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Impaired microvascular insulin-dependent dilation in women with a history of gestational diabetes
Journal article   Peer reviewed

Impaired microvascular insulin-dependent dilation in women with a history of gestational diabetes

Kelsey S Schwartz, Paola V Hernandez, Grace S Maurer, Elizabeth M Wetzel, Mingyao Sun, Diana I Jalal and Anna E Stanhewicz
American journal of physiology. Heart and circulatory physiology, Vol.327(4), pp.H793-H803
07/26/2024
DOI: 10.1152/ajpheart.00223.2024
PMCID: PMC11482287
PMID: 39058435
url
https://pmc.ncbi.nlm.nih.gov/articles/PMC11482287/View
Open Access

Abstract

Women with a history of gestational diabetes mellitus (GDM) have significantly greater lifetime risk of developing cardiovascular disease and type 2 diabetes compared to 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 measurement of cutaneous vascular conductance responses to graded infusion of acetylcholine (10-10 - 10-1M) and insulin (10-8 - 10-4M) in control sites and sites treated with 15mM L-NAME [NG-nitro-l-arginine methyl ester; NO-synthase (NOS) inhibitor] or 5mM 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- (P<0.001) and insulin- (P<0.001) mediated dilation and the NO-dependent responses to both acetylcholine (P=0.006) and insulin (P=0.006) were reduced in GDM compared to HC. Insulin stimulation increased phosphorylated eNOS content in HC (P=0.009) but had no effect in GDM (P=0.306). Ascorbate treatment increased acetylcholine- (P<0.001) and insulin- (P<0.001) mediated dilation in GDM, and endothelial cell nitrotyrosine expression was higher in GDM compared to HC (P=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 implicate increased endothelial oxidative stress in this microvascular insulin resistance.Women with a history of gestational diabetes mellitus (GDM) have significantly greater lifetime risk of developing cardiovascular disease and type 2 diabetes compared to 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 measurement of cutaneous vascular conductance responses to graded infusion of acetylcholine (10-10 - 10-1M) and insulin (10-8 - 10-4M) in control sites and sites treated with 15mM L-NAME [NG-nitro-l-arginine methyl ester; NO-synthase (NOS) inhibitor] or 5mM 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- (P<0.001) and insulin- (P<0.001) mediated dilation and the NO-dependent responses to both acetylcholine (P=0.006) and insulin (P=0.006) were reduced in GDM compared to HC. Insulin stimulation increased phosphorylated eNOS content in HC (P=0.009) but had no effect in GDM (P=0.306). Ascorbate treatment increased acetylcholine- (P<0.001) and insulin- (P<0.001) mediated dilation in GDM, and endothelial cell nitrotyrosine expression was higher in GDM compared to HC (P=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 implicate increased endothelial oxidative stress in this microvascular insulin resistance.
 endothelial function gestational diabetes insulin resistance microvascular nitric oxide

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