipid trials. A: PDH site 1 phosphorylation/PDH protein expression. B: PDH site 2 phosphorylation/PDH protein expression. C: Representative Western blots of PDH protein expression and site-specific phosphorylation protein expression and phosphorylation show the quality and signal obtained with the corresponding antibody and represent one subject; thus, they do not necessarily represent an exact mean of all subjects. Data are expressed as means ± SEM (n = 8). (#)P = 0.08 vs. saline trial; †P < 0.05 vs. rested leg. AU, arbitrary units.
FIG. 6.
FIG. 6.
GS activity in rested or exercised (Ex’d) vastus lateralis muscle in the saline and lipid trials. A: GS activity (% I-form). B: GS activity (% FV). Data are expressed as means ± SEM (n = 8). ***P < 0.001 vs. basal (0 min.) in respective trial; †††P < 0.001 vs. rested leg. AU, arbitrary units.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Boden G, Lebed B, Schatz M, Homko C, Lemieux S. Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance in healthy subjects. Diabetes 2001;50:1612–1617 - PubMed
    1. Schenk S, Horowitz JF. Acute exercise increases triglyceride synthesis in skeletal muscle and prevents fatty acid-induced insulin resistance. J Clin Invest 2007;117:1690–1698 - PMC - PubMed
    1. Itani SI, Ruderman NB, Schmieder F, Boden G. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes 2002;51:2005–2011 - PubMed
    1. Chavez JA, Summers SA. Characterizing the effects of saturated fatty acids on insulin signaling and ceramide and diacylglycerol accumulation in 3T3-L1 adipocytes and C2C12 myotubes. Arch Biochem Biophys 2003;419:101–109 - PubMed
    1. Itani SI, Zhou Q, Pories WJ, MacDonald KG, Dohm GL. Involvement of protein kinase C in human skeletal muscle insulin resistance and obesity. Diabetes 2000;49:1353–1358 - PubMed

Publication types

MeSH terms