Our objective is to study the effects of insulin and insulin-like growth factor II (IGF-II), or lack thereof, in the development and growth of the sensory and sympathetic nervous system, in malignant human neuroblastoma cells, and in diabetes.  Diabetic neuropathy is characterized in part by reduced conduction velocity, reduced nerve fiber diameter and loss of axons.  Human neuroblastoma is characterized in part by escape from the requirement of nerve growth factor for survival and for growth regulation (K.H. Sonnenfeld and D.N. Ishii, J. Neurosci.  Res.  in press, 1982).  One means by which escape may occur is through acquisition of inappropriate sensitivity to other growth factors.  Our recent findings show that neuroblastoma cells are stimulated to divide by insulin and IGF-II, but not late stage embryonic sensory and sympathetic neurons in culture.  Whether earlier developmental stages are affected is not known.  Moreover, insulin can enhance neurite outgrowth in neuroblastoma cells.  These results suggest insulin may have direct effects on the peripheral nervous system, and whether diabetic neuropathy is the consequence of direct or indirect insulin effects may be tested.  Our aims are: a) to more completely study how insulin and IGF-II affects growth, survival and neurite outgrowth in neuroblastoma and in pheochromocytoma PC12 cells, b) to determine whether neuroblastoma cells can synthesize insulin and produce its own growth factor, c) to study whether insulin can alter response to nerve growth factor, d) to study the role of insulin, IGF-II, and anti-insulin serum on maturation, growth, protein synthesis, and survival of sensory and sympathetic neuroblasts during development, and e) to study the time course and magnitude of effects on nerve growth factor binding, axonal transport, protein synthesis, survival, and specific enzyme activity following onset of diabetes in rats to test whether insulin may directly be involved in neuropathy, and explain the syndrome described above.