Pancreatic deletion of the interleukin-1 receptor disrupts whole body glucose homeostasis and promotes islet β-cell de-differentiation.
Pancreatic deletion of the interleukin-1 receptor disrupts whole body glucose homeostasis and promotes islet β-cell de-differentiation.
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DOI：
10.1016/j.molmet.2018.06.003
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发表时间：
2018-08
影响因子：
8.1
通讯作者：
Collier JJ
中科院分区：
文献类型：
--
作者：
Burke SJ;Batdorf HM;Burk DH;Martin TM;Mendoza T;Stadler K;Alami W;Karlstad MD;Robson MJ;Blakely RD;Mynatt RL;Collier JJ
胰腺组织，尤其是胰岛，富含白细胞介素-1受体I型（IL-1R）的表达。由于这种富集，胰岛β细胞对IL-1R配体IL-1α和IL-1β非常敏感，这表明通过该途径的信号传导调节了胰岛β细胞的健康和功能。在此，我们报道了C57BL/6J小鼠和C57遗传背景的db/db小鼠胰腺组织中IL-1R的靶向缺失（IL-1RPdx1−/−）。免疫荧光染色分析胰岛形态、β细胞转录因子丰度和去分化标志物Aldh1a3的表达。葡萄糖和胰岛素耐量试验用于检查这些基因操作的代谢状态。葡萄糖刺激的胰岛素分泌在体内和离体胰岛通过外灌注进行评估。胰腺IL-1R缺失导致糖耐量受损，这种表型随着年龄的增长而加剧。IL-1RPdx1−/−与db/db小鼠杂交会使葡萄糖耐量恶化，但不会改变体重。IL-1RPdx1 - / -小鼠和同窝对照之间的胰岛素耐受性没有可检测到的变化。然而，与对照胰岛相比，从IL-1RPdx1 - / -分离的胰岛中葡萄糖刺激的胰岛素分泌减少。与同窝对照相比，IL-1RPdx1 - / -小鼠体内葡萄糖刺激后的胰岛素输出也显著减少。IL-1RPdx1−/−小鼠的胰岛显示Aldh1a3（去分化标记物）的升高，β细胞转录因子MafA的核丰度降低。Nkx6.1丰度未发生变化。在体内，胰腺IL-1R通过抑制Aldh1a3的表达、维持MafA丰度和支持葡萄糖刺激的胰岛素分泌来促进葡萄糖稳态，具有重要的生理作用。胰腺IL-1R缺失会损害年轻和老年雄性小鼠的糖耐量。胰腺IL-1R缺失使肥胖db/db小鼠的糖耐量恶化。IL-1R的缺失触发去分化标志物Aldh1a3的表达。胰腺组织中的IL-1信号影响胰岛的健康和功能。
Pancreatic tissue, and islets in particular, are enriched in expression of the interleukin-1 receptor type I (IL-1R). Because of this enrichment, islet β-cells are exquisitely sensitive to the IL-1R ligands IL-1α and IL-1β, suggesting that signaling through this pathway regulates health and function of islet β-cells. Herein, we report a targeted deletion of IL-1R in pancreatic tissue (IL-1RPdx1−/−) in C57BL/6J mice and in db/db mice on the C57 genetic background. Islet morphology, β-cell transcription factor abundance, and expression of the de-differentiation marker Aldh1a3 were analyzed by immunofluorescent staining. Glucose and insulin tolerance tests were used to examine metabolic status of these genetic manipulations. Glucose-stimulated insulin secretion was evaluated in vivo and in isolated islets ex vivo by perifusion. Pancreatic deletion of IL-1R leads to impaired glucose tolerance, a phenotype that is exacerbated by age. Crossing the IL-1RPdx1−/− with db/db mice worsened glucose tolerance without altering body weight. There were no detectable alterations in insulin tolerance between IL-1RPdx1−/− mice and littermate controls. However, glucose-stimulated insulin secretion was reduced in islets isolated from IL-1RPdx1−/− relative to control islets. Insulin output in vivo after a glucose challenge was also markedly reduced in IL-1RPdx1−/− mice when compared with littermate controls. Pancreatic islets from IL-1RPdx1−/− mice displayed elevations in Aldh1a3, a marker of de-differentiation, and reduction in nuclear abundance of the β-cell transcription factor MafA. Nkx6.1 abundance was unaltered. There is an important physiological role for pancreatic IL-1R to promote glucose homeostasis by suppressing expression of Aldh1a3, sustaining MafA abundance, and supporting glucose-stimulated insulin secretion in vivo. Pancreatic deletion of IL-1R impairs glucose tolerance in young and old male mice. Pancreatic deletion of IL-1R worsens glucose tolerance in obese db/db mice. Deletion of IL-1R triggers expression of the de-differentiation marker Aldh1a3. IL-1 signaling in pancreatic tissue influences islet health and function.
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影响因子：
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作者：
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影响因子：
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Burke, Susan J.;Batdorf, Heidi M.;Collier, J. Jason
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