REGULATED EXPRESSION OF HUMAN INSULIN IN THE LIVER OF TRANSGENIC MICECORRECTS DIABETIC ALTERATIONS

Transgenic mice expressing the P-enolpyruvate carboxykinase (PEPCK)/hu man insulin chimeric gene have been obtained as a model to study the f easibility of gene therapy for diabetes. These transgenic animals were healthy and normoglycemic and expressed human insulin in a physiologi cally regulated manner, mainly in the liver. Streptozotocin-treated tr ansgenic mice had high levels of human insulin immunoreactivity in ser um and showed a significant decrease (up to 40%) in glycemia compared with streptozotocin-treated control mice. The expression of genes invo lved in liver glucose metabolism, such as glucokinase, pyruvate kinase , and PEPCK, which is markedly altered by diabetes, was significantly recovered in transgenic mice treated with streptozotocin. In addition, the activity of both glucokinase and glycogen synthase, and the conte nt of glucose 6-phosphate and glycogen, were normal in the liver, even when transgenic animals were treated with diabetogenic doses of strep tozotocin. These results constitute an indication in vivo that diabete s gene therapy is possible, by means of the production of insulin in e xtrapancreatic tissues.