Differential activation of protein kinase B and p70(S6K) by glucose and insulin-like growth factor 1 in pancreatic beta-cells (INS-1)

It has been shown that IGF-1-induced pancreatic beta -cell proliferation is glucose-dependent; however, the mechanisms responsible for this glucose de pendence are not known. Adenoviral mediated expression of constitutively ac tive phosphatidylinositol 3-kinase (PI3K) in the pancreatic beta -cells, IN S-1, suggested that PI3K was not necessary for glucose-induced beta -cell p roliferation but was required for IGF-1-induced mitogenesis, Examination of the signaling components downstream of PI3K, 3-phosphoinositide-dependent kinase 1, protein kinase B (PKB), glycogen synthase kinase-3, and p70-kDa-S 6-kinase (p70(S6K)), suggested that a major part of glucose-dependent beta -cell proliferation requires activation of mammalian target of rapamycin/p7 0(S6K), independent of phosphoinositide-dependent kinase 1/PKB activation. Adenoviral expression of the kinase-dead form of PKB in INS-1 cells decreas ed IGF-1-induced beta -cell proliferation. However, a surprisingly similar decrease was also observed in adenoviral wild type and constitutively activ e PKB-infected cells. Upon analysis of extracellular signal-regulated prote in kinase 1 and 2 (ERK1/ERK2), an increase in ERK1/ERK2 phosphorylation act ivation by glucose and IGF-1 was observed in kinase-dead PKB-infected cells , but this phosphorylation activation was inhibited in the constitutively a ctive PKB-infected cells. Hence, there is a requirement for the activation of both ERK1/ERK2 and mammalian target of rapamycin/p70(S6K) signal transdu ction pathways for a full commitment to glucose-induced pancreatic beta -ce ll mitogenesis. However, for IGF-1-induced activation, these pathways must be carefully balanced, because chronic activation of one (PI3K/PKB) can lea d to dampening of the other (ERK1/2), reducing the mitogenic response.