与安慰剂相比，利拉利汀可改善接受二甲双胍和/或胰岛素治疗的 2 型糖尿病合并慢性肾脏病患者的 CD34+ve 内皮祖细胞：一项随机对照试验。

Linagliptin, when compared to placebo, improves CD34+ve endothelial progenitor cells in type 2 diabetes subjects with chronic kidney disease taking metformin and/or insulin: a randomized controlled trial.

机构信息

The GW Medical Faculty Associates, 2300 M Street NW, Washington, DC, 20037, USA.

Department of Medicine, The George Washington University, 2300 I St NW, SMHS Room 462, Washington, DC, 20052, USA.

出版信息

Cardiovasc Diabetol. 2020 Jun 3;19(1):72. doi: 10.1186/s12933-020-01046-z.

BACKGROUND

Endothelial Progenitor cells (EPCs) has been shown to be dysfunctional in both type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) leading to poor regeneration of endothelium and renal perfusion. EPCs have been shown to be a robust cardiovascular disease (CVD) risk indicator. Cellular mechanisms of DPP4 inhibitors such as linagliptin (LG) on CVD risk, in patients with T2DM with established CKD has not been established. Linagliptin, a DPP4 inhibitor when added to insulin, metformin or both may improve endothelial dysfunction in a diabetic kidney disease (DKD) population.

METHODS

31 subjects taking metformin and/or Insulin were enrolled in this 12 weeks, double blind, randomized placebo matched trial, with 5 mg LG compared to placebo. Type 2 diabetes subjects (30-70 years old), HbA1c of 6.5-10%, CKD Stage 1-3 were included. CD34+ cell number, migratory function, gene expression along with vascular parameters such as arterial stiffness, biochemistry, resting energy expenditure and body composition were measured. Data were collected at week 0, 6 and 12. A mixed model regression analysis was done with p value < 0.05 considered significant.

RESULTS

A double positive CD34/CD184 cell count had a statistically significant increase (p < 0.02) as determined by flow cytometry in LG group where CD184 is SDF1a cell surface receptor. Though mRNA differences in CD34+ve was more pronounced CD34- cell mRNA analysis showed increase in antioxidants (superoxide dismutase 2 or SOD2, Catalase and Glutathione Peroxidase or GPX) and prominent endothelial markers (PECAM1, VEGF-A, vWF and NOS3). Arterial stiffness measures such as augmentation Index (AI) (p < 0.04) and pulse wave analysis (PWV) were improved (reduced in stiffness) in LG group. A reduction in LDL: HDL ratio was noted in treatment group (p < 0.04). Urinary exosome protein examining podocyte health (podocalyxin, Wilms tumor and nephrin) showed reduction or improvement.

CONCLUSIONS

In DKD subjects, Linagliptin promotes an increase in CXCR4 expression on CD34 + progenitor cells with a concomitant improvement in vascular and renal parameters at 12 weeks. Trial Registration Number NCT02467478 Date of Registration: 06/08/2015.

背景

内皮祖细胞（EPCs）在 2 型糖尿病（T2DM）和慢性肾脏病（CKD）中功能失调，导致内皮细胞和肾脏灌注不良。EPCs 已被证明是心血管疾病（CVD）的一个强有力的风险指标。西格列汀（LG）等 DPP4 抑制剂的细胞机制对 T2DM 合并 CKD 患者的 CVD 风险尚未确定。当添加到胰岛素、二甲双胍或两者中时，DPP4 抑制剂利格列汀（LG）可能会改善糖尿病肾病（DKD）人群的内皮功能障碍。

方法

31 名服用二甲双胍和/或胰岛素的受试者参加了这项为期 12 周的双盲、随机安慰剂对照试验，将 5mg LG 与安慰剂进行比较。纳入 2 型糖尿病患者（30-70 岁），HbA1c 为 6.5-10%，CKD 1-3 期。测量 CD34+细胞数量、迁移功能、基因表达以及血管参数，如动脉僵硬、生化指标、静息能量消耗和身体成分。数据在 0、6 和 12 周收集。采用混合模型回归分析，p 值<0.05 为差异有统计学意义。

结果

通过流式细胞术检测，LG 组 CD34/CD184 双阳性细胞计数有统计学意义的增加（p<0.02），CD184 是 SDF1a 细胞表面受体。虽然 CD34+ve 的 mRNA 差异更为明显，但 CD34-细胞的 mRNA 分析显示抗氧化剂（超氧化物歧化酶 2 或 SOD2、过氧化氢酶和谷胱甘肽过氧化物酶或 GPX）和突出的内皮标志物（PECAM1、VEGF-A、vWF 和 NOS3）增加。LG 组的动脉僵硬指标如增强指数（AI）（p<0.04）和脉搏波分析（PWV）得到改善（僵硬度降低）。治疗组 LDL：HDL 比值降低（p<0.04）。尿外泌体蛋白检查足细胞健康（足细胞蛋白、Wilms 肿瘤和肾钙素）显示减少或改善。