INSULIN-LIKE-GROWTH-FACTOR-I (IGF-I)-STIMULATED PANCREATIC BETA-CELL GROWTH IS GLUCOSE-DEPENDENT - SYNERGISTIC ACTIVATION OF INSULIN-RECEPTOR SUBSTRATE-MEDIATED SIGNAL-TRANSDUCTION PATHWAYS BY GLUCOSE AND IGF-I IN INS-1 CELLS

Nutrients and certain growth factors stimulate pancreatic beta-cell mi togenesis, however, the appropriate mitogenic signal transduction path ways have not been defined, In the glucose sensitive pancreatic beta-c ell line, INS-I, it was found that glucose (6-18 mM) independently inc reased INS-1 cell proliferation (>20-fold at 15 mM glucose). Insulin-l ike growth factor I (IGF-I)-induced INS-1 cell proliferation was gluco se-dependent only in the physiologically relevant concentration range (6-18 mm glucose), The combination of IGF-I and glucose was synergisti c, increasing INS-1 cell-proliferation >20-fold at 15 mM glucose + 10 nM IGF-I, Glucose metabolism and phosphatidylinositol S'-kinase (PI 3' -kinase) activation were necessary for both glucose and IGF-I-stimulat ed INS-1 cell proliferation, IGF-I and 15 mM glucose increased tyrosin e phosphorylation mediated recruitment of Grb2/mSOS and PI 3'-kinase t o IRS-2 and pp60, Glucose and IGF-I also induced Shc association with Grb2/ mSOS, Glucose (3-18 mM) and IGF-I, independently of glucose, act ivated mitogen-activated protein kinase but this did not correlate wit h IGF-I-induced beta-cell proliferation, In contrast, p70(S6K) was act ivated with increasing glucose concentration (between 6 and 18 mM), an d potentiated by IGF I in the same glucose concentration range which c orrelated with INS-1 cell proliferation rate. Thus, glucose and IGF-I- induced beta-cell proliferation were mediated via a signaling mechanis m that was facilitated by mitogen-activated protein kinase but de pend ent on IRS-mediated induction of PI 3'-kinase activity and downstream activation of p70S6K. The glucose dependence of IGF-I mediated INS-1 c ell proliferation emphasizes beta-cell signaling mechanisms are rather unique in being tightly linked to glycolytic metabolic flux.