IGF-I and GH post-receptor signaling mechanisms for pancreatic beta-cell replication.
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.
Rhodes
C J
CJ
Pacific Northwest Research Institute and Department of Pharmacology, University of Washington, Seattle, Washington 98122, USA. cjr@pnri.org
D002455:Cell Division / Q000187:drug effects; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology / Q000628:therapy; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology / Q000628:therapy; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology* / Q000473:pathology; D016381:Islets of Langerhans Transplantation; D011986:Receptors, Somatotropin / Q000378:metabolism*; D015398:Signal Transduction
D011986:Receptors, Somatotropin; D007334:Insulin-Like Growth Factor I; D005947:Glucose