Department of Health and Human Physiology, The University of Iowa, Iowa City, Iowa, United States.
Department of Internal Medicine, Carver College of Medicine, Iowa City, Iowa, United States.
Am J Physiol Heart Circ Physiol. 2024 Oct 1;327(4):H793-H803. doi: 10.1152/ajpheart.00223.2024. Epub 2024 Jul 26.
Women with a history of gestational diabetes mellitus (GDM) have a significantly greater lifetime risk of developing cardiovascular disease and type 2 diabetes compared with women who had an uncomplicated pregnancy (HC). Microvascular endothelial dysfunction, mediated via reduced nitric oxide (NO)-dependent dilation secondary to increases in oxidative stress, persists after pregnancy complicated by GDM. We examined whether this microvascular dysfunction reduces insulin-mediated vascular responses in women with a history of GDM. We assessed in vivo microvascular endothelium-dependent vasodilator function by measuring cutaneous vascular conductance responses to graded infusions of acetylcholine (10-10 M) and insulin (10-10 M) in control sites and sites treated with 15 mM l-NAME [-nitro-l-arginine methyl ester; NO-synthase (NOS) inhibitor] or 5 mM l-ascorbate. We also measured protein expression of total endothelial NOS (eNOS), insulin-mediated eNOS phosphorylation, and endothelial nitrotyrosine in isolated endothelial cells from GDM and HC. Women with a history of GDM had reduced acetylcholine ( < 0.001)- and insulin ( < 0.001)-mediated dilation, and the NO-dependent responses to both acetylcholine ( = 0.006) and insulin ( = 0.006) were reduced in GDM compared with HC. Insulin stimulation increased phosphorylated eNOS content in HC ( = 0.009) but had no effect in GDM ( = 0.306). Ascorbate treatment increased acetylcholine ( < 0.001)- and insulin ( < 0.001)-mediated dilation in GDM, and endothelial cell nitrotyrosine expression was higher in GDM compared with HC ( = 0.014). Women with a history of GDM have attenuated microvascular vasodilation responses to insulin, and this attenuation is mediated, in part, by reduced NO-dependent mechanisms. Our findings further implicate increased endothelial oxidative stress in this microvascular insulin resistance. Women who have gestational diabetes during pregnancy are at a greater risk for cardiovascular disease and type 2 diabetes in the decade following pregnancy. The mechanisms mediating this increased risk are unclear. Herein, we demonstrate that insulin-dependent microvascular responses are reduced in women who had gestational diabetes, despite the remission of glucose intolerance. This reduced microvascular sensitivity to insulin may contribute to increased cardiovascular disease and type 2 diabetes risk in these women.
患有妊娠糖尿病（GDM）病史的女性与无并发症妊娠（HC）的女性相比，终生患心血管疾病和 2 型糖尿病的风险显著增加。微血管内皮功能障碍通过氧化应激增加导致的一氧化氮（NO）依赖性扩张减少而持续存在于 GDM 合并妊娠后。我们研究了这种微血管功能障碍是否会降低患有 GDM 病史的女性的胰岛素介导的血管反应。我们通过测量乙酰胆碱（10-10 M）和胰岛素（10-10 M）分级输注时控制部位和用 15 mM l-NAME [-硝基-l-精氨酸甲酯；NOS（NOS）抑制剂]或 5 mM l-抗坏血酸处理部位的皮肤血管传导率反应来评估体内微血管内皮依赖性血管舒张功能。我们还测量了来自 GDM 和 HC 的分离内皮细胞中总内皮 NOS（eNOS）、胰岛素介导的 eNOS 磷酸化和内皮硝基酪氨酸的蛋白表达。患有 GDM 病史的女性乙酰胆碱（<0.001）和胰岛素（<0.001）介导的扩张减少，并且与 HC 相比，GDM 中乙酰胆碱（=0.006）和胰岛素（=0.006）的 NO 依赖性反应均减少。胰岛素刺激增加了 HC 中磷酸化 eNOS 含量（=0.009），但对 GDM 没有影响（=0.306）。抗坏血酸处理增加了 GDM 中乙酰胆碱（<0.001）和胰岛素（<0.001）介导的扩张，并且 GDM 中内皮细胞硝基酪氨酸的表达高于 HC（=0.014）。患有 GDM 病史的女性对胰岛素的微血管血管舒张反应减弱，这种减弱部分是由减少的 NO 依赖性机制介导的。我们的发现进一步表明，内皮氧化应激增加与这种微血管胰岛素抵抗有关。在怀孕期间患有妊娠糖尿病的女性在怀孕后十年内患心血管疾病和 2 型糖尿病的风险增加。介导这种风险增加的机制尚不清楚。在此，我们证明尽管葡萄糖耐量恢复正常，但患有妊娠糖尿病的女性胰岛素依赖性微血管反应减弱。这种对胰岛素的微血管敏感性降低可能导致这些女性心血管疾病和 2 型糖尿病风险增加。
