PXBioVisioN GmbH, Feodor-Lynen-Straße 31, 30625, Hannover, Germany.
Department of Pediatrics, University Marburg, Marburg, Germany.
Sci Rep. 2023 Jan 12;13(1):601. doi: 10.1038/s41598-023-27648-7.
Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor used for the treatment of type 2 diabetes, with additional beneficial effects for the kidney. Treatment of mice with linagliptin revealed increased storage of cobalamin (Cbl, Vitamin B12) in organs if a standard Cbl diet (30 µg Cbl/kg chow) is given. In order to translate these findings to humans, we determined methylmalonic acid (MMA), a surrogate marker of functional Cbl homeostasis, in human plasma and urine samples (n = 1092) from baseline and end of trial (6 months after baseline) of the previously completed MARLINA-T2D clinical trial. We found that individuals with medium Cbl levels (MMA between 50 and 270 nmol/L for plasma, 0.4 and 3.5 µmol/mmol creatinine for urine, at baseline and end of trial) exhibited higher MMA values at the end of study in placebo compared with linagliptin. Linagliptin might inhibit the N-terminal degradation of the transcobalamin receptor CD320, which is necessary for uptake of Cbl into endothelial cells. Because we demonstrate that linagliptin led to increased organ levels of Cbl in mice, sustained constant medium MMA levels in humans, and inhibited CD320 processing by DPP-4 in-vitro, we speculate that linagliptin promotes intra-cellular uptake of Cbl by prolonging half-life of CD320.
利拉利汀是一种二肽基肽酶-4（DPP-4）抑制剂，用于治疗 2 型糖尿病，对肾脏有额外的有益作用。用利拉利汀治疗小鼠，如果给予标准钴胺素（Cbl，维生素 B12）饮食（30μg Cbl/kg 饲料），则会导致器官中钴胺素的储存增加。为了将这些发现转化为人类，我们在之前完成的 MARLINA-T2D 临床试验的基线和试验结束时（基线后 6 个月），从 1092 名人类血浆和尿液样本（n = 1092）中测定了甲基丙二酸（MMA），这是功能性 Cbl 体内平衡的替代标志物。我们发现，在基线和试验结束时（基线后 6 个月），中 Cbl 水平（血浆中 MMA 为 50-270nmol/L，尿液中 0.4-3.5µmol/mmol 肌酐）的个体，在安慰剂组中，与利拉利汀相比，在研究结束时 MMA 值更高。利拉利汀可能抑制转钴胺素受体 CD320 的 N 端降解，这是内皮细胞摄取 Cbl 所必需的。因为我们证明利拉利汀导致小鼠的 Cbl 器官水平增加，在人类中保持持续的中等 MMA 水平，并且在体外抑制 DPP-4 对 CD320 的加工，所以我们推测利拉利汀通过延长 CD320 的半衰期来促进 Cbl 的细胞内摄取。
