Intramyocellular lipids (IMCL) hamper insulin sensitivity albeit not in endurance-trained athletes (Trained). Compared to type 2 diabetes patients (T2DM), Trained subjects have high levels of Perilipin 5 (PLIN5). Here, we tested if the fraction of PLIN5 coated LDs is a determinant of skeletal muscle insulin sensitivity and contributes to the athlete's paradox. Muscle biopsies were taken from 8 Trained, Lean sedentary, Obese and T2DM subjects. Trained, Obese and T2DM subjects were matched for total IMCL content. Confocal images were analysed for lipid area fraction, LD size and number and PLIN5+ and PLIN5- LDs were measured. A stepwise linear regression was performed to identify factors explaining observed variance in GIR. Trained and T2DM subjects stored IMCL differently; Trained had a higher number of LDs compared to T2DM (0.037 ± 0.004 μm−2vs. 0.023 ± 0.003 μm−2, P = 0.024), that were non-significantly smaller (0.27 ± 0.01 μm2vs. 0.32 ± 0.02 μm2, P = 0.197, Trained vs. T2DM). Even though total PLIN5 protein content was almost double in Trained vs. T2DM (1.65 ± 0.21 AU vs. 0.89 ± 0.09 AU, P = 0.004), PLIN5 coating did not affect LD number or size significantly. Of the observed variance in GIR, the largest fraction by far (70.2%) was explained by maximal oxygen uptake, adding PLIN5 protein content or PLIN5+ LDs increased the explained variance in GIR (74.7% and 80.7% for PLIN5 protein content and PLIN5+ LDs, respectively). Thus, the putative relation between PLIN5 and insulin sensitivity is at best indirect and is apparent only in conjunction with maximal oxygen uptake. Hence, PLIN5 abundance cannot be causally linked to the athlete's paradox.
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