Conophylline: A novel differentiation inducer for pancreatic β cells

Reduction of the β cell mass is critical in the pathogenesis of diabetes mellitus. The discovery of agents, which induce differentiation of pancreatic progenitors to β cells, would be useful to develop a new therapeutic approach to treat diabetes. To identify a new agent to stimulate differentiation of pancreatic progenitor cells to β cells, we screened various compounds using pancreatic AR42J cells, a model of pancreatic progenitor cells. Among various compounds and extracts tested, we found that conophylline, a vinca alkaloid extracted from leaves of a tropical plant Ervatamia microphylla, was effective in converting AR42J into endocrine cells. Conophylline reproduces the differentiation-inducing activity of activin A. Unlike activin A, however, conophylline does not induce apoptosis. To induce differentiation of AR42J cells, conophylline increases the expression of neurogenin-3 by activating p38 mitogen-activated protein kinase. Conophylline also induces differentiation in cultured pancreatic progenitor cells obtained from fetal and neonatal rats. More importantly, conophylline is effective in reversing hyperglycemia in neonatal streptozotocin-treated rats, and both the insulin content and the β cell mass are increased by conophylline. Histologically, conophylline increases the numbers of ductal cells positive for pancreatic-duodenal-homeobox protein-1 and islet-like cell clusters. Conophylline and related compounds are useful in inducing differentiation of pancreatic β cells both in vivo and in vitro.