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Intracellular localization of diacylglycerols and sphingolipids influences insulin sensitivity and mitochondrial function in human skeletal muscle
Leigh Perreault, … , Paul S. MacLean, Bryan C. Bergman
Leigh Perreault, … , Paul S. MacLean, Bryan C. Bergman
Published May 17, 2018; First published February 8, 2018
Citation Information: JCI Insight. 2018;3(3):e96805. https://doi.org/10.1172/jci.insight.96805.
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Categories: Clinical Medicine Endocrinology Metabolism

Intracellular localization of diacylglycerols and sphingolipids influences insulin sensitivity and mitochondrial function in human skeletal muscle

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Abstract

BACKGROUND. Accumulation of diacylglycerol (DAG) and sphingolipids is thought to promote skeletal muscle insulin resistance by altering cellular signaling specific to their location. However,the subcellular localization of bioactive lipids in human skeletal muscle is largely unknown. METHODS. We evaluated subcellular localization of skeletal muscle DAGs and sphingolipids in lean individuals (n = 15), endurance-trained athletes (n = 16), and obese men and women with (n = 12) and without type 2 diabetes (n = 15). Muscle biopsies were fractionated into sarcolemmal, cytosolic, mitochondrial/ER, and nuclear compartments. Lipids were measured using liquid chromatography tandem mass spectrometry, and insulin sensitivity was measured using hyperinsulinemic-euglycemic clamp. RESULTS. Sarcolemmal 1,2-DAGs were not significantly related to insulin sensitivity. Sarcolemmal ceramides were inversely related to insulin sensitivity, with a significant relationship found for the C18:0 species. Sarcolemmal sphingomyelins were also inversely related to insulin sensitivity, with the strongest relationships found for the C18:1, C18:0, and C18:2 species. In the mitochondrial/ER and nuclear fractions, 1,2-DAGs were positively related to, while ceramides were inversely related to, insulin sensitivity. Cytosolic lipids as well as 1,3-DAG, dihydroceramides, and glucosylceramides in any compartment were not related to insulin sensitivity. All sphingolipids but only specific DAGs administered to isolated mitochondria decreased mitochondrial state 3 respiration. CONCLUSION. These data reveal previously unknown differences in subcellular localization of skeletal muscle DAGs and sphingolipids that relate to whole-body insulin sensitivity and mitochondrial function in humans. These data suggest that whole-cell concentrations of lipids obscure meaningful differences in compartmentalization and suggest that subcellular localization of lipids should be considered when developing therapeutic interventions to treat insulin resistance. FUNDING. National Institutes of Health General Clinical Research Center (RR-00036), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01DK089170), NIDDK (T32 DK07658), and Colorado Nutrition Obesity Research Center (P30DK048520).

Authors

Leigh Perreault, Sean A. Newsom, Allison Strauss, Anna Kerege, Darcy E. Kahn, Kathleen A. Harrison, Janet K. Snell-Bergeon, Travis Nemkov, Angelo D’Alessandro, Matthew R. Jackman, Paul S. MacLean, Bryan C. Bergman

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Figure 7

Cytosolic lipid localization in skeletal muscle in endurance-trained athletes, lean controls, obese individuals, and individuals with type 2 diabetes.

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Cytosolic lipid localization in skeletal muscle in endurance-trained ath...
Data are shown for DAG concentration (A), sphingolipid concentration (B), 1,2-DAG species, (C) ceramide species (D), sphingomyelin species (E), and lactosylceramide species (F). The box plot shows the median and 25th and 75th percentiles, and the whiskers represent the 10th and 90th percentiles. n = 16 athletes, 14 lean, 15 obese, and 12 T2D. CER, ceramides; DHCER, dihydroceramides; SPM, sphingomyelins; GluCER, glucosylceramides; LacCER, lactosylceramides. ¥P < 0.05, compared with lean, #P < 0.05, compared with athletes, analyzed with 1-way ANOVA and corrected for multiple comparisons
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