EXOCYTOSIS OF INSULIN PROMOTES INSULIN GENE-TRANSCRIPTION VIA THE INSULIN-RECEPTOR PI-3 KINASE P70 S6 KINASE AND CAM KINASE PATHWAYS

The control of glucose homeostasis by insulin requires, in addition to the glucose-induced insulin release, a highly dynamic control of insu lin biosynthesis. Although elevated glucose concentrations have been s hown to trigger insulin biosynthesis at the levels of transcription an d translation, the molecular mechanisms underlying the immediate trans criptional control are poorly understood. By investigating signal tran sduction pathways involved in the ''glucose-dependent'' transcriptiona l control, thereby analyzing endogenous (prepro)insulin mRNA levels an d monitoring on-line insulin promoter-driven GFP expression, we provid e, for the first time, evidence that physiologically stimulated insuli n secretion from the pancreatic beta cell promotes insulin biosynthesi s by enhancing insulin gene transcription in an autocrine manner. We s how that secreted insulin acts via beta-cell insulin receptors and up- regulates insulin gene transcription by signaling through the IRS-2/PI -3 kinase/p70 s6k and CaM kinase pathways.