Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Oregon State University, Corvallis, OR, USA.
Diabetologia. 2021 Jan;64(1):168-180. doi: 10.1007/s00125-020-05315-0. Epub 2020 Oct 31.
AIMS/HYPOTHESIS: Subcellular localisation is an important factor in the known impact of bioactive lipids, such as diacylglycerol and sphingolipids, on insulin sensitivity in skeletal muscle; yet, the role of localised intramuscular triacylglycerol (IMTG) is yet to be described. Excess accumulation of IMTG in skeletal muscle is associated with insulin resistance, and we hypothesised that differences in subcellular localisation and composition of IMTG would relate to metabolic health status in humans.
We evaluated subcellular localisation of IMTG in lean participants, endurance-trained athletes, individuals with obesity and individuals with type 2 diabetes using LC-MS/MS of fractionated muscle biopsies and insulin clamps.
Insulin sensitivity was significantly different between each group (athletes>lean>obese>type 2 diabetes; p < 0.001). Sarcolemmal IMTG was significantly greater in individuals with obesity and type 2 diabetes compared with lean control participants and athletes, but individuals with type 2 diabetes were the only group with significantly increased saturated IMTG. Sarcolemmal IMTG was inversely related to insulin sensitivity. Nuclear IMTG was significantly greater in individuals with type 2 diabetes compared with lean control participants and athletes, and total and saturated IMTG localised in the nucleus had a significant inverse relationship with insulin sensitivity. Total cytosolic IMTG was not different between groups, but saturated cytosolic IMTG species were significantly increased in individuals with type 2 diabetes compared with all other groups. There were no significant differences between groups for IMTG concentration in the mitochondria/endoplasmic reticulum.
CONCLUSIONS/INTERPRETATION: These data reveal previously unknown differences in subcellular IMTG localisation based on metabolic health status and indicate the influence of sarcolemmal and nuclear IMTG on insulin sensitivity. Additionally, these studies suggest saturated IMTG may be uniquely deleterious for muscle insulin sensitivity. Graphical abstract.
目的/假设：生物活性脂质（如二酰基甘油和鞘脂）对骨骼肌胰岛素敏感性的已知影响的一个重要因素是亚细胞定位；然而，局部肌内三酰基甘油（IMTG）的作用尚未描述。骨骼肌中 IMTG 的过度积累与胰岛素抵抗有关，我们假设 IMTG 的亚细胞定位和组成的差异与人类的代谢健康状况有关。
我们使用 LC-MS/MS 对分离的肌肉活检和胰岛素钳夹，评估了瘦参与者、耐力训练运动员、肥胖者和 2 型糖尿病患者的 IMTG 亚细胞定位。
胰岛素敏感性在每组之间有显著差异（运动员>瘦>肥胖>2 型糖尿病；p<0.001）。与瘦对照组和运动员相比，肥胖者和 2 型糖尿病患者的肌细胞膜 IMTG 明显增加，但只有 2 型糖尿病患者的饱和 IMTG 显著增加。肌细胞膜 IMTG 与胰岛素敏感性呈负相关。与瘦对照组和运动员相比，2 型糖尿病患者的核 IMTG 明显增加，且定位于核内的总 IMTG 和饱和 IMTG 与胰岛素敏感性呈显著负相关。各组之间总胞质 IMTG 无差异，但与所有其他组相比，2 型糖尿病患者的饱和胞质 IMTG 种类明显增加。各组间线粒体/内质网 IMTG 浓度无显著差异。
结论/解释：这些数据根据代谢健康状况揭示了亚细胞 IMTG 定位的先前未知差异，并表明肌细胞膜和核内 IMTG 对胰岛素敏感性的影响。此外，这些研究表明饱和 IMTG 可能对肌肉胰岛素敏感性具有独特的有害作用。
