期刊
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
卷 319, 期 6, 页码 C1011-C1019出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00157.2020
关键词
glycogen synthesis; glycolysis; glucose oxidation; human skeletal muscle cell; pyruvate dehydrogenase; TCA cycle
资金
- National Institute of Diabetes and Digestive and Kidney Diseases [U24DK100469]
- National Institutes of Health Director's Common Fund
- Janssen Research & Development, LLC
- National Institutes of Health [DK56112]
- American Heart Association [15POST25080003]
- UMass Boston
- Golden LEAF Foundation
The purpose of this study was to determine whether intramyocellular glucose partitioning was altered in primary human myotubes derived from severely obese women with type 2 diabetes. Human skeletal muscle cells were obtained from lean nondiabetic and severely obese Caucasian females with type 2 diabetes [body mass index (BMI): 23.6 +/- 2.6 vs. 48.8 +/- 1.9 kg/m(2), fasting glucose: 86.9 +/- 1.6 vs. 135.6 +/- 12.0 mg/dL, n = 9/group]. 1-[C-14]-Glucose metabolism (glycogen synthesis, glucose oxidation, and nonoxidized glycolysis) and 1and 2-[C-14]pyruvate oxidation were examined in fully differentiated myotubes under basal and insulin-stimulated conditions. Tricarboxylic acid cycle intermediates were determined via targeted metabolomics. Myotubes derived from severely obese individuals with type 2 diabetes exhibited impaired insulin-mediated glucose partitioning with reduced rates of glycogen synthesis and glucose oxidation and increased rates of nonoxidized glycolytic products, when compared with myotubes derived from the nondiabetic individuals (P < 0.05). Both 1and 2-[C-14]-pyruvate oxidation rates were significantly blunted in myotubes from severely obese women with type 2 diabetes compared with myotubes from the nondiabetic controls. Lastly, concentrations of tricarboxylic acid cycle intermediates, namely, citrate (P < 0.05), cis-aconitic acid (P = 0.07), and a-ketoglutarate (P < 0.05), were lower in myotubes from severely obese women with type 2 diabetes. These data suggest that intramyocellular insulin-mediated glucose partitioning is intrinsically altered in the skeletal muscle of severely obese women with type 2 diabetes in a manner that favors the production of glycolytic end products. Defects in pyruvate dehydrogenase and tricarboxylic acid cycle may be responsible for this metabolic derangement associated with type 2 diabetes.
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