Glucose-regulierte Insulinproduktion nach Gentransfer in die Leber

Abstract

Current therapy of insulin dependent diabetes mellitus (IDDM) consists of multiple insulin injections, insulin pump, islet or whole pancreas transplantation. However, proper glycemic control is not always achieved. All treatment options have significant limitations, which lead to an intensive search for novel treatment strategies. Gene therapy using autologous hepatocytes is believed to be an effective and safe therapeutic approach to induce insulin secretion within physiologic range in response to glucose challenge. We generated adenoviral vectors (Ad.SAM) encoding different numbers of glucose inducible regulatory element (GIRE) units, the liver specific promoter albumin, and a modified proinsulin cleavable by the ubiquitously expressed protease furin. In vitro results from primary hepatocytes transduced with Ad.SAM showed that the secreted amount of insulin depends on the number of GIRE units used in the insulin gene construct, the concentration of glucose in the medium, and the length of expression. In vivo analysis of streptozotocin (STZ)-treated diabetic Lewis rats, which received Ad.SAM-injection in different sites of the liver, revealed the following: 1) fasting blood glucose levels were reduced to normal; 2) blood glucose levels of STZ-treated diabetic Lewis rats, fed ad libitum, were significantly reduced; and 3) peak blood glucose levels during glucose tolerance tests (GTT) were significantly reduced although still elevated. These results demonstrate an excellent in vitro and in vivo glucose-regulated insulin secretion from non-β cells potent enough to reduce fasting blood glucose levels and improve GTT.