Departments of Laboratory Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
Diabetes Res Clin Pract. 2018 Jun;140:107-117. doi: 10.1016/j.diabres.2018.03.028. Epub 2018 Mar 27.
We evaluated specific alterations in amino acids (AAs) profile in patients with type 2 diabetes mellitus (T2DM) and impaired fasting glucose (IFG) compared with healthy controls. In addition, we tried to find the mechanisms behind these AA alterations.
Twenty AAs, TNF-α, and IL-6 were analyzed in fasting serum samples from a total of 198 individuals (56 drug-naïve patients with T2DM, 69 patients IFG, and 73 healthy controls). The C2C12 mouse myoblast cell lines were used to examine the changes of MAFbx and MuRF1 expressions, which are muscle specific E3 ligases acting as major mediators of skeletal muscle proteolysis, after development of insulin resistance induced by palmitate treatment.
In addition to branched chain amino acids BCAAs, fasting serum AAs such as glutamic acid, lysine, phenylalanine, arginine, alanine, tyrosine, aspartic acid, were higher in patients with T2DM and intermediately elevated in patients with IFG compared with normoglycemic controls. These serum AA concentrations positively correlated with fasting glucose, homeostasis model assessment of insulin resistance (HOMA-IR), and pro-inflammatory cytokines. In addition, HOMA-IR and pro-inflammatory cytokines were two important independent predictors of serum AA levels. In vitro experiments showed that palmitate treatment in C2C12 myotubes induced insulin resistance, increased pro-inflammatory cytokine gene expression, and increased MAFbx gene and protein expression.
The increase in fasting serum AAs can be an early manifestation of insulin resistance. Increased muscle proteolysis induced by insulin resistance and inflammatory cytokines can be a possible mechanism for the rise in serum AA levels.
我们评估了 2 型糖尿病（T2DM）和空腹血糖受损（IFG）患者与健康对照者相比，氨基酸（AA）谱的特定变化。此外，我们试图寻找这些 AA 变化背后的机制。
在总共 198 名个体（56 名未经药物治疗的 T2DM 患者、69 名 IFG 患者和 73 名健康对照者）的空腹血清样本中分析了 20 种 AA、TNF-α 和 IL-6。使用 C2C12 小鼠成肌细胞系，研究了在棕榈酸处理诱导胰岛素抵抗后，作为骨骼肌蛋白水解主要介质的肌肉特异性 E3 连接酶 MAFbx 和 MuRF1 的表达变化。
除支链氨基酸（BCAA）外，T2DM 患者和 IFG 患者空腹血清 AA（如谷氨酸、赖氨酸、苯丙氨酸、精氨酸、丙氨酸、酪氨酸、天冬氨酸）水平升高，且高于血糖正常的对照组。这些血清 AA 浓度与空腹血糖、稳态模型评估的胰岛素抵抗（HOMA-IR）和促炎细胞因子呈正相关。此外，HOMA-IR 和促炎细胞因子是血清 AA 水平的两个重要独立预测因子。体外实验表明，棕榈酸处理 C2C12 肌管可诱导胰岛素抵抗，增加促炎细胞因子基因表达，并增加 MAFbx 基因和蛋白表达。
空腹血清 AA 的增加可能是胰岛素抵抗的早期表现。胰岛素抵抗和炎症细胞因子引起的肌肉蛋白水解增加可能是血清 AA 水平升高的一个可能机制。
