Pancreatic β-cell-specific deletion of insulin-degrading enzyme leads to dysregulated insulin secretion and β-cell functional immaturity
Pancreatic β-cell-specific deletion of insulin-degrading enzyme leads to dysregulated insulin secretion and β-cell functional immaturity
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DOI：
10.1152/ajpendo.00040.2019
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发表时间：
2019-11-01
影响因子：
5.1
通讯作者：
Cozar-Castellano, Irene
中科院分区：
文献类型：
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作者：
Fernandez-Diaz, Cristina M.;Merino, Beatriz;Cozar-Castellano, Irene
抑制胰岛素降解酶（IDE）已被认为是治疗2型糖尿病的可能靶点。然而，IDE在葡萄糖稳态中的作用的许多方面需要澄清。鉴于此，需要新的临床前模型来阐明这种蛋白酶在与胰岛素处理相关的主要组织中的特定作用。为了解决这个问题，在这里，我们产生了一种新的小鼠品系，在胰腺β细胞内选择性缺失Ide基因，B-IDE-KO小鼠，其特征在于多个代谢终点，包括血糖，血浆C肽，和腹膜内葡萄糖耐量试验。此外，在分离的胰岛中定量葡萄糖刺激的胰岛素分泌，并通过RT-PCR表征β细胞分化标志物和胰岛素分泌机制。此外，IDE在INS-1 E细胞以及啮齿动物和人胰岛中受到遗传和代谢抑制，并评估了胰岛素分泌。我们的研究结果表明，在体内，从β细胞中终身缺失IDE会导致血浆C肽水平升高。从B-IDE-KO小鼠分离的胰岛显示组成型胰岛素分泌，这是β细胞功能不成熟的标志，证实了这些发现。出乎意料的是，我们发现Glut 1（一种高亲和力/低K-m葡萄糖转运蛋白）增加了60%，这表明在低葡萄糖水平下葡萄糖转运到β细胞中的增加，这可能与组成型胰岛素分泌有关。同时，INS-1 E和胰岛细胞中的IDE抑制导致葡萄糖激发后胰岛素分泌受损。我们得出结论，IDE是葡萄糖刺激胰岛素分泌所必需的。当IDE被抑制时，胰岛素分泌机制受到干扰，导致在高葡萄糖浓度下抑制胰岛素释放或组成性分泌。
Inhibition of insulin-degrading enzyme (IDE) has been proposed as a possible therapeutic target for type 2 diabetes treatment. However, many aspects of IDE's role in glucose homeostasis need to be clarified. In light of this, new preclinical models are required to elucidate the specific role of this protease in the main tissues related to insulin handling. To address this, here we generated a novel line of mice with selective deletion of the Ide gene within pancreatic betacells, B-IDE-KO mice, which have been characterized in terms of multiple metabolic end points, including blood glucose, plasma C-peptide, and intraperitoneal glucose tolerance tests. In addition, glucose-stimulated insulin secretion was quantified in isolated pancreatic islets and beta-cell differentiation markers and insulin secretion machinery were characterized by RT-PCR. Additionally, IDE was genetically and pharmacologically inhibited in INS-1E cells and rodent and human islets, and insulin secretion was assessed. Our results show that, in vivo, life-long deletion of IDE from beta-cells results in increased plasma C-peptide levels. Corroborating these findings, isolated islets from B-IDE-KO mice showed constitutive insulin secretion, a hallmark of beta-cell functional immaturity. Unexpectedly, we found 60% increase in Glut1 (a high-affinity/low-K-m glucose transporter), suggesting increased glucose transport into the beta-cell at low glucose levels, which may be related to constitutive insulin secretion. In parallel, IDE inhibition in INS-1E and islet cells resulted in impaired insulin secretion after glucose challenge. We conclude that IDE is required for glucose-stimulated insulin secretion. When IDE is inhibited, insulin secretion machinery is perturbed, causing either inhibition of insulin release at high glucose concentrations or constitutive secretion.