Background: Long noncoding RNAs (lncRNAs) are involved in diabetes related diseases. However, the role of lncRNAs in the pathogenesis of type 2 diabetes with macrovascular complication (DMC) has seldomly been recognized. This study aimed to screen lncRNA profiles of leukocytes from DMC patients in order to explore the protective role of lncRNA LYPLAL1-DT in endothelial cells (EC) under high glucose (HG) and inflammatory conditions (IS).Methods: RNA sequencing was performed for critically pair-grouped blood samples of DMC patients and healthy control. Then the differentially expressed (DE) lncRNAs from circulating leukocytes were identified. Real-time PCR analyses were used to select the DE-lncRNAs within expanding cohorts. CCK8, transwell, Western blot, dual-luciferase system, and RIP were used to investigate the influence and molecular mechanisms of validated DE-lncRNAs in EC under HG and IS conditions. RNA sequencing was also used to identify DE-lncRNAs in exosomes isolated from the DMC serum and healthy control. Results: A total of 477 DE-lncRNAs were identified between DMC and healthy control. The enrichment and pathway analysis showed that most of them belonged to inflammatory, metabolic, and vascular diseases. A set of 12 of the 16 lncRNAs was validated as significant DE-lncRNAs in expanding cohorts. Furthermore, these DE-lncRNAs were shown to be significantly related to hypoxia, high glucose, and TNF-α stimulus (IS) in EC with an apparent metabolic memory of high glucose, especially novel lncRNA LYPLAL1-DT. LYPLAL1-DT overexpression results in the promotion of proliferation, migration of EC, as well as an elevation of autophagy under HG, and IS conditions. Overexpressed LYPLAL1-DT reduces the adhesion of monocytes to EC, boosts anti-inflammation, and suppresses inflammatory molecules secreted in the medium. Mechanistically, LYPLAL1-DT acts as ceRNA by downregulating miR-204-5p, therefore enhancing SIRT1 and protecting EC autophagy function; thus, alleviating apoptosis. Finally, exosome sequencing revealed LYPLAL1-DT expression was 4 times lower in DMC cells than in healthy samples. Conclusion: We identified 12 DE-lncRNAs related to DMC. Out of the 12 DE-lncRNAs lncRNA LYPLAL1-DT was identified to have protective effects on EC as ceRNA mediated through the miR-204-5p/SIRT1 pathway. Therefore, it inhibits the autophagy of EC as well as modulating systemic inflammation. This approach could be regarded as a new potential therapeutic target in DMC.