Glucokinase-maturity onset diabetes of the young (GCK-MODY) represents a rare genetic disorder due to mutation in the glucokinase (GCK) gene. The low incidence of vascular complications in GCK-MODY makes it a natural paradigm for interrogating molecular mechanisms promoting vascular health under prolonged hyperglycemia. Clinical rate of misdiagnosis has remained high, and a reliable serum lipid biomarker that precedes genetic screening can facilitate correct diagnosis and treatment. Herein, we comprehensively quantitated 565 serum lipids from 25 classes in 105 subjects (42 nondiabetic controls, 30 GC K-MODY patients, 33 drug-naïve, and newly-onset T2D patients). At false-discovery rate (FDR) < 0.05, several phosphatidylcholines (PCs) and plasmalogen PCs were specifically increased in GCK-MODY, while triacylglycerols (TAGs) and diacylglycerols (DAGs) were reduced. Correlation matrices between lipids uncovered coregulation between plasmalogen PCs (PCps) and glycerolipid precursors was distinctly enhanced in GCK-MODY compared to T2D. Strengthened positive correlations between serum PCps and circulating HDLs was specifically observed in hyperglycemic subjects (i.e. T2D and GCK-MODY) compared to normglycemic controls, suggesting that HDL-PCps may elicit distinct physiological effects under hyperglycemia. Amongst GCK-MODY patients, individuals harboring variants of GCK mutations with elevated PCps also exhibited higher HDLs. Isolated HDLs displayed localized increases (p < 0.05) in very-long-chain PUFA-PCs and PCps in GCK-MODY. Protein analyses revealed elevated levels of HDL-resident ATGL (P = 0.003) and CEPT1 (P < 0.0001), which mediate critical steps of PCps production along the TAG-DAG-PC axis, in GCK-MODY relative to T2D. A panel of four lipids differentiated GCK-MODY from T2D with AUC of 0.950 (95% CI 0.903–9.997). This study provides the first evidence that enhanced recruitment of CEPT1 and ATGL onto HDLs essentially underlie the atheroprotective profiles associated with GCK-MODY. Resultant increases in the production of HDL-PCps and PUFA-PCs provides an active, circulating form of protection towards the vasculature of GCK-MODY, thereby lowering the incidence of vascular complications despite chronic exposure to hyperglycemia since birth.

年轻人的葡萄糖激酶成熟型糖尿病（GCK-MODY）由于葡萄糖激酶（GCK）基因。GCK-MODY中血管并发症的低发生率使其成为询问长期血糖过高时促进血管健康的分子机制的自然范例。临床误诊率一直很高，在基因筛查之前可靠的血清脂质生物标志物可以促进正确的诊断和治疗。在本文中，我们对105位受试者（42位非糖尿病对照，30位GC K-MODY患者，33位单纯药物和新发T2D患者）的25个类别的565种血脂进行了全面定量。在假发现率（FDR）<0.05时，GCK-MODY中特异性增加了数种磷脂酰胆碱（PCs）和缩醛磷脂PC，而三酰甘油（TAGs）和二酰甘油（DAGs）降低了。与T2D相比，在GCK-MODY中，未发现缩醛磷脂PC（PCps）和甘油脂前体之间的共调节的脂质之间的相关矩阵显着增强。与正常血糖对照组相比，在高血糖受试者（即T2D和GCK-MODY）中特别观察到血清PCps与循环HDL之间增强的正相关性，表明HDL-PCps可能在高血糖症下引起独特的生理效应。在GCK-MODY患者中，具有GCKPCps升高的突变也表现出更高的HDL。单独的HDL在非常长链的PUFA-PC和GCK-MODY中的PCps中显示局部增加（p <0.05）。蛋白质分析显示，相对于T2D，GCK-MODY中居于HDL的ATGL（P = 0.003）和CEPT1（P <0.0001）的水平升高，这介导了沿TAG-DAG-PC轴的PCps产生的关键步骤。一组四个脂质将GCK-MODY与T2D区别开来，AUC为0.950（95％CI 0.903-9.997）。这项研究提供了第一个证据，证明CEPT1和ATGL在HDL上的增强募集基本上是与GCK-MODY相关的动脉粥样硬化防护基础。HDL-PCps和PUFA-PC产量的最终增加为GCK-MODY的脉管系统提供了一种活跃的循环保护形式，