Amino Acids ( IF 3.0 ) Pub Date : 2023-01-13 , DOI: 10.1007/s00726-022-03230-9 Joseph J Matthews 1, 2 , Mark D Turner 3 , Livia Santos 1 , Kirsty J Elliott-Sale 1, 4 , Craig Sale 1, 4
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Type-2 diabetes (T2D) is characterised by a dysregulation of metabolism, including skeletal muscle insulin resistance, mitochondrial dysfunction, and oxidative stress. Reactive species, such as methylglyoxal (MGO) and 4-hydroxynonenal (4-HNE), positively associate with T2D disease severity and can directly interfere with insulin signalling and glucose uptake in skeletal muscle by modifying cellular proteins. The multifunctional dipeptide carnosine, and its rate-limiting precursor β-alanine, have recently been shown to improve glycaemic control in humans and rodents with diabetes. However, the precise mechanisms are unclear and research in human skeletal muscle is limited. Herein, we present novel findings in primary human T2D and lean healthy control (LHC) skeletal muscle cells. Cells were differentiated to myotubes, and treated with 10 mM carnosine, 10 mM β-alanine, or control for 4-days. T2D cells had reduced ATP-linked and maximal respiration compared with LHC cells (p = 0.016 and p = 0.005). Treatment with 10 mM carnosine significantly increased insulin-stimulated glucose uptake in T2D cells (p = 0.047); with no effect in LHC cells. Insulin-stimulation increased MGO-modified proteins in T2D cells by 47%; treatment with carnosine attenuated this increase to 9.7% (p = 0.011). There was no effect treatment on cell viability or expression of other proteins. These findings suggest that the beneficial effects of carnosine on glycaemic control may be explained by its scavenging actions in human skeletal muscle.
中文翻译:
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肌肽增加胰岛素刺激的葡萄糖摄取并减少 2 型糖尿病人骨骼肌细胞中的甲基乙二醛修饰蛋白
2 型糖尿病 (T2D) 的特征是代谢失调,包括骨骼肌胰岛素抵抗、线粒体功能障碍和氧化应激。活性物质,例如甲基乙二醛 (MGO) 和 4-羟基壬烯醛 (4-HNE),与 T2D 疾病的严重程度呈正相关,并且可以通过修饰细胞蛋白直接干扰骨骼肌中的胰岛素信号传导和葡萄糖摄取。多功能二肽肌肽及其限速前体β-丙氨酸,最近已被证明可以改善人类和糖尿病啮齿动物的血糖控制。然而,确切的机制尚不清楚,对人体骨骼肌的研究也很有限。在此,我们介绍了原代人类 T2D 和精益健康对照 (LHC) 骨骼肌细胞的新发现。细胞分化为肌管,并用 10 mM 肌肽、10 mM β-丙氨酸或对照处理 4 天。与 LHC 细胞相比,T2D 细胞减少了 ATP 相关呼吸和最大呼吸(p = 0.016 和p = 0.005)。用 10 mM 肌肽处理可显着增加 T2D 细胞中胰岛素刺激的葡萄糖摄取(p = 0.047); 对 LHC 细胞没有影响。胰岛素刺激使 T2D 细胞中的 MGO 修饰蛋白增加了 47%;用肌肽治疗将这种增加减弱至 9.7% ( p = 0.011)。对细胞活力或其他蛋白质的表达没有影响处理。这些发现表明,肌肽对血糖控制的有益作用可以通过其在人体骨骼肌中的清除作用来解释。