Thesis
Role of oxidative stress in attenuated insulin-mediated microvascular responses in women with a history of gestational diabetes
University of Iowa
Master of Science (MS), University of Iowa
Spring 2023
DOI: 10.25820/etd.007046
Abstract
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;<0.001) compared to HC at the control site. L-NAME attenuated insulin-mediated dilation in HC (13.3 ± 5.4 %CVCmax, p<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>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>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>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.
Details
- Title: Subtitle
- Role of oxidative stress in attenuated insulin-mediated microvascular responses in women with a history of gestational diabetes
- Creators
- Paola Hernandez
- Contributors
- Anna Stanhewicz (Advisor)Erin Talbert (Committee Member)Nathaniel Jenkins (Committee Member)
- Resource Type
- Thesis
- Degree Awarded
- Master of Science (MS), University of Iowa
- Degree in
- Health and Human Physiology
- Date degree season
- Spring 2023
- DOI
- 10.25820/etd.007046
- Publisher
- University of Iowa
- Number of pages
- vii, 51, 1 pages
- Copyright
- Copyright 2023 Paola Hernandez
- Language
- English
- Date submitted
- 04/24/2023
- Date approved
- 05/03/2023
- Description illustrations
- illustrations, tables, graphs, forms
- Description bibliographic
- Includes bibliographical references (pages 24-29).
- Public Abstract (ETD)
- The symptoms associated with having gestational diabetes mellitus (GDM) during pregnancy resolve post- partum. However, women with a history of gestational diabetes are at an increased risk of developing cardiovascular disease (CVC) and Type II diabetes despite their recovery from gestational diabetes [18] [28]. While the association between GDM history and lifetime CVD and diabetes risk is known, the underlying cause of this association is not clear. Women with a history of GDM have microvascular dysfunction, leading to a decreased ability of the smallest blood vessels to respond to some stimuli. Whether this decreased microvessel function extends to insulin-mediated responses is unknown. Insulin causes vasodilation and plays a role in its own delivery to the tissue in part through capillary recruitment, for glucose uptake, and reductions in microvessel responses to insulin contribute to the development of CVD and diabetes. In this study, we examined insulin signaling in the microvasculature of women with a history of GDM. We found that compared to controls, women with a history of GDM have reduced insulin-mediated dilation and capillary recruitment in the microvessels, and that this reduced function in mediated in part by increased oxidative stress. These data suggest that in spite of the fact that gestational diabetes resolves after pregnancy, continued microvascular dysfunction may contribute to the increased lifetime risk of CVD and diabetes in women with a history of GDM.
- Academic Unit
- Health, Sport, and Human Physiology
- Record Identifier
- 9984437257902771
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