Insulin receptors in β-cells are critical for islet compensatory growth response to insulin resistance
Insulin receptors in β-cells are critical for islet compensatory growth response to insulin resistance
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DOI：
10.1073/pnas.0608703104
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发表时间：
2007-05-22
影响因子：
11.1
通讯作者：
Kulkarni, Rohit N.
中科院分区：
文献类型：
--
作者：
Okada, Terumasa;Liew, Chong Wee;Kulkarni, Rohit N.
胰岛素和胰岛素样生长因子 1 (IGF1) 是普遍存在的生长因子，可调节大多数哺乳动物组织（包括胰岛）的增殖。为了探索胰岛素受体在代偿性β细胞生长中的特异性，我们检查了两种胰岛素抵抗模型。在第一个模型中，我们使用了肝脏特异性胰岛素受体敲除 (LIRKO) 小鼠，该小鼠表现出高胰岛素血症，但由于 β 细胞质量代偿性增加而不会发展为糖尿病。 P 细胞中也缺乏功能性胰岛素受体（β IRKO/LIRKO）的 LIRKO 小鼠表现出严重的葡萄糖耐受不良，但未能出现代偿性胰岛增生，共同导致早期死亡。在第二个模型中，我们通过给 β IRKO 和 β 细胞特异性 IGF1 受体敲除 (β IGFRKO) 小鼠喂食高脂肪饮食，研究了胰岛素与 IGF1 受体在胰岛生长中的相对重要性。尽管高脂肪饮食的两组小鼠均出现了胰岛素抵抗（β IRKO，但未出现 β IGFRKO），但小鼠表现出与胰岛素刺激的磷酸化、FoxC11 核排斥和 Pdx-1 表达减少一致的胰岛生长不良。这些数据共同提供了直接的遗传证据，表明胰岛素/FoxO1/Pdx-1信号传导是胰岛对胰岛素抵抗的代偿性生长反应至关重要的一种途径。
Insulin and insulin-like growth factor 1 (IGF1) are ubiquitous growth factors that regulate proliferation in most mammalian tissues including pancreatic islets. To explore the specificity of insulin receptors in compensatory beta-cell growth, we examined two models of insulin resistance. In the first model, we used liver-specific insulin receptor knockout (LIRKO) mice, which exhibit hyperinsulinemia without developing diabetes due to a compensatory increase in beta-cell mass. LIRKO mice, also lacking functional insulin receptors in P-cells (beta IRKO/LIRKO), exhibited severe glucose intolerance but failed to develop compensatory islet hyperplasia, together leading to early death. In the second model, we examined the relative significance of insulin versus IGF1 receptors in islet growth by feeding high-fat diets to beta IRKO and beta-cell-specific IGF1 receptor knockout (beta IGFRKO) mice. Although both groups on the high-fat diet developed insulin resistance, beta IRKO, but not beta IGFRKO, mice exhibited poor islet growth consistent with insulin-stimulated phosphorylation, nuclear exclusion of FoxC11, and reduced expression of Pdx-1. Together these data provide direct genetic evidence that insulin/FoxO1/Pdx-1 signaling is one pathway that is crucial for islet compensatory growth response to insulin resistance.