Zhao Jiawei, Zhang Nina, He Min, Yang Zhihong, Tong Wei, Wang Qinghua, Hu Renming
Department of Endocrinology, Huashan Hospital, Institute of Endocrinology and Diabetology, Fudan University, Shanghai, China.
Cell Physiol Biochem. 2008;21(5-6):445-54. doi: 10.1159/000129637. Epub 2008 Apr 24.
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+/-21.8 g, 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.
β细胞质量的不适当调节是糖尿病高血糖症发生的主要原因。然而，β细胞质量在胰岛素抵抗反应或2型糖尿病发生过程中的调节机制仍不清楚。我们测定了OLETF大鼠β细胞中的胰岛素信号传导以及β细胞质量对胰岛素抵抗进展的适应性。到25周龄糖尿病发病时，与对照LETO大鼠相比，OLETF大鼠出现肥胖（体重：LETO vs OLETF = 474.0±9.5 vs 581.3±21.8 g，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；甘油三酯：LETO vs OLETF = 0.36±0.05 vs 1.36±0.12 mM，P < 0.001，n = 6）和糖耐量受损（曲线下面积：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大鼠出现了严重的胰岛素抵抗。通过酶联免疫吸附测定（ELISA）测量血浆胰岛素水平表明，在糖尿病发病时，与年龄匹配的LETO大鼠相比，OLETF大鼠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），这提示存在高胰岛素血症。免疫染色检测到OLETF大鼠β细胞中胰岛素受体底物1（IRS1）显著减少（减少54%，P < 0.001）和IRS2显著减少（减少55%，P < 0.001）。有趣的是，虽然发现OLETF大鼠的β细胞质量增加了（增加2.2倍；P < .001），但与对照组相比，通过免疫染色测定的OLETF大鼠β细胞胰岛素含量显著降低了32%（P < 0.001）。我们的研究结果表明，尽管β细胞质量增加，但β细胞胰岛素信号传导受损和β细胞胰岛素含量降低可能导致OLETF大鼠显性糖尿病的发生。
