Abstract
BackgroundEndothelial 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.Methods31 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.ResultsA 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.ConclusionsIn 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
Highlights
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
In diabetic kidney disease (DKD) subjects, Linagliptin promotes an increase in C-X-C Motif chemokine receptor 4 (CXCR4) expression on Progenitor marker (CD34) + progenitor cells with a concomitant improvement in vascular and renal parameters at 12 weeks
The flowcytometric analysis of the cell numbers as shown in the Fig. 1a, the number of cells purified from Mononuclear cells (MNCs) did not show any significant difference between the groups, at visit 3, the CD34+ cell number increased from visit 1 to 3 in linagliptin group
Summary
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. Diabetes and chronic kidney disease (CKD) are conditions that are responsible for vascular damage and complications, both micro and macrovascular, including endothelial dysfunction, endothelial cell inflammation, oxidative stress, and cardiovascular pro-thrombotic states [3,4,5]. Endothelial progenitor cells (EPCS, defined here as CD34 + cells) are specialized stem cells responsible for repair of the endothelial cell lining of blood vessels and angiogenesis. These cells can be harvested from peripheral whole blood derived mononuclear cells (MNC) by positive sorting for CD34 peripheral cell surface receptor. Other studies have shown that healthy CD34 + cells can effectively repair damaged endothelial cell lining [11]
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