Control of insulin biosynthesis in the human fetal beta cell

The inability of the human fetal beta cell to secrete insulin in response to glucose has been exhaustively studied. In comparison, little attempt has been made to understand if the kinetics of insulin synthesis are as mature as those of an adult beta cell. Using a purified cell population in which 41% of the cells are beta cells, we generated a dose-response curve to glucose with half-maximal synthesis at 4.6 mM glucose, identical to that seen in adult islets. Unlike adult islets, however, in the absence of glucose, agents that raise cyclicAMP (cAMP) (theophylline and forskolin) generated dose-response curves similar to those obtained for glucose. cAMP levels in these cells were enhanced twofold in response to glucose and fourfold to theophylline. Inhibition of cAMP metabolism with 1 mM MDL 12,330A (RMI) reduced insulin synthesis stimulated by glucose and completely inhibited insulin synthesis stimulated by theophylline. Substances that block glucose transport (100 microM cytochalasin B) and protein synthesis (1 mM cycloheximide) also markedly reduced insulin biosynthesis. These results indicate that the regulation of insulin biosynthesis in the human fetal beta cell is cAMP dependent, although glucose transport is a limiting factor when glucose is used as the stimulus. Thus, the human fetal beta cell is relatively mature in its synthesis of insulin, unlike its immaturity in insulin release.