ELEVATED GLUCOSE INCREASES MESANGIAL CELL SENSITIVITY TO INSULIN-LIKE-GROWTH-FACTOR-I

To determine the effects of glucose on Insulin-like growth factor I (I GF-I)-induced mesangial cell (MC) proliferation, we have examined the relationships between IGF binding protein 2 (IGFBP-2) secretion and pr oliferation in murine MCs (MMCs). MMCs incubated in high glucose (HG, 25 mM) exhibited a 25-30% reduction in IGFBP-2 secretion compared with cells in normal glucose (NG, 5.6 mM). This loss was not due to cell s urface binding; it correlated with a 3.1-fold decrease in IGFBP-2 mRNA . IGFBP-2 secretion was stimulated by IGF-I in NG but was unaltered in HG. Insulin treatment yielded similar results at 10-fold higher doses , indicating that this response is IGF-I receptor dependent. MMCs in H G displayed increased TGF-I-stimulated insulin receptor substrate-1/2 phosphorylation and activator protein-1 transcriptional activity compa red with NG controls. Accordingly, although IGF-I was not proliferativ e in NG, it increased [H-3]thymidine incorporation and cell number in HG to an extent proportional to the decrease in IGFBP-2. Thus hypergly cemia, as seen in diabetes, may increase MC IGF-I sensitivity by reduc ing IGFBP-2 expression, in turn increasing its proliferative and secre tory responses and contributing to the development of diabetic glomeru losclerosis.