IGF-I and GH post-receptor signaling mechanisms for pancreatic β-cell replication

被引:73
作者
Rhodes, CJ
机构
[1] Pacific NW Res Inst, Seattle, WA 98122 USA
[2] Univ Washington, Dept Pharmacol, Seattle, WA 98122 USA
关键词
D O I
10.1677/jme.0.0240303
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
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页码:303 / 311
页数:9
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