Open AccessImpaired glucose partitioning in primary myotubes from severely obese women with type 2 diabetes
Author(s) -
Kai Zou,
Kristen Turner,
Donghai Zheng,
J. Matthew Hinkley,
Benjamin A. Kugler,
Pamela J. Hornby,
James M. Lenhard,
Terry E. Jones,
Walter J. Pories,
G. Lynis Dohm,
Joseph A. Houmard
Publication year - 2020
Publication title -
american journal of physiology. cell physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.432
H-Index - 181
eISSN - 1522-1563
pISSN - 0363-6143
DOI - 10.1152/ajpcell.00157.2020
Subject(s) - medicine , endocrinology , glycolysis , myogenesis , citric acid cycle , type 2 diabetes , diabetes mellitus , skeletal muscle , carbohydrate metabolism , glycogen , insulin resistance , glycogen synthase , insulin , biology , metabolism
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-[ 14 C]-Glucose metabolism (glycogen synthesis, glucose oxidation, and nonoxidized glycolysis) and 1- and 2-[ 14 C]-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 1- and 2-[ 14 C]-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 α-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.