Liu Jieying, Xie Ziyan, Fu Junling, Yu Miao, Wang Tong, Qi Cuijuan, Liu Peng, Hui Xiangyi, Wang Dongmei, Ding Lu, Zhang Qian, Xie Ting, Xiao Xinhua
China Key Laboratory of Endocrinology of National Health Commission, Diabetes Research Center of Chinese Academy of Medical Sciences, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Wangfujing Street, Dongcheng District, Beijing, 100730, P. R. China.
Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China.
Diabetol Metab Syndr. 2023 Oct 24;15(1):206. doi: 10.1186/s13098-023-01175-x.
Maturity-onset diabetes of the young type 2 (MODY2) is a rare genetic disorder characterized as mild fasting hyperglycemia with low risk of vascular complications caused by glucokinase gene mutation. This study aims to investigate metabolites alteration associated with MODY2, exploring possible mechanism underlying characteristic clinical manifestations and low cardiovascular risks of MODY2 and providing serum metabolite biomarkers to facilitating MODY2 diagnosis.
Fasting serum samples from MODY2, type 1 diabetes (T1DM) and healthy individuals were collected. By using targeted metabolomics via liquid chromatography-tandem mass spectrometry platform, we quantified the metabolites involved in tricarboxylic acid (TCA) cycle and one-carbon metabolism.
Metabolomic profiling revealed significant difference of intermediates from central metabolism cycle, methionine cycle and several amino acids between MODY2 and T1DM groups. Among these, serum citrate, α-ketoglutaric acid, serine, glycine, glutamine and homocysteine were significantly elevated in MODY2 patients compared with T1DM patients; and compared with healthy subjects, malate and methionine levels were significantly increased in the two groups of diabetic patients. The correlation analysis with clinical indexes showed that α- ketoglutarate, serine, glycine, and glutamine were negatively correlated with blood glucose indicators including fasting blood glucose, HbA1c, and GA, while citrate was positively correlated with C-peptide. And homocysteine displayed positive correlation with HDL and negative with C-reactive protein, which shed light on the mechanism of mild symptoms and low risk of cardiovascular complications in MODY2 patients. A panel of 4 metabolites differentiated MODY2 from T1DM with AUC of 0.924, and a combination of clinical indices and metabolite also gained good diagnostic value with AUC 0.948.
In this research, we characterized the metabolite profiles of TCA cycle and one-carbon metabolism in MODY2 and T1DM and identified promising diagnostic biomarkers for MODY2. This study may provide novel insights into the pathogenesis and clinical manifestations of MODY2.
青年发病的成年型糖尿病2型（MODY2）是一种罕见的遗传性疾病，其特征为轻度空腹高血糖，由葡萄糖激酶基因突变导致血管并发症风险较低。本研究旨在调查与MODY2相关的代谢物改变，探索MODY2特征性临床表现及低心血管风险的潜在机制，并提供血清代谢物生物标志物以促进MODY2的诊断。
收集MODY2患者、1型糖尿病（T1DM）患者和健康个体的空腹血清样本。通过液相色谱 - 串联质谱平台进行靶向代谢组学分析，我们对参与三羧酸（TCA）循环和一碳代谢的代谢物进行了定量。
代谢组学分析显示，MODY2组和T1DM组在中心代谢循环、蛋氨酸循环的中间产物以及几种氨基酸方面存在显著差异。其中，与T1DM患者相比，MODY2患者血清中的柠檬酸、α - 酮戊二酸、丝氨酸、甘氨酸、谷氨酰胺和同型半胱氨酸显著升高；与健康受试者相比，两组糖尿病患者的苹果酸和蛋氨酸水平均显著升高。与临床指标的相关性分析表明，α - 酮戊二酸、丝氨酸、甘氨酸和谷氨酰胺与包括空腹血糖、糖化血红蛋白（HbA1c）和糖化白蛋白（GA）在内的血糖指标呈负相关，而柠檬酸与C肽呈正相关。同型半胱氨酸与高密度脂蛋白（HDL）呈正相关，与C反应蛋白呈负相关，这为MODY2患者症状较轻及心血管并发症风险较低的机制提供了线索。一组4种代谢物可将MODY2与T1DM区分开来，曲线下面积（AUC）为0.924，临床指标与代谢物的组合也具有良好的诊断价值，AUC为0.948。
在本研究中，我们描绘了MODY2和T1DM中TCA循环和一碳代谢的代谢物谱，并确定了有前景的MODY2诊断生物标志物。本研究可能为MODY2的发病机制和临床表现提供新的见解。
