Pancreatic β cell dedifferentiation in diabetes and redifferentiation following insulin therapy.
Pancreatic β cell dedifferentiation in diabetes and redifferentiation following insulin therapy.
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DOI：
10.1016/j.cmet.2014.03.010
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发表时间：
2014-05-06
期刊：
影响因子：
29
通讯作者：
Remedi MS
中科院分区：
文献类型：
--
作者：
Wang Z;York NW;Nichols CG;Remedi MS
糖尿病的特征是胰腺β细胞功能和胰岛素含量的“葡萄糖毒性”丧失，但潜在的机制仍不清楚。由β细胞不兴奋性（KATP功能获得性）诱导的胰岛素分泌缺陷的小鼠模型证实了糖尿病的发展并重申了人类新生儿糖尿病的特征。在糖尿病状态下，β细胞失去其成熟特性并去分化为神经生成素3阳性和胰岛素阴性细胞。谱系追踪实验表明，在通过胰岛素治疗降低血糖后，去分化的细胞随后可以再分化为成熟的神经生成素3阴性、胰岛素阳性的β细胞。我们在这里证明，β细胞去分化，而不是凋亡，是胰岛素阳性细胞损失的主要机制，再分化占这些动物中胰岛素含量和抗糖尿病药物反应的恢复。这些结果可能有助于解释长期糖尿病中β细胞质量的逐渐减少，以及2型糖尿病患者在胰岛素治疗后β细胞功能和药物反应性的恢复，并提出了一种拯救糖尿病中“耗尽”β细胞的方法。
Diabetes is characterized by ‘glucotoxic’ loss of pancreatic β-cell function and insulin content, but underlying mechanisms remain unclear. A mouse model of insulin-secretory deficiency induced by β-cell inexcitability (KATP gain-of-function) demonstrates development of diabetes and reiterates the features of human neonatal diabetes. In the diabetic state, β-cells lose their mature identity and dedifferentiate to neurogenin3-positive and insulin-negative cells. Lineage-tracing experiments show that dedifferentiated cells can subsequently re-differentiate to mature neurogenin3-negative, insulin-positive, β-cells after lowering of blood glucose by insulin therapy. We demonstrate here that β-cell dedifferentiation, rather than apoptosis, is the main mechanism of loss of insulin-positive cells, and re-differentiation accounts for restoration of insulin content and antidiabetic-drug responsivity in these animals. These results may help explain gradual decrease in β-cell mass in long-standing diabetes, and recovery of β-cell function and drug responsivity in type-2 diabetic patients following insulin therapy, and suggest an approach to rescuing ‘exhausted’ β-cells in diabetes.
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