背景:能量代谢失衡是2型糖尿病(T2D)的病因。尽管已知二甲双胍可以改善整体能量代谢失衡,但是二甲双胍与中心碳代谢(CCM)之间的直接相关性尚未得到彻底研究。在这项研究中,我们采用高效离子色谱-串联质谱(HPIC-MS/MS)技术检测了二甲双胍治疗T2D前后CCM的变化和意义.
方法:我们招募了29名参与者,包括10名最近诊断为T2D的个体(T2D组)。其中,10例患者接受了4-6周的二甲双胍治疗(MET组)。此外,我们包括9名健康受试者(CON组)。采用HPIC-MS/MS,我们定量分析了与CCM相关的18条生物相关代谢途径中的56种代谢物.利用单变量和多变量统计分析来鉴定差异代谢物。随后,相关分析和京都百科全书的基因和基因组(KEGG)途径分析进行了鉴定的差异代谢物。
结果:我们在患有T2D的个体中鉴定出7种不同的代谢物(p<0.05)。值得注意的是,循环3\',5'-单磷酸腺苷(AMP),葡萄糖6-磷酸,L-乳酸,马来酸,和苹果酸在二甲双胍治疗后表现出逆转至正常水平。此外,苹果酸与L-乳酸呈正相关(r=0.94,p<0.05),琥珀酸和苹果酸也是如此(r=0.81,p<0.05),L-乳酸与琥珀酸(r=0.78,p<0.05),和L-乳酸与葡萄糖-6-磷酸(r=0.72,p<0.05)。这些代谢物在丙酮酸代谢中显著富集(p=0.005),三羧酸循环(TCA)(p=0.007),丙酸代谢(p=0.007),糖酵解或糖异生(p=0.009),分别。
结论:我们使用HPIC-MS/MS来揭示最近诊断为T2D的个体在二甲双胍治疗前后CCM的改变。结果表明,二甲双胍可能通过减少CCM途径中的中间体来改善T2D的能量代谢失衡。
BACKGROUND: An imbalance in energy metabolism serves as a causal factor for type 2 diabetes (T2D). Although metformin has been known to ameliorate the overall energy metabolism imbalance, but the direct correlation between metformin and central carbon metabolism (CCM) has not been thoroughly investigated. In this study, we employed a high-performance ion chromatography-tandem mass spectrometry (HPIC-MS/MS) technique to examine the alterations and significance of CCM both before and after metformin treatment for T2D.
METHODS: We recruited 29 participants, comprising 10 individuals recently diagnosed with T2D (T2D group). Among these, 10 patients underwent a 4-6-week treatment with metformin (MET group). Additionally, we included 9 healthy subjects (CON group). Employing HPIC-MS/MS, we quantitatively analyzed 56 metabolites across 18 biologically relevant metabolic pathways associated with CCM. Univariate and multivariate statistical analyses were utilized to identify differential metabolites. Subsequently, correlation analyses and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted on the identified differential metabolites.
RESULTS: We identified seven distinct metabolites in individuals with T2D (p < 0.05). Notably, cyclic 3\',5\'-Adenosine MonoPhosphate (AMP), Glucose 6-phosphate, L-lactic acid, Maleic acid, and Malic acid exhibited a reversal to normal levels following metformin treatment. Furthermore, Malic acid demonstrated a positive correlation with L-lactic acid (r = 0.94, p < 0.05), as did succinic acid with malic acid (r = 0.81, p < 0.05), L-lactic acid with succinic acid (r = 0.78, p < 0.05), and L-lactic acid with glucose-6-phosphate (r = 0.72, p < 0.05). These metabolites were notably enriched in pyruvate metabolism (p = 0.005), tricarboxylic acid cycle (TCA) (p = 0.007), propanoate metabolism (p = 0.007), and glycolysis or gluconeogenesis (p = 0.009), respectively.
CONCLUSIONS: We employed HPIC-MS/MS to uncover alterations in CCM among individuals recently diagnosed with T2D before and after metformin treatment. The findings suggest that metformin may ameliorate the energy metabolism imbalance in T2D by reducing intermediates within the CCM pathway.