Adaptive beta-cell proliferation is severely restricted with advanced age.
Adaptive beta-cell proliferation is severely restricted with advanced age.
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DOI：
10.2337/db08-1198
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发表时间：
2009-06
期刊：
影响因子：
7.7
通讯作者：
Kushner JA
中科院分区：
文献类型：
--
作者：
Rankin MM;Kushner JA
分泌胰岛素的β细胞的再生是一个基本的研究目标，可以使1型或2型糖尿病患者受益。β-幼龄啮齿动物的细胞增殖可受到多种刺激的剧烈刺激。然而，这种适应性β细胞再生能力是否保留到老年尚不清楚。我们评估了不同年龄的成年小鼠在各种刺激下的适应性β细胞增殖能力：部分胰腺切除术，低剂量给药β细胞毒素链脲佐菌素和exendin-4，一种胰高血糖素样肽1 （GLP-1）激动剂。通过在饮用水中添加5-溴-2 ' -脱氧尿苷（BrdU）来检测β-细胞的增殖。随着年龄的增长，基底β细胞的增殖能力严重下降。部分胰腺切除术可显著刺激幼鼠β细胞增殖，但不能增加老年小鼠β细胞复制。链脲佐菌素对幼鼠β细胞复制有刺激作用，但对老年鼠影响不大。此外，GLP-1激动剂exendin-4在年轻小鼠中刺激β-细胞增殖，而在年老小鼠中没有。令人惊讶的是，适应性β细胞增殖能力在12个月后最低，这是成年小鼠寿命的早期中年。无论是通过部分胰腺切除术、低剂量链脲佐菌素还是exendin-4刺激，小鼠的适应性β细胞增殖都受到老年小鼠的严重限制。因此，中年小鼠的β细胞似乎大部分处于有丝分裂后。年轻的啮齿动物可能不能忠实地模拟成熟成年小鼠β-细胞的再生能力。
Regeneration of the insulin-secreting β-cells is a fundamental research goal that could benefit patients with either type 1 or type 2 diabetes. β-Cell proliferation can be acutely stimulated by a variety of stimuli in young rodents. However, it is unknown whether this adaptive β-cell regeneration capacity is retained into old age. We assessed adaptive β-cell proliferation capacity in adult mice across a wide range of ages with a variety of stimuli: partial pancreatectomy, low-dose administration of the β-cell toxin streptozotocin, and exendin-4, a glucagon-like peptide 1 (GLP-1) agonist. β-Cell proliferation was measured by administration of 5-bromo-2′-deoxyuridine (BrdU) in the drinking water. Basal β-cell proliferation was severely decreased with advanced age. Partial pancreatectomy greatly stimulated β-cell proliferation in young mice but failed to increase β-cell replication in old mice. Streptozotocin stimulated β-cell replication in young mice but had little effect in old mice. Moreover, administration of GLP-1 agonist exendin-4 stimulated β-cell proliferation in young but not in old mice. Surprisingly, adaptive β-cell proliferation capacity was minimal after 12 months of age, which is early middle age for the adult mouse life span. Adaptive β-cell proliferation is severely restricted with advanced age in mice, whether stimulated by partial pancreatectomy, low-dose streptozotocin, or exendin-4. Thus, β-cells in middle-aged mice appear to be largely postmitotic. Young rodents may not faithfully model the regenerative capacity of β-cells in mature adult mice.
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9.8
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