Targeted expression of placental lactogen in the beta cells of transgenic mice results in beta cell proliferation, islet mass augmentation, and hypoglycemia

The factors that regulate pancreatic beta cell proliferation are not well d efined. In order to explore the role of murine placental lactogen (PL)-I (m PL-I) in islet mass regulation in vivo, we developed transgenic mice in whi ch mPL-I is targeted to the beta cell using the rat insulin II promoter. Ra t insulin II-mPL-I mice displayed both fasting and postprandial hypoglycemi a (71 and 105 mg/dl, respectively) as compared with normal mice (92 and 129 mg/dl; p < 0.00005 for both). Plasma insulin concentrations were inappropr iately elevated, and insulin content in the pancreas was increased 2-fold. Glucose-stimulated insulin secretion by perifused islets was indistinguisha ble from controls at 7.5, 15, and 20 mM glucose. Beta cell proliferation ra tes were twice normal (p = 0.0005). This hyperplasia, together with a 20% i ncrease in beta cell size, resulted in a a-fold increase in islet mass (p = 0.0005) and a 1.45-fold increase in islet number (p = 0.0012). In mice, mu rine PL-I is a potent islet mitogen, is capable of increasing islet mass, a nd is associated with hypoglycemia over the long term. It can be targeted t o the beta cell using standard gene targeting techniques. Potential exists for beta cell engineering using this strategy.