Insulin-like Growth Factor I (IGF-I)-stimulated Pancreatic b-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 b-cell mitogenesis, however, the appropriate mitogenic signal transduction pathways have not been defined. In the glucose-sensitive pancreatic b-cell line, INS-1, it was found that glucose (6–18 mM) independently increased INS-1 cell proliferation (>20-fold at 15 mM glucose). Insulin-like growth factor I (IGF-I)-induced INS-1 cell proliferation was glucose-dependent only in the physiologically relevant concentration range (6–18 mM glucose). The combination of IGF-I and glucose was synergistic, increasing INS-1 cell proliferation >50-fold at 15 mM glucose 1 10 nM IGF-I. Glucose metabolism and phosphatidylinositol 3*-kinase (PI 3*-kinase) activation were necessary for both glucose and IGF-I-stimulated INS-1 cell proliferation. IGF-I and 15 mM glucose increased tyrosine phosphorylation mediated recruitment of Grb2/mSOS and PI 3*-kinase to 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, activated mitogen-activated protein kinase but this did not correlate with IGF-I-induced b-cell proliferation. In contrast, p70 was activated with increasing glucose concentration (between 6 and 18 mM), and potentiated by IGF-I in the same glucose concentration range which correlated with INS-1 cell proliferation rate. Thus, glucose and IGF-I-induced b-cell proliferation were mediated via a signaling mechanism that was facilitated by mitogen-activated protein kinase but dependent on IRS-mediated induction of PI 3*-kinase activity and downstream activation of p70. The glucose dependence of IGF-I mediated INS-1 cell proliferation emphasizes b-cell signaling mechanisms are rather unique in being tightly linked to glycolytic metabolic flux.