IGF-I and GH post-receptor signaling mechanisms for pancreatic beta-cell replication.
IGF-I and GH post-receptor signaling mechanisms for pancreatic beta-cell replication.
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DOI：
10.1677/jme.0.0240303
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发表时间：
2000-06
影响因子：
3.5
通讯作者：
CJ Rhodes
中科院分区：
文献类型：
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作者：
CJ Rhodes
某些营养素、药理学试剂和生长因子可以刺激胰腺β细胞增殖;然而，β细胞中的促有丝分裂信号转导途径尚未得到特别好的表征。作为一个模型系统，我们专注于表征β细胞中IGF-I和GH受体下游的信号转导途径。最初的想法是获得有丝分裂信号通路中的重要元素的想法，然后可以利用这些元素来产生β细胞增殖的显着增加。这种方法最终可能揭示一种在体外增加人胰腺内分泌细胞数量的方法，以获得用于I型糖尿病常规移植治疗的丰富的β细胞来源。然而，在我们的研究过程中，我们也揭示了一个意想不到的洞察肥胖相关的II型糖尿病的发病机制。已经观察到游离脂肪酸抑制葡萄糖和葡萄糖依赖性IGF-I/GH诱导的β细胞增殖。我们假设，在肥胖过程中β细胞中细胞内脂肪的逐渐积累最终会导致β细胞质量扩张的抑制，从而无法补偿外周胰岛素抵抗，从而导致II型糖尿病发病。
Certain nutrients, pharmacological agents and growth factors can stimulate pancreatic beta-cell proliferation; however, mitogenic signal transduction pathways in beta-cells have not been particularly well characterized. As a model system we have focussed on characterizing the signal transduction pathways immediately downstream of the IGF-I and GH receptors in beta-cells. The original idea was to gain an idea of important elements in mitogenic signaling pathways which might then be exploited to generate a marked increase in beta-cell proliferation. Such an approach could eventually reveal a means to increase the number of human pancreatic endocrine cells in vitro, in order to obtain an abundant source of beta-cells for routine transplantation therapy of type-I diabetes. However, in the course of our studies, we have also unveiled an unexpected insight into the pathogenesis of obesity-linked type-II diabetes. It has been observed that free fatty acids inhibit glucose- and glucose-dependent IGF-I/GH-induced beta-cell proliferation. We hypothesize that a gradual accumulation of intracellular fat in beta-cells during obesity can eventually lead to an inhibition of beta-cell mass expansion and hence failure to compensate for peripheral insulin resistance, so that type-II diabetes ensues.