Beta cell proliferation and growth factors

Formation of new beta cells can take place by two pathways: replication of already differentiated beta cells or neogenesis from putative islet stem ce lls. Under physiological conditions both processes are most pronounced duri ng the fetal and neonatal development of the pancreas. In adulthood little increase in the beta cell number seems to occur. In pregnancy, however, a m arked hy perplasia of the beta cells is observed both in rodents and man. I ncreased mitotic activity has been seen both in vivo and in vitro in islets exposed to placental lactogen (PL), prolactin (PRL) and growth hormone (CH ). Receptors for both GH and PRL are expressed in islet cells and are upreg ulated during pregnancy. By mutational analysis we have identified differen t functional domains of the cytoplasmic part of the GH receptor. Thus the m itotic signaling only requires the membrane proximal part of the receptor a nd activation of the tyrosine kinase JAK2 and the transcription factors STA T1 and 3. The activation of the insulin gene however also requires the dist al part of the receptor and activation of calcium uptake and STAT5. In orde r to identify putative autocrine growth factors or targets for growth facto rs we have cloned a novel GH/PRL stimulated rat islet gene product, Pref-l (preadipocyte factor-1). This protein contains six EGF-like motifs and may plays role both in embryonic pancreas differentiation and in beta cell grow th and function. In summary, the increasing knowledge about the mechanisms involved in beta cell differentiation and proliferation may lead to new way s of forming beta cells for treatment of diabetes in man.