Altered tricarboxylic acid cycle flux in primary myotubes from severely obese humans
| Autor: | James Lenhard, Donghai Zheng, Terry E. Jones, Kai Zou, J. Matthew Hinkley, Sanghee Park, G. Lynis Dohm, Walter J. Pories, Pamela J. Hornby, Joseph A. Houmard |
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| Rok vydání: | 2018 |
| Předmět: |
Adult
Male Pyruvate decarboxylation medicine.medical_specialty Endocrinology Diabetes and Metabolism medicine.medical_treatment Citric Acid Cycle Muscle Fibers Skeletal Primary Cell Culture Medicine (miscellaneous) 030209 endocrinology & metabolism 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Internal medicine medicine Humans Glycolysis 030212 general & internal medicine Glycogen synthase Cells Cultured Nutrition and Dietetics biology Glycogen Insulin Tricarboxylic Acids Skeletal muscle Obesity Morbid Citric acid cycle medicine.anatomical_structure Endocrinology chemistry Anaerobic glycolysis biology.protein Carbohydrate Metabolism Female |
| Zdroj: | International Journal of Obesity. 43:895-905 |
| ISSN: | 1476-5497 0307-0565 |
| DOI: | 10.1038/s41366-018-0137-7 |
| Popis: | The partitioning of glucose toward glycolytic end products rather than glucose oxidation and glycogen storage is evident in skeletal muscle with severe obesity and type 2 diabetes. The purpose of the present study was to determine the possible mechanism by which severe obesity alters insulin-mediated glucose partitioning in human skeletal muscle. Primary human skeletal muscle cells (HSkMC) were isolated from lean (BMI = 23.6 ± 2.6 kg/m2, n = 9) and severely obese (BMI = 48.8 ± 1.9 kg/m2, n = 8) female subjects. Glucose oxidation, glycogen synthesis, non-oxidized glycolysis, pyruvate oxidation, and targeted TCA cycle metabolomics were examined in differentiated myotubes under basal and insulin-stimulated conditions. Myotubes derived from severely obese subjects exhibited attenuated response of glycogen synthesis (20.3%; 95% CI [4.7, 28.8]; P = 0.017) and glucose oxidation (5.6%; 95% CI [0.3, 8.6]; P = 0.046) with a concomitant greater increase (23.8%; 95% CI [5.7, 47.8]; P = 0.004) in non-oxidized glycolytic end products with insulin stimulation in comparison to the lean group (34.2% [24.9, 45.1]; 13.1% [8.6, 16.4], and 2.9% [−4.1, 12.2], respectively). These obesity-related alterations in glucose partitioning appeared to be linked with reduced TCA cycle flux, as 2-[14C]-pyruvate oxidation (358.4 pmol/mg protein/min [303.7, 432.9] vs. lean 439.2 pmol/mg protein/min [393.6, 463.1]; P = 0.013) along with several TCA cycle intermediates, were suppressed in the skeletal muscle of severely obese individuals. These data suggest that with severe obesity the partitioning of glucose toward anaerobic glycolysis in response to insulin is a resilient characteristic of human skeletal muscle. This altered glucose partitioning appeared to be due, at least in part, to a reduction in TCA cycle flux. |
| Databáze: | OpenAIRE |
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