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. 2012 Oct;61(10):2472-8.
doi: 10.2337/db11-1832. Epub 2012 Jul 10.

High Oxidative Capacity Due to Chronic Exercise Training Attenuates Lipid-Induced Insulin Resistance

Free PMC article

High Oxidative Capacity Due to Chronic Exercise Training Attenuates Lipid-Induced Insulin Resistance

Esther Phielix et al. Diabetes. .
Free PMC article


Fat accumulation in skeletal muscle combined with low mitochondrial oxidative capacity is associated with insulin resistance (IR). Endurance-trained athletes, characterized by a high oxidative capacity, have elevated intramyocellular lipids, yet are highly insulin sensitive. We tested the hypothesis that a high oxidative capacity could attenuate lipid-induced IR. Nine endurance-trained (age = 23.4 ± 0.9 years; BMI = 21.2 ± 0.6 kg/m(2)) and 10 untrained subjects (age = 21.9 ± 0.9 years; BMI = 22.8 ± 0.6 kg/m(2)) were included and underwent a clamp with either infusion of glycerol or intralipid. Muscle biopsies were taken to perform high-resolution respirometry and protein phosphorylation/expression. Trained subjects had ~32% higher mitochondrial capacity and ~22% higher insulin sensitivity (P < 0.05 for both). Lipid infusion reduced insulin-stimulated glucose uptake by 63% in untrained subjects (P < 0.05), whereas this effect was blunted in trained subjects (29%, P < 0.05). In untrained subjects, lipid infusion reduced oxidative and nonoxidative glucose disposal (NOGD), whereas trained subjects were completely protected against lipid-induced reduction in NOGD, supported by dephosphorylation of glycogen synthase. We conclude that chronic exercise training attenuates lipid-induced IR and specifically attenuates the lipid-induced reduction in NOGD. Signaling data support the notion that high glucose uptake in trained subjects is maintained by shuttling glucose toward storage as glycogen.


FIG. 1.
FIG. 1.
Mitochondrial oxygen flux (pmol ⋅ mg−1 ⋅ s−1) measured in permeabilized muscle fibers in trained (black bars) and untrained (white bars) subjects (A) and normalized to mitochondrial content (B). *P < 0.05, trained vs. untrained subjects. mtDNA copy number calculated as the ratio ND1/LPL in arbitrary units (C). All data are expressed as mean ± SE. cytc, cytochrome c; FCCP, fluoro-carbonyl cyanide phenylhydrazone; M, malate; MG3, malate glutamate and ADP; MGS3, MG3 and succinate; MO, malate octanoyl-carnitine; MO3, MO and ADP; MOG3, MO3 and glutamate; MOGS3, MOG3 and succinate; O4, oligomycin.
FIG. 2.
FIG. 2.
Insulin sensitivity expressed as insulin-stimulated change of ΔRd (A), carbohydrate oxidation (B), and NOGD (C) (all parameters expressed as μmol ⋅ kg−1 ⋅ min−1) in trained (black bars) and untrained (white bars) subjects during a hyperinsulinemic-euglycemic clamp with simultaneous infusion of glycerol or lipid. Data expressed as mean ± SE. *P < 0.05.
FIG. 3.
FIG. 3.
The expression level of insulin receptor (A), pGSK3β (B), GS (C), phosphorylation of FOXO1 (pFOXO1) (D), and phosphorylation of PDK4 (E) in trained and untrained subjects before and after glycerol (white and light gray bars, respectively) as well as before and after lipid infusion (black and dark gray bars, respectively). Representative Western blots under baseline conditions (b), after glycerol (g), and after lipid (l) infusion, with (+) and without (−) insulin stimulation (F). Data expressed as mean ± SE. AU, arbitrary units.

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