Morphological and functional adaptation of pancreatic islet blood vessels to insulin resistance is impaired in diabetic db/db mice
Morphological and functional adaptation of pancreatic islet blood vessels to insulin resistance is impaired in diabetic db/db mice
复制标题
糖尿病 db/db 小鼠胰岛血管对胰岛素抵抗的形态和功能适应受损
DOI：
10.1016/j.bbadis.2022.166339
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Takeu
中科院分区：
文献类型：
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作者：
Okajima Yuka;Matsuzaka Takashi;Miyazaki Shun;Motomura Kaori;Ohno Hiroshi;Sharma Rahul;Shimura Takuya;Istiqamah Nurani;Han Song-iee;Mizunoe Yuhei;Osaki Yoshinori;Iwasaki Hitoshi;Yatoh Shigeru;Suzuki Hiroaki;Sone Hirohito;Miyamoto Takafumi;Aita Yuichi;Takeu
胰岛血管系统对于β细胞对肥胖相关胰岛素抵抗的反应至关重要。为了探讨胰岛血管改变在2型糖尿病发病机制中的作用，我们评估了两种胰岛素抵抗模型：ob/ob小鼠，其维持大β细胞质量和高胰岛素血症，以及db/db小鼠，其由于继发性β细胞补偿胰岛素分泌失败而进展为糖尿病。用番茄凝集素染色和活体成像研究胰岛血管和血流的时间依赖性变化。b/ob小鼠胰岛毛细血管扩张明显，而b/db小鼠胰岛毛细血管扩张的适应性改变减弱。胰岛血流量在ob/ob小鼠中增加，而在db/db小鼠中减少。总的和磷酸化的内皮型一氧化氮合酶（eNOS）在Ser 1177的蛋白浓度增加inob/obislets，而他们减少indb/db小鼠，表明eNOS活性下降。这伴随着晚期糖基化终产物在血管中的滞留增加。Elov 16缺乏对糖尿病的改善涉及毛细血管扩张、血流和内皮型一氧化氮合酶磷酸化的恢复。我们的研究结果表明，由于内皮功能障碍导致的胰岛毛细血管扩张障碍损害了局部胰岛血流，这可能在β细胞功能丧失中发挥作用，并进一步加重2型糖尿病。
The pancreatic islet vasculature is of fundamental importance to the β-cell response to obesity-associated insulin resistance. To explore islet vascular alterations in the pathogenesis of type 2 diabetes, we evaluated two insulin resistance models:ob/obmice, which sustain large β-cell mass and hyperinsulinemia, anddb/dbmice, which progress to diabetes due to secondary β-cell compensation failure for insulin secretion. Time-dependent changes in islet vasculature and blood flow were investigated using tomato lectin staining andin vivolive imaging. Marked islet capillary dilation was observed inob/obmice, but this adaptive change was blunted indb/dbmice. Islet blood flow volume was augmented inob/obmice, whereas it was reduced indb/dbmice. The protein concentrations of total and phosphorylated endothelial nitric oxide synthase (eNOS) at Ser1177 were increased inob/obislets, while they were diminished indb/dbmice, indicating decreased eNOS activity. This was accompanied by an increased retention of advanced glycation end-products indb/dbblood vessels. Amelioration of diabetes byElovl6deficiency involved a restoration of capillary dilation, blood flow, and eNOS phosphorylation indb/dbislets. Our findings suggest that the disability of islet capillary dilation due to endothelial dysfunction impairs local islet blood flow, which may play a role in the loss of β-cell function and further exacerbate type 2 diabetes.