ISSN:
1432-0428
Keywords:
Keywords Diabetes mellitus
;
insulin resistance
;
IGF-1
;
IRS-1
;
cell growth.
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract Aims/hypothesis. Although both increased cell growth and impaired insulin signalling have been associated with diabetes, this association has not been investigated. Insulin-like growth factor-1 (IGF-1), a structural and functional analog of insulin, may play a part in the aberrant insulin receptor-mediated signalling observed in diabetes. Methods. To investigate the consequence of this impaired signalling on cell proliferation and transformation, we transfected Chinese hamster ovary cells with cDNA encoding a kinase-defective insulin receptor. Results. In these mutant cells, the mitogenic and metabolic effects of insulin were reduced compared with control cells (p 〈 0.05) and this was due to a dominant negative effect. In contrast, these mutant cells showed a higher mitogenic response to IGF-1 than control cells, although IGF-1 receptor expression was similar in both cell lines. There was no statistically significant difference in mitogenic response, however, to platelet-derived growth factor, basic fibroblast growth factor and heparin-binding epidermal growth factor-like growth factor. Variables of the IGF-1 signalling pathway, including tyrosine phosphorylation of insulin receptor substrate-1 and activation of mitogen-activated protein kinase and phosphatidyl inositol 3 kinase, were also augmented in mutant cells. Insulin receptor substrate-1 message and protein abundance were higher in mutant than in control cells. Moreover, mutant cells had a higher mitogenic potential in low-serum-containing medium, suggesting that these cells have a transformed phenotype. Conclusion/interpretation. These findings suggest that an impaired insulin signalling may upregulate insulin receptor substrate-1 and that this, in turn, leads to increased IGF-1 signalling, a phenomenon that is possibly associated with increased cell growth in diabetes. [Diabetologia (1999) 42: 763–772]
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/s001250051226
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