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首页> 外文期刊>Cellular Physiology and Biochemistry >Increased beta-cell apoptosis and impaired insulin signaling pathway contributes to the onset of diabetes in OLETF rats
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Increased beta-cell apoptosis and impaired insulin signaling pathway contributes to the onset of diabetes in OLETF rats

机译：β细胞凋亡增加和胰岛素信号通路受损导致OLETF大鼠糖尿病发作

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Inappropriate adaptation of beta-cell mass is a primary cause of the development of diabetic hyperglycemia. However, the mechanisms underlying regulation of the beta-cell mass in response to insulin resistance or in the development of type 2 diabetes remain unclear. We determined the insulin signaling in the beta-cells and the adaptation of the beta-cell mass in response to the progression of insulin resistance in OLETF rats. By 25 weeks of age, at the onset of diabetes, compared to control LETO rats, OLETF rats developed obesity ( Body weight: LETO vs OLETF = 474.0 +/- 9.5 vs 581.3 +/- 21.8g, P < 0.001, n=6), hyperlipidemia ( Cholesterol: LETO vs OLETF = 1.67 +/- 0.07 vs 2.19 +/- 0.20 mM, P < 0.05, n=6; triglyceride: LETO vs OLETF = 0.36 +/- 0.05 vs 1.36 +/- 0.12 mM, P < 0.001, n=6), and impaired glucose tolerance (AUC: LETO vs OLETF = 10.3 +/- 3.4 vs 29.6 +/- 7.8 mM, P < 0.001, n=6). Insulin sensitivities as assessed by the insulin sensitivity index (ISI) and the homeostasis model assessment (HOMA) indicated that OLETF rats developed severe insulin resistance. The measurement of plasma insulin levels by ELISA demonstrated, at the onset of diabetes, that fasting insulin levels were increased by 1.2-fold, and 2 hr postprandial insulin levels were increased by 3-fold (P < 0.05, n=6) in OLETF rats compared to age-matched LETO mates which is suggestive of hyperinsulinemia. Immunostaining detected a significant reduction in the insulin receptor substrate 1 (IRS1) (by 54%, P < 0.001) and IRS2 (by 55%, P < 0.001) in the beta-cells of the OLETF rats. Interestingly, while the beta-cell mass was found to be increased (by 2.2-fold; P < 0.001), the beta-cell insulin content as determined by immunostaining was significantly reduced by 32% (P < 0.001) in the OLETF rats when compared to the controls. Our findings suggest that despite increasing beta-cell mass the impaired beta-cell insulin signaling and reduced beta-cell insulin content may contribute to the onset of overt diabetes in OLETF rats.
机译：β细胞质量的不适当适应是糖尿病高血糖症发展的主要原因。但是，响应胰岛素抵抗或2型糖尿病的发展，调节β细胞质量的潜在机制尚不清楚。我们确定响应于OLETF大鼠胰岛素抵抗的进展，β细胞中的胰岛素信号传导和β细胞质量的适应性。与对照组LETO大鼠相比，到糖尿病发作时25周龄，OLETF大鼠发展为肥胖（体重：LETO vs OLETF = 474.0 +/- 9.5 vs 581.3 +/- 21.8g，P <0.001，n = 6 ），高脂血症（胆固醇：LETO vs OLETF = 1.67 +/- 0.07 vs 2.19 +/- 0.20 mM，P <0.05，n = 6;甘油三酸酯：LETO vs OLETF = 0.36 +/- 0.05 vs 1.36 +/- 0.12 mM， P <0.001，n = 6）和受损的葡萄糖耐量（AUC：LETO vs OLETF = 10.3 +/- 3.4 vs 29.6 +/- 7.8 mM，P <0.001，n = 6）。通过胰岛素敏感性指数（ISI）和稳态模型评估（HOMA）评估的胰岛素敏感性表明OLETF大鼠发展为严重的胰岛素抵抗。通过ELISA测定血浆胰岛素水平表明，在糖尿病发作时，OLETF中的空腹胰岛素水平增加了1.2倍，餐后2小时胰岛素水平增加了3倍（P <0.05，n = 6）与年龄匹配的LETO伴侣相比，这提示高胰岛素血症。免疫染色检测到OLETF大鼠的β细胞中胰岛素受体底物1（IRS1）（IRS1）和IRS2（IRS2）（55％，P <0.001）显着降低。有趣的是，虽然发现OLETF大鼠中β细胞的质量增加了（增加了2.2倍; P <0.001），但通过免疫染色确定的β细胞胰岛素含量却显着降低了32％（P <0.001）。与控件相比。我们的发现表明，尽管增加了β细胞的数量，但受损的β细胞胰岛素信号传导和降低的β细胞胰岛素含量仍可能导致OLETF大鼠出现明显的糖尿病。

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