Impaired β-cell regeneration after partial pancreatectomy in the adult Goto-Kakizaki rat, a spontaneous model of type II diabetes
Impaired β-cell regeneration after partial pancreatectomy in the adult Goto-Kakizaki rat, a spontaneous model of type II diabetes
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DOI：
10.1007/s004180100302
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发表时间：
2001-08
影响因子：
2.3
通讯作者：
C. Plachot;J. Movassat;B. Portha
中科院分区：
文献类型：
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作者：
C. Plachot;J. Movassat;B. Portha
在Goto-Kakizaki（GK）大鼠（一种II型糖尿病的遗传模型）中，早在胎龄就存在β细胞质量的限制，其在成年动物中保持减少。为了研究成年高血糖GK大鼠的β细胞生长潜力，并确定其是否与非糖尿病Wistar（W）大鼠不同，我们对8- 10周龄雄性动物进行了90%胰腺切除术（Px）。通过免疫细胞化学和形态计量学在不同时间点（Px后第0天（D 0）、D2、D 7和D14）评价自发β细胞再生和参与β细胞复制、导管前体的β细胞新分化和β细胞凋亡。在GK大鼠中，D2时糖尿病状态恶化，伴有严重和慢性高血糖，而在W/Px中，观察到正常至中度高血糖。在W/Px大鼠中，与非Px W大鼠相比，总β细胞质量在D2、D 7和D14逐渐增加。相比之下，在GK/Px大鼠中，与相关非Px组相比，仅存在总β细胞质量增加的非显著趋势。成年GK大鼠β细胞增殖率低于W.与对照组相比，W/Px组和GK/Px组大鼠在D2时β细胞增殖早期增加，GK组在D 7和D14时β细胞增殖恢复至非Px值，而W/Px组β细胞增殖持续增加。在W和GK（非Px或Px）中，D 0、D2、D 7和D14时的凋亡β细胞频率非常低，因此我们无法得出结论，认为不同组之间存在任何显著差异。与W/Px相比，发现GK/Px大鼠中导管（更具体地说是再生灶）的β细胞新形成活化较少。总之，这些结果表明，在经历Px的成年高血糖GK大鼠中，β细胞仍然具有再生能力，但与非糖尿病W大鼠相比，效率较低。GK大鼠中的这种缺陷是遗传易感性和环境因素（慢性高血糖症）的结果，遗传易感性导致新生期已经存在的β细胞新生潜力改变，环境因素导致成年动物特有的β细胞增殖能力降低。
In the Goto-Kakizaki (GK) rat, a genetic model of type II diabetes, there is a restriction of the β-cell mass as early as fetal age, which is maintained reduced in the adult animal. In order to investigate the β-cell growth potential in the adult hyperglycemic GK rat, and to determine whether it differs from non-diabetic Wistar (W) rats, we have performed 90% pancreatectomy (Px) in 8- to 10-week-old male animals. Spontaneous β-cell regeneration and involvement of β-cell replication, β-cell neodifferentiation from ductal precursor, and β-cell apoptosis were evaluated by immunocytochemistry and morphometry at different time points: day 0 (D0), D2, D7, and D14 after Px. In GK rats, deterioration of the diabetic state with severe and chronic hyperglycemia was evident as soon as D2, while in W/Px, normoglycemia to moderate hyperglycemia was observed. In W/Px rats, the total β-cell mass gradually increased on D2, D7, and D14, as compared to non-Px W rats. By contrast, in GK/Px rats, there was only a non-significant tendency to increased total β-cell mass, as compared to related non-Px group. Adult GK rats displayed lower β-cell proliferation rates compared to W. In response to Px, early increase of β-cell proliferation was present in both W/Px and GK/Px rats on D2, but it returned to non-Px values in GK rats on D7 and D14, while in W/Px rats β-cell proliferation was maintained increased as compared to non-Px W rats. The very low apoptotic β-cell frequency on D0, D2, D7, and D14, in both W and GK, either non-Px or Px, did not allow us to conclude that any significant differences exist between the different groups. β-cell neoformation from ducts, and more specifically from foci of regeneration, was found to be less activated in GK/Px rats as compared to W/Px. Together, these results suggest that in the adult hyperglycemic GK rat undergoing Px, β-cells still have the capacity to regenerate, but with a lower efficiency as compared to non-diabetic W rats. This defect in the GK rat is the result of both genetic predisposition contributing to an altered β-cell neogenesis potential already present in the neonatal period, and environmental factors (chronic hyperglycemia) leading to a reduced β-cell proliferative capacity specific to the adult animals.