Role of oxidative stress in attenuated insulin-mediated microvascular responses in women with a history of gestational diabetes
Creators: name: Hernandez, Paola
Publisher: name: University of Iowa
Year: 2023
Subjects: public abstract

description: Women with a history of gestational diabetes mellitus (GDM) are at greater risk for cardiovascular disease (CVD) and type II diabetes mellitus (T2DM). Endothelium- and nitric oxide-dependent dilation are attenuated in the microvasculature of otherwise healthy women with a history of GDM and this reduction is mediated, in part, by increased oxidative stress. However, whether this attenuation also reduces insulin-mediated microvascular responses in these women is unknown. We hypothesized that 1) Insulin-mediated vasodilation and capillary recruitment would be attenuated in women with a history of GDM compared to control women with a history of uncomplicated pregnancy (healthy control, HC) 2) attenuated responses in GDM would be mediated by a reduction in NO-dependent dilation, and 3) local antioxidant treatment (L-ascorbate) would increase these responses in women with a history of GDM but not in HC. Twelve HC (35 ± 4) and 10 GDM (34 ± 4) participated in 1 experimental visit. Three microdialysis fibers were placed in the ventral forearm for the local delivery of lactated Ringer’s (control), 15mM N G-nitro-L-arginine methyl ester (L-NAME; NO synthase-inhibition), or 5mM ascorbate (non-specific antioxidant). Following baseline measurements, post-occlusive reactive hyperemia (PORH) was performed with a 5-minute arterial occlusion followed by 10 minutes recovery. Following the PORH, ascending concentrations of insulin [10-8-10-4 M] were added to the perfusates at each microdialysis site. After the insulin dose response, 10-4 M insulin was continually perfused and a second PORH was performed. Finally, maximal vasodilation was achieved at each site (local temperature 43°C + 28mM sodium nitroprusside). Red blood cell flux was measured continuously over each microdialysis site using laser-Doppler flowmetry, and cutaneous vascular conductance was calculated (CVC=flux/MAP) and standardized to maximum (%CVC max). Subjects with GDM had attenuated insulin-mediated vasodilation (GDM:18.2 ± 9.8 vs. HC:32.3 ± 12.2 %CVCmax;&lt;0.001) compared to HC at the control site. L-NAME attenuated insulin-mediated dilation in HC (13.3 ± 5.4 %CVCmax, p&lt;0.001) but not in GDM (11.71 ± 4.1 %CVCmax, p=0.09). Local ascorbate perfusion increased insulin-mediated dilation in GDM (29.2 ± 15.5 %CVCmax; p=0.002) but had no effect in HC (p=0.57). Insulin increased capillary recruitment (PORH area under the curve, AUC) at the Ringer’s site in HC, but not GDM (HC: 8738.1 ± 1556.8 %CVC max, p=0.01; GDM:5873.1 ± 1057.9%CVC max p=0.54). L-NAME perfusion prevented the insulin-mediated increase in AUC in both groups (HC:4155.6 ± 1285.8%CVC max, p=0.99; GDM:3986.9 ±823.4%CVC max, p&gt;0.99). Insulin increased AUC at the ascorbate site in HC but not GDM (HC:9701.0 ± 2396.8%CVC max, p=0.009; GDM:6172.6 ± 2100.7%CVC max, p=0.47). There were no group differences in AUC across microdialysis sites (Ringer’s HC vs GDM: p=0.34; L-NAME HC vs GDM: p&gt;0.99; Ascorbate HC vs GDM: p=0.14). NOS-inhibition (L-NAME) significantly reduced ΔAUC in HC but not GDM (HC: ** p=0.009, GDM: p=0.77). Ascorbate perfusion did not affect ΔAUC in HC or GDM groups (HC: p=0.98; GDM: p&gt;0.99). These data suggest that women with a history of GDM have attenuated microvascular responses to insulin, mediated in part by reduced NO-dependent dilation and increased oxidative stress.