Impaired glucose partitioning in primary myotubes from severely obese women with type 2 diabetes.
Impaired glucose partitioning in primary myotubes from severely obese women with type 2 diabetes.
复制标题
患有 2 型糖尿病的严重肥胖女性的原代肌管中的葡萄糖分配受损。
DOI：
10.1152/ajpcell.00157.2020
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Houmard,JosephA
中科院分区：
文献类型：
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作者：
Zou,Kai;Turner,Kristen;Zheng,Donghai;Hinkley,JMatthew;Kugler,BenjaminA;Hornby,PamelaJ;Lenhard,James;Jones,TerryE;Pories,WalterJ;Dohm,GLynis;Houmard,JosephA
这项研究的目的是确定在患有2型糖尿病的严重肥胖女性的原始人类肌管中，细胞内葡萄糖分配是否发生了改变。人骨骼肌细胞来源于非糖尿病和严重肥胖的高加索女性2型糖尿病患者[体重指数：2 3.6±2.6比48.8±1.9 kg/m2，空腹血糖：86.9±1.6比135.6±12.0 mg/dL，n=9/组]。在基础和胰岛素刺激条件下，在完全分化的肌管中检测1-[14C]-葡萄糖代谢(糖原合成、葡萄糖氧化和非氧化糖酵解)以及1-和2-[14C]-丙酮酸氧化。通过靶向代谢组学测定三羧酸循环中间体。与非糖尿病患者相比，严重肥胖2型糖尿病患者的肌管显示胰岛素介导的葡萄糖分配受损，糖原合成和葡萄糖氧化速率降低，非氧化糖酵解产物的比例增加(P<；0.05)。与非糖尿病对照组相比，患有2型糖尿病的严重肥胖女性肌管的1-和2-[14C]-丙酮酸氧化率均显著降低。最后，在严重肥胖的2型糖尿病患者的肌管中，三羧酸循环中间产物柠檬酸(P<；0.05)、顺式乌头酸(P=0.07)和α-酮戊二酸(P<；0.05)的浓度较低。这些数据表明，在患有2型糖尿病的严重肥胖女性的骨骼肌中，细胞内胰岛素介导的葡萄糖分配发生了本质上的改变，这种改变有利于糖酵解最终产物的产生。丙酮酸脱氢酶和三羧酸循环的缺陷可能是与2型糖尿病相关的代谢紊乱的原因。
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/m2, fasting glucose: 86.9 ± 1.6 vs. 135.6 ± 12.0 mg/dL,n= 9/group]. 1-[14C]-Glucose metabolism (glycogen synthesis, glucose oxidation, and nonoxidized glycolysis) and 1- and 2-[14C]-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-[14C]-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.