Role of tyrosine kinase signaling for β-cell replication and survival

Diabetes mellitus is commonly considered as a disease of a scant beta -cell mass that fails to respond adequately to the functional demand. Tyrosine kinases may play a role for beta -cell replication, differentiation (neoformation) and survival. Transfection of beta -cells with DNA constructs coding for tyrosine kinase receptors yields a ligand-dependent increase of DNA synthesis in beta -cells. A PCR-based technique was adopted to assess the repertoire of tyrosine kinases expressed in fetal islet-like structures, adult islets or RINm5F cells. Several tyrosine kinase receptors, such as the VEGFR-2 (vascular endothelial growth factor receptor 2) and c-Kit, were found to be present in pancreatic duct cells. Because ducts are thought to harbor beta -cell precursor cells, these receptors may play a role for the neoformation of beta -cells. The Src-like tyrosine kinase mouse Gtk (previously named Bsk/Iyk) is expressed in islet cells, and was found to inhibit cell proliferation. Furthermore, it conferred decreased viability in response to cytokine exposure. Shb is a Src homology 2 domain adaptor protein which participates in tyrosine kinase signaling. Transgenic mice overexpressing Shb in beta -cells exhibit an increase in the neonatal beta -cell mass, an improved glucose homeostasis, but also decreased survival in response to cytokines and streptozotocin. It is concluded that tyrosine kinase signaling may generate multiple responses in beta -cells, involving proliferation, survival and differentiation.