Rouintan Z, Farrokhfall K, Karbalaei N, Ghasemi A
Department of Physiology, Faculty of Medicine; Shahid Beheshti University of Medical Sciences, International Branch, Tehran, Iran.
Department of Physiology and Pharmacology, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran.
Horm Metab Res. 2016 Feb;48(2):145-50. doi: 10.1055/s-0035-1555807. Epub 2015 Sep 8.
Thyroid hormones have developmental effects during fetal life. Fetal hypothyroidism leads to glucose intolerance and reduced insulin secretion capacity. Activity of nitric oxide synthases follows a heterogeneous pattern in hypothyroidism. Overactivity of constitutive nitric oxide synthase (NOS), inhibits glucose-stimulated insulin release. The aim of this study was to examine if reduction in insulin secretion in fetal hypothyroidism is due to overproduction of nitric oxide. Pregnant Wistar rats were divided into 2 groups; the experimental group consumed water containing 0.02% of 6-propyl-2-thiouracil till delivery, while the control group consumed tap water. After delivery serum thyroid hormones were measured. Intravenous glucose tolerance test was performed in 6-month old offspring (n=8). After 3 weeks recovery, pancreatic islets were isolated and insulin secretion, inducible and constitutive nitric oxide synthase activity were measured (n=4). Compared to controls, during intravenous glucose tolerance test, fetal hypothyroid rats had high plasma glucose concentration (p=0.003) and low plasma insulin levels (p=0.012) at 5-20 min and their insulin secretion from isolated islets at basal glucose concentration and in the presence of l-arginine was lower. The nitric oxide synthase inhibitor, NG-nitro-l-arginine methyl ester significantly improved insulin secretion in fetal hypothyroid rats at basal glucose concentration and in the presence of l-arginine. The results showed higher NOS activities in fetal hypothyroid rats (constitutive 17.60±1.09 vs. 47.34±4.44 and inducible 4.09±0.96 vs. 19.97±1.14 pmol/min/mg proteins, p=0.002). In conclusion, NO overproduction through NOS participates in decreased insulin secretion in fetal hypothyroid rats.
甲状腺激素在胎儿期具有发育效应。胎儿甲状腺功能减退会导致葡萄糖不耐受和胰岛素分泌能力降低。一氧化氮合酶的活性在甲状腺功能减退时呈现异质性模式。组成型一氧化氮合酶（NOS）活性过高会抑制葡萄糖刺激的胰岛素释放。本研究的目的是探讨胎儿甲状腺功能减退时胰岛素分泌减少是否是由于一氧化氮产生过多所致。将怀孕的Wistar大鼠分为两组；实验组在分娩前饮用含0.02% 6-丙基-2-硫脲嘧啶的水，而对照组饮用自来水。分娩后测定血清甲状腺激素。对6月龄后代（n = 8）进行静脉葡萄糖耐量试验。恢复3周后，分离胰岛并测定胰岛素分泌、诱导型和组成型一氧化氮合酶活性（n = 4）。与对照组相比，在静脉葡萄糖耐量试验期间，胎儿甲状腺功能减退大鼠在5 - 20分钟时血浆葡萄糖浓度较高（p = 0.003），血浆胰岛素水平较低（p = 0.012），并且其在基础葡萄糖浓度和存在L-精氨酸时分离胰岛的胰岛素分泌较低。一氧化氮合酶抑制剂NG-硝基-L-精氨酸甲酯在基础葡萄糖浓度和存在L-精氨酸时显著改善了胎儿甲状腺功能减退大鼠的胰岛素分泌。结果显示胎儿甲状腺功能减退大鼠的NOS活性较高（组成型17.60±1.09对47.34±4.44，诱导型4.09±0.96对19.97±1.14 pmol/min/mg蛋白质，p = 0.002）。总之，通过NOS产生的NO过多参与了胎儿甲状腺功能减退大鼠胰岛素分泌的减少。
