Differences in endothelial function between patients with Type 1 and Type 2 diabetes: effects of red blood cells and arginase

Abstract

The mechanisms underlying endothelial dysfunction in Type 1 and Type 2 diabetes (T1DM and T2DM) are unresolved. The red blood cells (RBCs) with increased arginase activity induce endothelial dysfunction in T2DM, but the implications of RBCs and the role of arginase inhibition in T1DM are unexplored. We aimed to investigate the differences in endothelial function in patients with T1DM and T2DM, with focus on RBCs and arginase. Thirteen patients with T1DM and twenty-six patients with T2DM, matched for HbA1c and sex were included. In vivo endothelium-dependent and -independent vasodilation (EDV and EIDV) were assessed by venous occlusion plethysmography before and after administration of an arginase inhibitor. RBCs were co-incubated with rat aortic segments for 18h followed by evaluation of endothelium-dependent (EDR) and -independent relaxation (EIDR) in isolated organ chambers. In vivo EDV, but not EIDV, was significantly impaired in patients with T2DM compared with patients with T1DM. Arginase inhibition resulted in improved EDV only in T2DM. RBCs from patients with T2DM induced impaired EDR but not EIDR in isolated aortic segments, whereas RBCs from patients with T1DM did not affect EDR nor EIDR. The present study demonstrates markedly impaired EDV in patients with T2DM in comparison with T1DM. In addition, it highlights the divergent roles of RBCs and arginase in mediating endothelial dysfunction in T1DM and T2DM. While endothelial dysfunction is mediated via RBCs and arginase in T2DM, these phenomena are not prominent in T1DM thereby indicating distinct differences in underlying mechanisms.

Keywords: arginase; diabetes mellitus; endothelial dysfunction; red blood cells.

Figure 1. Patients with T2DM have impaired endothelial function compared with patients with T1DM

Change in forearm blood flow as measures of endothelium-dependent (A) and -independent (B) vasodilatation induced by intra-arterial infusion of serotonin and sodium nitroprusside (SNP), respectively, in patients with T1DM (n=12) and T2DM (n=12). Data are presented as mean ± SEM. Statistical differences were analyzed with two-way ANOVA with repeated measures. *P<0.05 comparing the entire curves.

Figure 2. Arginase inhibition improves endothelium-dependent function in patients with T2DM but not T1DM

Change in forearm blood flow as measures of endothelium-dependent vasodilatation induced by intra-arterial infusion of serotonin in patients with T1DM (A; n=12) and T2DM (B; n=12), respectively, at baseline during infusion of NaCl and after 2 h intra-arterial infusion of the arginase inhibitor nor-NOHA. Data are presented as mean ± SEM. Statistical differences were analyzed with two-way ANOVA with repeated measures. *P<0.05 comparing the entire curves.

Figure 3. Arginase inhibition improves endothelium-independent function in patients with T1DM but not T2DM

Change in forearm blood flow as measures of endothelium-independent vasodilatation induced by intra-arterial infusion of SNP in patients with T1DM (A; n=12) and T2DM (B; n=12), respectively, at baseline during infusion of NaCl and after 2 h intra-arterial infusion of the arginase inhibitor nor-NOHA. Data are presented as mean ± SEM. Statistical differences were analyzed with two-way ANOVA with repeated measures. *P<0.05 comparing the entire curves.

Figure 4. RBCs from patients with T2DM induces endothelium dependent impairment compared with RBC from patients with T1DM

Endothelium-dependent relaxation (A) and endothelium-independent relaxation (B) induced by acetylcholine (ACh) and sodium nitroprusside (SNP), respectively, in isolated rat aortas after 18 h incubation with either RBCs from patients with T1DM (T1DM RBC; A; n=8, B; n=8) or T2DM (T2DM RBC; A; n=12, B; n=7) or KH buffer (KH; n=18) as control. Data are presented as mean ± SEM. *P<0.05, ***P<0.001 comparing the entire curves using two-way ANOVA with repeated measures (A) and Mann–Whitney U test (B).